Population-based, government-funded exome sequencing for fetal abnormalities: a state-wide implementation model for equity and clinical consistency

Population-based, government-funded exome sequencing for fetal abnormalities: a state-wide implementation model for equity and clinical consistency | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Population-based, government-funded exome sequencing for fetal abnormalities: a state-wide implementation model for equity and clinical consistency Willem Gheysen, Calder Hamill, Susan Fawcett, Tenielle Davis, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6302126/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Congenital anomalies are a leading cause of perinatal mortality, with many having a genetic basis. Exome sequencing (ES) has transformed the diagnostic approach in the prenatal and post-mortem work-up of fetal congenital anomalies. Despite its benefits, population-based implementation programs that address equity and clinical consistency are scarce. Objective: To analyze perinatal cases referred for funding from the state government clinical sequencing initiative for patient eligibility, diagnostic yield, and clinical utility of ES. Methods: A retrospective analysis was conducted on prospectively collected data for 195 cases referred for perinatal ES from 2018 to 2022 in Victoria, Australia. All cases underwent eligibility review against the published criteria for funding by one of 3 multidisciplinary teams (MDT) with members drawn from 4 tertiary fetal medicine units. Descriptive statistics of eligibility assessment, indication for referral, results, diagnostic yield, turn-around time, and pregnancy outcomes were performed. Subgroup analysis was performed for prenatal and post-mortem cases. Differences in proportions were analyzed with the z-test, with p<0.05 considered significant. Results: Of the 195 referred cases, 179 (93%) were deemed eligible for publicly funded ES. The most frequent indications for ES were multisystem anomalies, brain anomalies, and skeletal abnormalities. The overall diagnostic yield was 38% (95% Confidence Interval (CI) [0.31-0.45]), with causative genes identified in 37.5% (95% CI [0.27-0.49]) of prenatal and 38% (95% CI [0.30-0.48]) of post-mortem cases. Prenatal ES had demonstrable clinical utility: the termination of pregnancy rate was significantly higher in cases with a causative finding on ES compared with those without (67% vs 17%, P< 0.0001). The average turnaround time was 21 calendar days for prenatal cases and 125 days for post-mortem cases. Conclusion: In conclusion, this study provides a model for a multicenter, MDT-led framework for perinatal ES that achieves high consistency regarding referrals, clinical utility, and diagnostic yield. Supported by public funding, this model serves as a benchmark for integrating ES into maternal fetal medicine services, ensuring equitable access and informed reproductive decision-making. Future research should focus on the long-term impact of ES on subsequent pregnancies and refine strategies to reduce turnaround times. Maternal & Fetal Medicine prenatal diagnosis exome sequencing congenital abnormalities post-mortem exome sequencing Figures Figure 1 Figure 2 INTRODUCTION Congenital anomalies account for one-third of perinatal deaths in Australia, with many having a genetic basis.( 1 ) Over the last decade, advances in genetic testing and ultrasound technology have transformed the approach to pregnancies with fetal anomalies. Since 2012, chromosomal microarrays (CMA) have been the standard for chromosome analysis in structurally anomalous fetuses.( 2 ) In recent years, exome sequencing (ES) has become available after nondiagnostic CMA, with two Lancet studies published in 2019 reporting additional clinically significant diagnoses in 8.5% and 10.3% of cases, respectively.( 3 , 4 ) Genomic autopsy studies have further demonstrated the potential of exome sequencing for the investigation of stillbirths with structural abnormalities.( 5 ) Challenges remain in implementing perinatal ES, which entails appropriate case selection, high costs, and specialized fetal medicine and genetics expertise. Current evidence suggests the diagnostic yield is highest when a multidisciplinary panel reviews cases.( 6 , 7 ) In the Australian state of Victoria, the Department of Health’s Rare Diseases Program has supported clinical genomic sequencing for adult and paediatric patients since 2018, with perinatal cases becoming eligible in 2019. This public program has pre-defined eligibility criteria for funding, including the requirement for an MDT to agree that each case has a high likelihood of a monogenic etiology and expected clinical utility for the pregnant person. The clinical utility of ES is influenced by legal, economic, cultural, and healthcare system factors, most sharply evident when used in prenatal management and decisions around pregnancy termination. However, a systematic review of fetal ES studies highlighted that only a minority of publications report how ES results influence prenatal decision-making and reproductive counselling.( 6 ) Furthermore, those studies that report on clinical utility vary in methodology and definitions of clinical impact, and are often limited to prenatal or post-mortem genomic autopsy cohorts. In our setting, ES is offered as part of clinical care for appropriately selected cases in public tertiary hospitals, without financial barriers for patients or gestational age limits on termination of pregnancy (TOP). This arrangement provides a unique opportunity to examine the clinical outcomes and decision-making processes associated with perinatal ES. In this study, we audited the state-wide clinical genomic sequencing initiative for fetal anomaly referrals, focusing on eligibility for public funding, diagnostic yield, and the clinical and personal utility of ES. We also investigated the proportion of pregnant women who chose post-mortem exome sequencing following termination of pregnancy rather than continuing the pregnancy to await the results of prenatal fetal exome sequencing. MATERIAL AND METHODS Study design We conducted a state-wide, multicenter, retrospective cohort study reviewing prospectively collected health service records of perinatal ES tests performed between January 1st, 2018, and December 31, 2022, within the Victorian Clinical Genomic Sequencing Initiative. Participants All patients referred to a tertiary maternity center multidisciplinary team (MDT) meeting for assessing eligibility for perinatal ES from January 2018 to December 2022 were included in the analysis. Patients who underwent perinatal ES under a research protocol (either prenatal or post-mortem) or were self-funded were excluded from the study. Perinatal ES referrals included requests for prenatal diagnosis on live fetuses and post-mortem ES following stillbirth or termination of pregnancy with non-diagnostic autopsy investigations. Prenatal cases were defined as cases referred to an MDT during pregnancy, and the ES results were anticipated to come back during pregnancy to inform clinical management. Post-mortem cases were defined as cases where a result was expected to be returned after TOP, or after a stillbirth. Exome sequencing for critically ill newborns is funded through a separate program and is not included in this study. Ethical approval for this work was obtained through the Human Research Ethics Committee at the Murdoch Children Research Institute (MCRI- HREC/88751/RCHM-2022). MDT procedures The Victorian Clinical Genomic Sequencing Initiative introduced its first eligibility framework for publicly funded ES in 2018. All cases are reviewed by an MDT, typically comprising at least one medical geneticist, a maternal fetal medicine specialist, and a genetic counsellor. Perinatal exome sequencing can only be ordered by or in consultation with a clinical geneticist. The three MDTs, each affiliated with a different health service, are located at the Mercy Hospital for Women, Monash Medical Centre, and the Royal Women’s Hospital/Western Health (combined). The Department of Health eligibility criteria for publicly funded perinatal ES during the study period were: the possible underlying condition should have a high likelihood of a monogenic basis, which is difficult to diagnose by traditional non-genomic means (e.g. karyotype or microarray) the patient should reside in Victoria, or their appropriate genetic service is in Victoria the information will impact current or future reproductive decision making (clinical utility) Clinical utility was defined as (i) “ Reproductive options will be recommended/ used if the proband’s gene changes are identified (e.g. prenatal diagnosis or PGD/IVF)”, and/or (ii) “Management, including management in pregnancy or after birth, is likely to be better directed or altered if a gene change is identified .” In all cases, a normal microarray result was returned before referral for ES. Full details on eligibility and exclusion criteria are provided in Supplemental Appendix 1. After MDT review, cases are assigned to one of three categories: ‘green’, ‘amber’ or ‘red’. Green cases may proceed with testing following the MDT, whilst amber warrants further discussion and case-by-case approval. Alternative funding pathways for ‘amber’ cases include self-funding by the patient, or local health service funding. Red category would mean that the case is not eligible for government funding, and that ES is not clinically recommended. ES ordering procedures Under the Victorian Clinical Sequencing Initiative, a fixed amount of AUD 2500 was provided for each approved case to hospitals for testing and administration costs. This price was benchmarked to the cost of a singleton ES. All prenatal cases were preferentially analyzed as a rapid trio. At the time of writing, the cost for a rapid trio prenatal exome, with a turnaround time of 15 business days, was AUD 4,400. Where parental samples were not available, singleton or duo testing could be performed. All additional costs for trio ES, rapid ES (turnaround time 15 business days) or whole genome sequencing were covered by the hospital. The hospital also covered any additional segregation studies required to interpret potential clinically significant variants of uncertain significance (VUS). Laboratory reporting practices ES findings were classified as causative if a pathogenic or likely pathogenic variant was detected, using the American College for Medical Genetics (ACMG) and the Association for Clinical Genomic Science (ACGS) classifications.(8-10) Secondary findings were classified as pathogenic or likely pathogenic variants unrelated to the findings on ultrasound and the indication for performing the exome sequencing. A variant of uncertain significance (VUS) was only reported on a prenatal ES if, the classification was approaching likely pathogenic, there was a correlation with the sonographic phenotype and after discussion with the referring clinician. Legal context for termination of pregnancy Termination of pregnancy is legal across Australia and is regulated at a state/territory level. In Victoria, a pregnant person can access abortion upon request up to 24 weeks’ gestation. Beyond 24 weeks’ gestation, a registered medical practitioner may perform an abortion only when two medical practitioners agree that the procedure is appropriate considering the woman's current and future physical, psychological, and social circumstances. In practice, requests for termination of pregnancy after 24 weeks of gestation typically go through a hospital Termination Review Committee, which consists of at least 2 medical practitioners.(11) During the study period, there was no upper gestational age limit for MDT referral for exome testing. Data collection Prospectively collected data obtained for clinical care were retrospectively collected by the site-specific principal investigators for this study and deidentified results were uploaded and managed using REDCap electronic data capture tools hosted at the Murdoch Children’s Research Institute (MCRI). The data fields collected included: gestational date at time of MDT, MDT-site, outcome of MDT, indication for exome sequencing, type of fetal structural abnormality, turn-around time, timing of exome sequencing (prenatal, post-mortem), results, and clinical outcome. Total costs were estimated by reviewing the number of different exome sequencing tests ordered (trio, duo, single) and multiplying by the cost for each test. Outcomes The primary outcomes were the proportion of referred cases assessed as ‘green’ (eligible) and the overall diagnostic yield of ES. We also measured diagnostic yield in prenatal and post-mortem subgroups and by fetal anomaly classified by organ system. We measured clinical utility by analyzing how the presence or absence of a causative variant was associated with TOP. We compared the TOP rates in the prenatal cohort by ES result using the z-test, with a p<0.05 considered statistically significant. RESULTS During the 5-year study period, 195 perinatal cases were referred to an MDT for ES. (Figure 1) Most cases (181/195, 93%) were deemed eligible for state funding and received a ‘green’ outcome by the MDT. More than half of eligible referrals were for post-mortem ES (107/179, 60%). The most common indication group was fetal multisystem anomalies (70/179, 39%). Among cases involving a single organ system, the majority were referred following the detection of brain (37/109, 34%) or musculoskeletal anomalies (20/109, 20%) (Table 2) The clinical characteristics for the approved cases are summarized in Table 1. A comparative breakdown of the indications in the prenatal and post-mortem cohort is provided in Supplemental table 1. A causative variant was found in 38% (68/179, (95% CI [0.31-0.45]) of total cases, with similar yields for the prenatal (27/72, 37.5%, 95% CI [0.27-0.49]) and post-mortem (41/107, 38%, 95% CI [0.30-0.48]) cohort. (Table 3,4) A total of 55 monogenic conditions were identified that related to the observed clinical phenotype in the total cohort. Variants in the PTPN11 gene, associated with Noonan syndrome, were the most frequently reported (n = 6). The next most common condition was Costello syndrome caused by pathogenic variants in the HRAS gene (n=3). The complete list of the causative genes is provided in Supplemental Table 2. Prenatal cohort (n=72) Among the prenatal cohort, the largest proportion of cases was referred between 16- and 28-weeks’ gestation and the majority were performed as rapid trios (89%). (Figure 2) A pathogenic or likely pathogenic variant was reported in 37.5% (27/72, 95% CI [0.27-0.49]) of prenatal cases, and no causative variant was found in 51% (37/72). The remaining prenatal cases had a VUS (3/72) or a secondary finding (3/72) detected. Diagnostic yield was the highest for cases that were referred with hydrops fetalis (3/4, 75%) multisystem abnormalities (11/22, 50%) or skeletal abnormalities (3/6, 50%). The lowest yield was reported in cases referred with abdominal and cardiac anomalies (Figure 2). The average turnaround time of prenatal exome sequencing was 21 calendar days with no significant difference between the different study sites. (Table 4) Termination of pregnancy was significantly more frequent in pregnancies with a causative variant identified on prenatal ES (18/27, 67%) compared with prenatal cases without (6/36, 17%) (p<0.0001). In 6 cases, a TOP was performed based on the ultrasound findings alone, prior to the ES results being returned. (Table 5) Post-mortem cohort (n=107) Compared with the prenatal cohort, ES yielded a similar proportion of causative variants in the post-mortem cohort (41/107, 38%, 95% CI [0.30-0.48]). A higher percentage of VUS was reported in the post-mortem cohort (23/107, 21%), which was attributed to the lower rate of trio ES (18%). The highest diagnostic yields in the post-mortem cohort by indication were hydrops fetalis (4/7, 57%), skeletal abnormalities (8/14, 57%), renal abnormalities (3/6, 50%) and multisystem abnormalities (16/48, 33%). The average turnaround time in the postmortem cohort was 125 days. Costings for prenatal trios The costs for all 83 trio-exomes ordered through the scheme amounted to AUD 365,200, of which AUD 207,500 (56.8%) was directly funded by the state government. The individual health services bore the remaining costs of AUD 157,700 (43.2%). We did not calculate the costs of the time allocated by the different health care professionals for the pre-and post-test counselling. DISCUSSION During the first 4 years of the Victorian Clinical Sequencing Initiative, 195 perinatal cases were referred, with 93% meeting the eligibility criteria. This high approval rate is evidence of a strong consensus among clinicians on appropriate case selection. As anticipated from scientific literature, diagnostic yield was highest in cases with multisystem anomalies, hydrops, or skeletal abnormalities. The clinical utility of ES was most evident in the prenatal cohort, where TOP was more common following the identification of a pathogenic variant than in cases without a causative variant. The overall diagnostic yield of 38% in our cohort is comparable to previous studies of fetal ES that employ an MDT selection process. Mellis et al. reported an incremental yield from 15% to 42% when cases were pre-selected for a likelihood monogenic etiology.(6) Similarly, a recent analysis of prenatal ES implementation in the UK showed a 35% diagnostic yield comparable to a 37% yield reported in a small South Australian cohort of 43 cases.(12) These quantitative results on the outcomes of the MDT assessments complement a related qualitative study from our group.(13) Semi-structured interviews with MDT members in Victoria revealed that the MDT review process was highly valued for supporting an appropriate selection of cases for ES. Furthermore, the MDT was viewed as an important educational resource for team members, allowing them to participate in discussion of all referred cases and results. Although the diagnostic yield was similar in both the prenatal and post-mortem cohorts, exome sequencing had a different impact in each group. In the prenatal cohort, ES was used to inform a decision about whether to continue a pregnancy, with TOP being more common among those with a causative variant (18/27, 66.7%) than among those without. Notably, the majority of women who opted for TOP after receiving a diagnostic result had to make this decision beyond 22 weeks’ gestation (14/18), highlighting the challenges of this patient population. These findings align with a UK study reporting that, in cases where a causative variant was identified, 63.6% of TOPs occurred after 22 weeks’ gestation. (14) Other publications have similarly confirmed the influence of diagnostic results on TOP rates. (7) In the cases where a prenatal ES returned no pathogenic findings, most pregnancies resulted in a live birth (21/36, 58%). This aligns with previous feedback from families and health care professionals that a nondiagnostic result still provides clinical utility by offering a sense of reassurance to continue a pregnancy with a fetal structural anomaly.(13, 15) Furthermore, a qualitative study conducted in the United Kingdom highlighted the importance of post-test counselling in the absence of a definitive diagnosis. The study found that some families may interpret the absence of a diagnosis as more reassuring than clinicians intended, particularly when the medical team continues to harbor concerns based on imaging findings.(16) In contrast, the main clinical utility of post-mortem ES is to provide prognostic information for future pregnancies. For example, couples identified as carriers of an autosomal recessive condition could consider reproductive options such as pre-implantation genetic testing or prenatal diagnosis via chorionic villus sampling. In our study, the diagnostic yield in the post-mortem cohort was 38%, higher than the 21% incremental yield reported in a genomic autopsy cohort following fetal or neonatal death (5). This discrepancy likely stems from the highly selected nature of our cohort, which included only fetuses with congenital abnormalities strongly suggestive of a monogenic etiology. A systematic review encompassing over 2,000 cases reported an overall diagnostic yield of 33% for genomic autopsy, although there was considerable heterogeneity across the included studies (15). There are limited data on the possible impact on future pregnancies of ES in the post-mortem cohort. Of the 200 families included in Australian genomic autopsy study, exome sequencing guided the management (e.g. PGD or antenatal invasive testing) in 5% of subsequent pregnancies. We were unable to collect follow-up data from our cohort to investigate the impact of testing on future pregnancies. Turnaround time As Victoria has no gestational age limit on TOP, a median turnaround time of 21 calendar days was considered acceptable. In contrast, in the South Australian study, where 22 weeks and 6 days was the upper limit for TOP, a shorter median turnaround time of 12 days (range 7-21) was used as their benchmark. (12) Our median turnaround time for post-mortem exomes of 125 calendar days - is similar to that reported in an Australian perinatal genomic autopsy study.(5) We also observed substantial variation in the post-mortem turnaround times (interquartile range of 87 days), which could affect options for couples considering pre-implantation genetic testing for their subsequent pregnancies. Variants of Uncertain Significance The proportion of variants of uncertain significance (VUS) identified in our prenatal cohort (4%) is consistent with findings from a study on VUS in prenatal exome sequencing, which reported a rate of 2%.(17) The higher percentage of VUS in the post-mortem compared to prenatal ES (21% vs 4%), can be explained by several factors. First, the higher proportion of trio exomes performed in the antenatal cohort (89%) compared to the post-mortem period (18%) would lead to a lower degree of VUS reported in the antenatal cohort. Furthermore, as mentioned above, a VUS detected in an antenatal exome would only be reported if there is a clear correlation with the clinical phenotype, and it is proven to be de novo. Clinical implications This study highlights that the framework for publicly funded perinatal ES in Victoria is performing at the expected level regarding referral of cases, diagnostic yield, turnaround time and clinical utility. These quantitative data, interpreted alongside our associated qualitative study of health professionals’ perspectives, support the case for maintaining an MDT-led framework to promote clinical quality in this rapidly evolving field.(13) A well-established pathway also benefits the families involved by ensuring consistent, standardized, and equitable counselling and follow-up across the state. Our methods and results therefore provide a potential model and benchmark for fetal medicine units in other jurisdictions. Strengths and Limitations This is the first Australian population-based study reporting on the diagnostic yield and clinical outcomes of publicly funded perinatal ES in routine clinical care. Although this was a retrospective study, all the data were prospectively recorded in a standardized way in all participating centers. This study is also the first to examine the financial implications of a publicly funded perinatal ES program, revealing the hidden genomic testing expenditures incurred by hospitals that are not directly reimbursed by a government program that was designed to reimburse adult and pediatric services. While we did not calculate the professional costs associated with the range of highly experienced health professionals required to counsel these patients, these costs are important considerations with respect to the ongoing availability of this service. Our study provides data on patient choices following the diagnosis of a fetal anomaly with a nondiagnostic chromosomal microarray (CMA). More than half of our cohort opted for TOP rather than waiting several weeks for prenatal ES results, suggesting that the prognostic information obtained from fetal imaging alone was sufficient for many women to decide. Nevertheless, our qualitative findings indicate that clinicians still perceived both personal and clinical value in offering post-mortem ES to these patients. (11) One of the limitations of our study was the lack of long-term follow-up data on the impact of the results and the impact of turnaround time on future management (such as access to PGT-M in a timely manner) in the post-mortem cases. Future research could focus on gathering this data for health economic analysis. Furthermore, we have no detailed data on how the results of post-mortem investigations (e.g. chromosomal microarray, autopsy, external examinations, MRI) influenced the decision for exome sequencing in the post-mortem cohort. Further research is needed to investigate the clinical and personal utility for the cohort who accesses exome sequencing as part of a genomic autopsy after deciding for a termination of pregnancy. CONCLUSION In conclusion, this study provides a model for a multicenter, MDT-led framework for perinatal ES that achieves high consistency regarding referrals, clinical utility, and diagnostic yield. Supported by public funding, this model serves as a benchmark for integrating ES into maternal fetal medicine services, ensuring equitable access and informed reproductive decision-making. Future research should focus on the long-term impact of ES on subsequent pregnancies and refine strategies to reduce turnaround times. Declarations AUTHOR CONTRIBUTIONS Willem Gheysen : conceptualization, methodology, data curation, writing – original draft, writing – review and editing, funding acquisition, project administration Calder Hamill: conceptualization, investigation, data curation, visualization Susan Fawcett: investigation, data curation, writing – review and editing Tenielle Davis: investigation, data curation, writing – review and editing Anand Vasudevan: writing – review and editing Stefan Kane: writing – review and editing Melissa Graetz: investigation, data curation, writing – review and editing Candice Dao investigation, data curation, writing – review and editing David Amor: conceptualization, supervision, writing – review and editing Michael Fahey: writing – review and editing Kirsten Palmer: writing – review and editing Nikki Gelfand: investigation, data curation, writing – review and editing Yael Prawer: investigation, data curation, writing – review and editing Joanne M. Said: writing – review and editing Kate Riley: investigation, data curation, writing – review and editing Lilian Downie: review and editing Lisa Hui: conceptualization, supervision, methodology, data curation, writing – review and editing, project administration ACKNOWLEDGEMENTS This study was supported by an Innovation Grant provided by the Norman Beischer Medical Research Foundation. Infrastructure support was provided by the Murdoch Children’s Research Institute. Collaborators: Stefan C. Kane, Department of Maternal Fetal Medicine, Royal Women’s Hospital, Parkville, VIC, Australia Department of Obstetrics, Gynaecology and Newborn Health, The University of Melbourne, Parkville, Victoria, Australia Kirsten Palmer , Department of Clinical Genetics, Monash Medical Centre, Clayton, VIC, Australia Joanne M. Said, Department of Maternal Fetal Medicine, Joan Kirner Women’s and Children’s Hospital, St Albans, VIC, Australia Department of Obstetrics, Gynaecology and Newborn Health, The University of Melbourne, Parkville, Victoria, Australia Lilian Downie, Department of Perinatal Medicine, Mercy Hospital for Women, Heidelberg, VIC, Australia Murdoch Children’s Research Institute, Parkville, VIC, Australia University of Melbourne Department of Paediatrics, Royal Children’s Hospital, Parkville, VIC, Australia References Australian Institute of Health & Welfare. Australia's mothers and babies. December 2024. (Available from https://www.aihw.gov.au/reports/mothers-babies/australias-mothers-babies). Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):2175-84. Petrovski S, Aggarwal V, Giordano JL, Stosic M, Wou K, Bier L, et al. 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Clinical characteristics of ‘green’ approved cases (n=179) Median maternal age in years at time MDT † , (IQR * ) 32 (6) Country of birth Australia 119 (66%) Metropolitan residence 137 (77%) No interpreter required 166 (93%) Parity 0 91 (52%) 1 50 (28%) 2 22 (13%) ≥ 3 13 (7%) SEIFA ‡ Quintiles 1 – Most disadvantaged 28 2 36 3 40 4 32 5 – Most advantaged 43 Timing of exome Prenatal 72 Post-mortem 107 * Interquartile range † Multi-Disciplinary team meeting ‡ Socio-Economic Indexes for Areas Table 2. Indications for exome in ‘green’ approved cohort (n=179) Multisystem anomaly Single organ system anomaly (total) 70 (39%) 109 (61%) Organ system Brain 37 (34%) Skeletal 20 (18%) Increased nuchal translucency (>5mm) 16 (15%) Hydrops 11 (10%) Cardiac 10 (9%) Renal 6 (5.5%) Abdominal 5 (4.5%) Facial 4 (4%) Table 3. Results Exome Sequencing total cohort (n=179) Total (n=179) Prenatal (n=72) Post-mortem (n=107) Results Causative variant 27 (37.5%) 41 (38%) Secondary findings 3 (4%) 3 (3%) VUS 3 (4%) 23 (21%) Carrier status 2 (3%) 7 (7%) No Findings 37 (51%) 32 (30%) No data 0 (0%) 1 (1%) Median Turn Around Time, days (IQR*) 21 (10) 125 (87) Type Testing Trio 64 (89%) 19 (18%) Single 5 (7%) 86 (80%) Duo 2 (3%) 0 (0%) Quad 1 (1%) 1 (1%) No data / 1 (1%) Pregnancy outcome Livebirth 31 (43%) 3 (2.8%) Termination of Pregnancy 25 (35%) 82 (76.6%) Neonatal Death 2 (3%) 6 (5.6%) Stillbirth 3 (4%) 16 (15%) Missing data† 11 (15%) 0 * Interquartile range † data unavailable as patients delivered in other hospital Table 4. Diagnostic yield according to indication for testing Diagnostic yield in prenatal cohort (n=72) Diagnostic yield in post-mortem cohort (n=107) Diagnostic yield in total combined cohort (n=179) Indication for testing n/N % 95% CI n/N % 95% CI n/N % 95% CI Multisystem anomalies 11/22 50 0.31-0.69 16/48 33 0.22-0.47 27/70 39 0.28-0.50 Brain 5/13 38 0.17-0.65 7/24 29 0.15-0.49 12/37 32 0.20-0.49 Skeletal 3/6 50 0.19-0.81 8/14 57 0.33-0.78 11/20 55 0.34-0.74 Increased NT* (> 5mm) 4/15 27 0.11-0.52 1/1 100 0.21-1.00 5/16 31 0.14-0.56 Hydrops 3/4 75 0.31-0.95 4/7 57 0.25-0.84 7/11 64 0.35-0.84 Cardiac 0/4 0 0.00-0.49 2/6 33 0.10-0.70 2/10 20 0.06-0.51 Facial 1/4 25 0.05-0.70 0/0 - - 1/4 25 0.05-0.70 Abdominal 0/4 0 0.00-0.49 0/1 0 0.00-0.79 0/5 0 0.00-0.43 Renal 0/0 0 - 3/6 50 0.19-0.81 3/6 50 0.19-0.81 TOTAL 27/72 37.5 0.27-0.49 41/107 38 0.30-0.48 68/179 38 0.31-0.45 *Nuchal translucency Table 5. Perinatal outcomes in the antenatal cohort by exome result (n=72) Perinatal outcomes Causative variants (n=27) No findings (n=36) Secondary findings (n=3) VUS (n=3) Carrier status (n=2) Termination of pregnancy 18* (67%) 6 † (17%) 1 1 0 Livebirths 7 (26%) 21 (58%) 0 1 1 Neonatal Deaths 1 (4%) 1 (3%) 0 0 0 Stillbirths 0 (0%) 2 (6%) 0 1 0 Unknown 1 (4%) 6 (16%) 2 0 1 * In 3 cases TOP was requested prior to the return of the exome result † in 3 cases TOP was requested prior to the return of the exome result Additional Declarations The authors declare no competing interests. Supplementary Files Supplemental.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6302126","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":433668809,"identity":"a2dc4c99-3f6d-4ac4-8c30-79da7b3f5427","order_by":0,"name":"Willem Gheysen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/0lEQVRIiWNgGAWjYDACZubGAyDaAMK1AWJGiAhuLYwNyFrSQFoa8GthQNVyGEzi1WJwHKjlYw6D3Xb2HuMPH3ect1vbfhhoSI1NNE4thxkbDs7cxpC8s+eMmeTMM7eTt51JBGo5lpbbgEOLGVDLYV6gFoMbOWbMvG23k80OALUABfFr+QvScv+N8ee/beeSzc4/JEIL4zYGO4MbPAbSjG0H7MxuELDFHuSX3m0SCQZn0soke9uSE8xuAG1JwOMXyf7DBx/83GZjb3D88OYPP9vs7M3Opz988KHGBqcWKJBIbGDgAEdNIlhlAn7lEAcyMLA/gDJGwSgYBaNgFKACAH+zbB8UdhHVAAAAAElFTkSuQmCC","orcid":"","institution":"Mercy Hospital for Women, Heidelberg, VIC, Australia","correspondingAuthor":true,"prefix":"","firstName":"Willem","middleName":"","lastName":"Gheysen","suffix":""},{"id":433668810,"identity":"33e514bf-327d-4b0a-8ea0-9612001f9d1f","order_by":1,"name":"Calder Hamill","email":"","orcid":"","institution":"Monash Medical Centre, Clayton, VIC, Australia","correspondingAuthor":false,"prefix":"","firstName":"Calder","middleName":"","lastName":"Hamill","suffix":""},{"id":433668811,"identity":"37dbc41a-6184-4da3-a096-6c80bae7f140","order_by":2,"name":"Susan Fawcett","email":"","orcid":"","institution":"Royal Women’s Hospital, Parkville, VIC, Australia","correspondingAuthor":false,"prefix":"","firstName":"Susan","middleName":"","lastName":"Fawcett","suffix":""},{"id":433668812,"identity":"68c56370-b42c-401b-9a87-d598097e118e","order_by":3,"name":"Tenielle Davis","email":"","orcid":"","institution":"Royal Women’s Hospital, Parkville, VIC, Australia","correspondingAuthor":false,"prefix":"","firstName":"Tenielle","middleName":"","lastName":"Davis","suffix":""},{"id":433668813,"identity":"46aec7a4-3533-46c7-8490-471bef9b78f2","order_by":4,"name":"Anand Vasudevan","email":"","orcid":"","institution":"Royal Women’s Hospital, Parkville, VIC, Australia","correspondingAuthor":false,"prefix":"","firstName":"Anand","middleName":"","lastName":"Vasudevan","suffix":""},{"id":433668814,"identity":"499ddd17-1191-4050-9c7d-cd1b30783f44","order_by":5,"name":"Melissa Graetz","email":"","orcid":"","institution":"Mercy Hospital for Women, Heidelberg, VIC, Australia","correspondingAuthor":false,"prefix":"","firstName":"Melissa","middleName":"","lastName":"Graetz","suffix":""},{"id":433668815,"identity":"4ea6cdc0-3a4b-40eb-a8b5-102812bc6b4e","order_by":6,"name":"Candice Dao","email":"","orcid":"","institution":"Mercy Hospital for Women, Heidelberg, VIC, Australia","correspondingAuthor":false,"prefix":"","firstName":"Candice","middleName":"","lastName":"Dao","suffix":""},{"id":433668816,"identity":"4a1755f4-0847-47d9-aa10-153aaafc9b2c","order_by":7,"name":"David Amor","email":"","orcid":"","institution":"Murdoch Children’s Research Institute, Parkville, VIC, Australia","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Amor","suffix":""},{"id":433668817,"identity":"f2f9625c-b480-4658-b8fb-c20f4beffba9","order_by":8,"name":"Michael C. Fahey","email":"","orcid":"","institution":"Monash Medical Centre, Clayton, VIC, Australia","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"C.","lastName":"Fahey","suffix":""},{"id":433668818,"identity":"829d7a08-6746-4061-8c57-801a134986d5","order_by":9,"name":"Nikki Gelfand","email":"","orcid":"","institution":"Monash Medical Centre, Clayton, VIC, Australia","correspondingAuthor":false,"prefix":"","firstName":"Nikki","middleName":"","lastName":"Gelfand","suffix":""},{"id":433668819,"identity":"8b1f6023-9abe-47e7-9a92-edb7b16a159f","order_by":10,"name":"Kate Riley","email":"","orcid":"","institution":"Joan Kirner Women’s and Children’s Hospital, St Albans, VIC, Australia","correspondingAuthor":false,"prefix":"","firstName":"Kate","middleName":"","lastName":"Riley","suffix":""},{"id":433668820,"identity":"a9297bce-4ecc-49fa-93d5-6faeb1f5f3fe","order_by":11,"name":"Joanne Said","email":"","orcid":"","institution":"Joan Kirner Women’s and Children’s Hospital, 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Australia","correspondingAuthor":false,"prefix":"","firstName":"Kirsten","middleName":"","lastName":"Palmer","suffix":""},{"id":433668824,"identity":"834c1d8d-b81b-42ba-9d36-36f8bad0d03b","order_by":15,"name":"Lisa Hui","email":"","orcid":"","institution":"Mercy Hospital for Women, Heidelberg, VIC, Australia","correspondingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"","lastName":"Hui","suffix":""}],"badges":[],"createdAt":"2025-03-25 09:10:33","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6302126/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6302126/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79266000,"identity":"b9b86f53-5afb-499d-be4e-acc446999a53","added_by":"auto","created_at":"2025-03-26 10:08:09","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":72518,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure1Flowchartofcasesreferredformultidisciplinaryteamreview.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6302126/v1/d414b07eb2b336672624c996.jpg"},{"id":79265420,"identity":"5715340a-0be7-447a-a865-6e3fceca4133","added_by":"auto","created_at":"2025-03-26 10:00:09","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":39048,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6302126/v1/1fc3fd983df1997821a2ea5c.jpg"},{"id":79266709,"identity":"bffaecc9-13ce-47fe-9242-d2d3ea272aa0","added_by":"auto","created_at":"2025-03-26 10:16:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1267098,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6302126/v1/10aa659f-587a-4f7d-9a84-234f097c5f32.pdf"},{"id":79265418,"identity":"3faf5362-206b-4559-8fd3-e72975bef897","added_by":"auto","created_at":"2025-03-26 10:00:09","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24779,"visible":true,"origin":"","legend":"","description":"","filename":"Supplemental.docx","url":"https://assets-eu.researchsquare.com/files/rs-6302126/v1/c8b89b003d27de18b0a3682b.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003ePopulation-based, government-funded exome sequencing for fetal abnormalities: a state-wide implementation model for equity and clinical consistency\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCongenital anomalies account for one-third of perinatal deaths in Australia, with many having a genetic basis.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Over the last decade, advances in genetic testing and ultrasound technology have transformed the approach to pregnancies with fetal anomalies. Since 2012, chromosomal microarrays (CMA) have been the standard for chromosome analysis in structurally anomalous fetuses.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) In recent years, exome sequencing (ES) has become available after nondiagnostic CMA, with two \u003cem\u003eLancet\u003c/em\u003e studies published in 2019 reporting additional clinically significant diagnoses in 8.5% and 10.3% of cases, respectively.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Genomic autopsy studies have further demonstrated the potential of exome sequencing for the investigation of stillbirths with structural abnormalities.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eChallenges remain in implementing perinatal ES, which entails appropriate case selection, high costs, and specialized fetal medicine and genetics expertise. Current evidence suggests the diagnostic yield is highest when a multidisciplinary panel reviews cases.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) In the Australian state of Victoria, the Department of Health\u0026rsquo;s Rare Diseases Program has supported clinical genomic sequencing for adult and paediatric patients since 2018, with perinatal cases becoming eligible in 2019. This public program has pre-defined eligibility criteria for funding, including the requirement for an MDT to agree that each case has a high likelihood of a monogenic etiology and expected clinical utility for the pregnant person.\u003c/p\u003e \u003cp\u003eThe clinical utility of ES is influenced by legal, economic, cultural, and healthcare system factors, most sharply evident when used in prenatal management and decisions around pregnancy termination. However, a systematic review of fetal ES studies highlighted that only a minority of publications report how ES results influence prenatal decision-making and reproductive counselling.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Furthermore, those studies that report on clinical utility vary in methodology and definitions of clinical impact, and are often limited to prenatal or post-mortem genomic autopsy cohorts.\u003c/p\u003e \u003cp\u003eIn our setting, ES is offered as part of clinical care for appropriately selected cases in public tertiary hospitals, without financial barriers for patients or gestational age limits on termination of pregnancy (TOP). This arrangement provides a unique opportunity to examine the clinical outcomes and decision-making processes associated with perinatal ES. In this study, we audited the state-wide clinical genomic sequencing initiative for fetal anomaly referrals, focusing on eligibility for public funding, diagnostic yield, and the clinical and personal utility of ES. We also investigated the proportion of pregnant women who chose post-mortem exome sequencing following termination of pregnancy rather than continuing the pregnancy to await the results of prenatal fetal exome sequencing.\u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cp\u003e\u003cem\u003eStudy design\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a state-wide, multicenter, retrospective cohort study reviewing prospectively collected health service records of perinatal ES tests performed between January 1st, 2018, and December 31, 2022, within the Victorian Clinical Genomic Sequencing Initiative. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eParticipants\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll patients referred to a tertiary maternity center multidisciplinary team (MDT) meeting for assessing eligibility for perinatal ES from January 2018 to December 2022 were included in the analysis. \u0026nbsp;Patients who underwent perinatal ES under a research protocol (either prenatal or post-mortem) or were self-funded were excluded from the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePerinatal ES referrals included requests for prenatal diagnosis on live fetuses and post-mortem ES following stillbirth or termination of pregnancy with non-diagnostic autopsy investigations. Prenatal cases were defined as cases referred to an MDT during pregnancy, and the ES results were anticipated to come back during pregnancy to inform clinical management.\u003c/p\u003e\n\u003cp\u003ePost-mortem cases were defined as cases where a result was expected to be returned after TOP, or after a stillbirth. \u0026nbsp;Exome sequencing for critically ill newborns is funded through a separate program and is not included in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthical approval for this work was obtained through the Human Research Ethics Committee at the Murdoch Children Research Institute (MCRI- HREC/88751/RCHM-2022).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMDT procedures\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe Victorian Clinical Genomic Sequencing Initiative introduced its first eligibility framework for publicly funded ES in 2018. All cases are reviewed by an MDT, typically comprising at least one medical geneticist, a maternal fetal medicine specialist, and a genetic counsellor. Perinatal exome sequencing can only be ordered by or in consultation with a clinical geneticist. The three MDTs, each affiliated with a different health service, are located at the Mercy Hospital for Women, Monash Medical Centre, and the Royal Women\u0026rsquo;s Hospital/Western Health (combined).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe Department of Health eligibility criteria for publicly funded perinatal ES during the study period were:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cem\u003ethe possible underlying condition should have a high likelihood of a monogenic basis, which is difficult to diagnose by traditional non-genomic means (e.g. karyotype or microarray)\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003ethe patient should reside in Victoria, or their appropriate genetic service is in Victoria\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003ethe information will impact current or future reproductive decision making (clinical utility)\u003c/em\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eClinical utility was defined as (i) \u0026ldquo;\u003cem\u003eReproductive options will be recommended/ used if the proband\u0026rsquo;s gene changes are identified (e.g. prenatal diagnosis or PGD/IVF)\u0026rdquo;,\u0026nbsp;\u003c/em\u003eand/or\u003cem\u003e\u0026nbsp;(ii) \u0026ldquo;Management, including management in pregnancy or after birth, is likely to be better directed or altered if a gene change is identified\u003c/em\u003e.\u0026rdquo; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn all cases, a normal microarray result was returned before referral for ES.\u003c/p\u003e\n\u003cp\u003eFull details on eligibility and exclusion criteria are provided in Supplemental Appendix 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter MDT review, cases are assigned to one of three categories: \u0026lsquo;green\u0026rsquo;, \u0026lsquo;amber\u0026rsquo; or \u0026lsquo;red\u0026rsquo;. Green cases may proceed with testing following the MDT, whilst amber warrants further discussion and case-by-case approval. Alternative funding pathways for \u0026lsquo;amber\u0026rsquo; cases include self-funding by the patient, or local health service funding. Red category would mean that the case is not eligible for government funding, and that ES is not clinically recommended.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eES ordering procedures\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eUnder the Victorian Clinical Sequencing Initiative, a fixed amount of AUD 2500 was provided for each approved case to hospitals for testing and administration costs. This price was benchmarked to the cost of a singleton ES. All prenatal cases were preferentially analyzed as a rapid trio. At the time of writing, the cost for a rapid trio prenatal exome, with a turnaround time of 15 business days, was AUD 4,400. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhere parental samples were not available, singleton or duo testing could be performed. All additional costs for trio ES, rapid ES (turnaround time 15 business days) or whole genome sequencing were covered by the hospital. \u0026nbsp; The hospital also covered any additional segregation studies required to interpret potential clinically significant variants of uncertain significance (VUS).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLaboratory reporting practices\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eES findings were classified as causative if a pathogenic or likely pathogenic variant was detected, using the American College for Medical Genetics (ACMG) and the Association for Clinical Genomic Science (ACGS) classifications.(8-10) \u0026nbsp;Secondary findings were classified as pathogenic or likely pathogenic variants unrelated to the findings on ultrasound and the indication for performing the exome sequencing. \u0026nbsp;A variant of uncertain significance (VUS) was only reported on a prenatal ES if, the classification was approaching likely pathogenic, there was a correlation with the sonographic phenotype and after discussion with the referring clinician.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLegal context for termination of pregnancy\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTermination of pregnancy is legal across Australia and is regulated at a state/territory level. In Victoria, a pregnant person can access abortion upon request up to 24 weeks\u0026rsquo; gestation. Beyond 24 weeks\u0026rsquo; gestation, a registered medical practitioner may perform an abortion only when two medical practitioners agree that the procedure is appropriate considering the woman\u0026apos;s current and future physical, psychological, and social circumstances. In practice, requests for termination of pregnancy after 24 weeks of gestation typically go through a hospital Termination Review Committee, which consists of at least 2 medical practitioners.(11) During the study period, there was no upper gestational age limit for MDT referral for exome testing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData collection\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eProspectively collected data obtained for clinical care were retrospectively collected by the site-specific principal investigators for this study and deidentified results were uploaded and managed using REDCap electronic data capture tools hosted at the Murdoch Children\u0026rsquo;s Research Institute (MCRI). The data fields collected included: gestational date at time of MDT, MDT-site, outcome of MDT, indication for exome sequencing, type of fetal structural abnormality, turn-around time, timing of exome sequencing (prenatal, post-mortem), results, and clinical outcome. Total costs were estimated by reviewing the number of different exome sequencing tests ordered (trio, duo, single) and multiplying by the cost for each test.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eOutcomes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcomes were the proportion of referred cases assessed as \u0026lsquo;green\u0026rsquo; (eligible) and the overall diagnostic yield of ES. We also measured diagnostic yield in prenatal and post-mortem subgroups and by fetal anomaly classified by organ system.\u003c/p\u003e\n\u003cp\u003eWe measured clinical utility by analyzing how the presence or absence of a causative variant was associated with TOP. We compared the TOP rates in the prenatal cohort by ES result using the z-test, with a p\u0026lt;0.05 considered statistically significant.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eDuring the 5-year study period, 195 perinatal cases were referred to an MDT for ES. (Figure 1) Most cases (181/195, 93%) were deemed eligible for state funding and received a \u0026lsquo;green\u0026rsquo; outcome by the MDT. More than half of eligible referrals were for post-mortem ES (107/179, 60%). The most common indication group was fetal multisystem anomalies (70/179, 39%). Among cases involving a single organ system, the majority were referred following the detection of brain (37/109, 34%) or musculoskeletal anomalies (20/109, 20%) (Table 2) The clinical characteristics for the approved cases are summarized in Table 1. A comparative breakdown of the indications in the prenatal and post-mortem cohort is provided in Supplemental table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA causative variant was found in 38% (68/179, (95% CI [0.31-0.45]) of total cases, with similar yields for the prenatal (27/72, 37.5%, 95% CI [0.27-0.49]) and post-mortem (41/107, 38%, 95% CI [0.30-0.48]) cohort. (Table 3,4) A total of 55 monogenic conditions were identified that related to the observed clinical phenotype in the total cohort. Variants in the \u003cem\u003ePTPN11\u003c/em\u003e gene, associated with Noonan syndrome, were the most frequently reported (n = 6). The next most common condition was Costello syndrome caused by pathogenic variants in the \u003cem\u003eHRAS\u003c/em\u003e gene (n=3). The complete list of the causative genes is provided in Supplemental Table 2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePrenatal cohort (n=72)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAmong the prenatal cohort, the largest proportion of cases was referred between 16- and 28-weeks\u0026rsquo; gestation and the majority were performed as rapid trios (89%). (Figure 2) A pathogenic or likely pathogenic variant was reported in 37.5% (27/72, 95% CI [0.27-0.49]) of prenatal cases, and no causative variant was found in 51% (37/72). \u0026nbsp;The remaining prenatal cases had a VUS (3/72) or a secondary finding (3/72) detected.\u003c/p\u003e\n\u003cp\u003eDiagnostic yield was the highest for cases that were referred with hydrops fetalis (3/4, 75%) multisystem abnormalities (11/22, 50%) or skeletal abnormalities (3/6, 50%). The lowest yield was reported in cases referred with abdominal and cardiac anomalies (Figure 2). The average turnaround time of prenatal exome sequencing was 21 calendar days with no significant difference between the different study sites. (Table 4)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTermination of pregnancy was significantly more frequent in pregnancies with a causative variant identified on prenatal ES (18/27, 67%) compared with prenatal cases without (6/36, 17%) (p\u0026lt;0.0001). In 6 cases, a TOP was performed based on the ultrasound findings alone, prior to the ES results being returned. (Table 5)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePost-mortem cohort (n=107)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCompared with the prenatal cohort, ES yielded a similar proportion of causative variants in the post-mortem cohort (41/107, 38%, 95% CI [0.30-0.48]). A higher percentage of VUS was reported in the post-mortem cohort (23/107, 21%), which was attributed to the lower rate of trio ES (18%). The highest diagnostic yields in the post-mortem cohort by indication were hydrops fetalis (4/7, 57%), skeletal abnormalities (8/14, 57%), renal abnormalities (3/6, 50%) and multisystem abnormalities (16/48, 33%). The average turnaround time in the postmortem cohort was 125 days.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCostings for prenatal trios\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe costs for all 83 trio-exomes ordered through the scheme amounted to AUD 365,200, of which AUD 207,500 (56.8%) was directly funded by the state government. The individual health services bore the remaining costs of AUD 157,700 (43.2%). We did not calculate the costs of the time allocated by the different health care professionals for the pre-and post-test counselling.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eDuring the first 4 years of the Victorian Clinical Sequencing Initiative, 195 perinatal cases were referred, with 93% meeting the eligibility criteria. This high approval rate is evidence of a strong consensus among clinicians on appropriate case selection. As anticipated from scientific literature, diagnostic yield was highest in cases with\u003cu\u003e\u0026nbsp;\u003c/u\u003emultisystem anomalies, hydrops, or skeletal abnormalities. The clinical utility of ES was most evident in the prenatal cohort, where TOP was more common following the identification of a pathogenic variant than in cases without a causative variant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe overall diagnostic yield of 38% in our cohort is comparable to previous studies of fetal ES that employ an MDT selection process. Mellis et al. reported an incremental yield from 15% to 42% when cases were pre-selected for a likelihood monogenic etiology.(6) \u0026nbsp;Similarly, a recent analysis of prenatal ES implementation in the UK showed a 35% diagnostic yield comparable to a 37% yield reported in a small South Australian cohort of 43 cases.(12)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThese quantitative results on the outcomes of the MDT assessments complement a related qualitative study from our group.(13) Semi-structured interviews with MDT members in Victoria revealed that the MDT review process was highly valued for supporting an appropriate selection of cases for ES. \u0026nbsp;Furthermore, the MDT was viewed as an important educational resource for team members, allowing them to participate in discussion of all referred cases and results.\u003c/p\u003e\n\u003cp\u003eAlthough the diagnostic yield was similar in both the prenatal and post-mortem cohorts, exome sequencing had a different impact in each group. In the prenatal cohort, ES was used to inform a decision about whether to continue a pregnancy, with TOP being more common among those with a causative variant (18/27, 66.7%) than among those without. Notably, the majority of women who opted for TOP after receiving a diagnostic result had to make this decision beyond 22 weeks\u0026rsquo; gestation (14/18), highlighting the challenges of this patient population. These findings align with a UK study reporting that, in cases where a causative variant was identified, 63.6% of TOPs occurred after 22 weeks\u0026rsquo; gestation. (14) Other publications have similarly confirmed the influence of diagnostic results on TOP rates. (7)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the cases where a prenatal ES returned no pathogenic findings, most pregnancies resulted in a live birth (21/36, 58%). This aligns with previous feedback from families and health care professionals that a nondiagnostic result still provides clinical utility by offering a sense of reassurance to continue a pregnancy with a fetal structural anomaly.(13, 15) Furthermore, a qualitative study conducted in the United Kingdom highlighted the importance of post-test counselling in the absence of a definitive diagnosis. The study found that some families may interpret the absence of a diagnosis as more reassuring than clinicians intended, particularly when the medical team continues to harbor concerns based on imaging findings.(16)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn contrast, the main clinical utility of post-mortem ES is to provide prognostic information for future pregnancies. For example, couples identified as carriers of an autosomal recessive condition could consider reproductive options such as pre-implantation genetic testing or prenatal diagnosis via chorionic villus sampling. In our study, the diagnostic yield in the post-mortem cohort was 38%, higher than the 21% incremental yield reported in a genomic autopsy cohort following fetal or neonatal death (5). This discrepancy likely stems from the highly selected nature of our cohort, which included only fetuses with congenital abnormalities strongly suggestive of a monogenic etiology. A systematic review encompassing over 2,000 cases reported an overall diagnostic yield of 33% for genomic autopsy, although there was considerable heterogeneity across the included studies (15).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere are limited data on the possible impact on future pregnancies of ES in the post-mortem cohort. Of the 200 families included in Australian genomic autopsy study, exome sequencing guided the management (e.g. PGD or antenatal invasive testing) in 5% of subsequent pregnancies. We were unable to collect follow-up data from our cohort to investigate the impact of testing on future pregnancies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTurnaround time\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs Victoria has no gestational age limit on TOP, a median turnaround time of 21 calendar days was considered acceptable. In contrast, in the South Australian study, where 22 weeks and 6 days was the upper limit for TOP, a shorter median turnaround time of 12 days (range 7-21) was used as their benchmark. (12)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Our median turnaround time for post-mortem exomes of 125 calendar days - is similar to that reported in an Australian perinatal genomic autopsy study.(5) \u0026nbsp;We also observed substantial variation in the post-mortem turnaround times (interquartile range of 87 days), which could affect options for couples considering pre-implantation genetic testing for their subsequent pregnancies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVariants of Uncertain Significance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe proportion of variants of uncertain significance (VUS) identified in our prenatal cohort (4%) is consistent with findings from a study on VUS in prenatal exome sequencing, which reported a rate of 2%.(17) The higher percentage of VUS in the post-mortem compared to prenatal ES (21% vs 4%), can be explained by several factors. First, the higher proportion of trio exomes performed in the antenatal cohort (89%) compared to the post-mortem period (18%) would lead to a lower degree of VUS reported in the antenatal cohort. Furthermore, as mentioned above, a VUS detected in an antenatal exome would only be reported if there is a clear correlation with the clinical phenotype, and it is proven to be de novo.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical implications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study highlights that the framework for publicly funded perinatal ES in Victoria is performing at the expected level regarding referral of cases, diagnostic yield, turnaround time and clinical utility. \u0026nbsp;These quantitative data, interpreted alongside our associated qualitative study of health professionals\u0026rsquo; perspectives, support the case for maintaining an MDT-led framework to promote clinical quality in this rapidly evolving field.(13) A well-established pathway also benefits the families involved by ensuring consistent, standardized, and equitable counselling and follow-up across the state. Our methods and results therefore provide a potential model and benchmark for fetal medicine units in other jurisdictions. \u0026nbsp;\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrengths and Limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is the first Australian population-based study reporting on the diagnostic yield and clinical outcomes of publicly funded perinatal ES in routine clinical care. Although this was a retrospective study, all the data were prospectively recorded in a standardized way in all participating centers. This study is also the first to examine the financial implications of a publicly funded perinatal ES program, revealing the hidden genomic testing expenditures incurred by hospitals that are not directly reimbursed by a government program that was designed to reimburse adult and pediatric services. While we did not calculate the professional costs associated with the range of highly experienced health professionals required to counsel these patients, these costs are important considerations with respect to the ongoing availability of this service.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study provides data on patient choices following the diagnosis of a fetal anomaly with a nondiagnostic chromosomal microarray (CMA). More than half of our cohort opted for TOP rather than waiting several weeks for prenatal ES results, suggesting that the prognostic information obtained from fetal imaging alone was sufficient for many women to decide. Nevertheless, our qualitative findings indicate that clinicians still perceived both personal and clinical value in offering post-mortem ES to these patients. (11)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOne of the limitations of our study was the lack of long-term follow-up data on the impact of the results and the impact of turnaround time on future management (such as access to PGT-M in a timely manner) in the post-mortem cases. Future research could focus on gathering this data for health economic analysis. Furthermore, we have no detailed data on how the results of post-mortem investigations (e.g. chromosomal microarray, autopsy, external examinations, MRI) influenced the decision for exome sequencing in the post-mortem cohort. \u0026nbsp; Further research is needed to investigate the clinical and personal utility for the cohort who accesses exome sequencing as part of a genomic autopsy after deciding for a termination of pregnancy.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, this study provides a model for a multicenter, MDT-led framework for perinatal ES that achieves high consistency regarding referrals, clinical utility, and diagnostic yield. Supported by public funding, this model serves as a benchmark for integrating ES into maternal fetal medicine services, ensuring equitable access and informed reproductive decision-making. Future research should focus on the long-term impact of ES on subsequent pregnancies and refine strategies to reduce turnaround times.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWillem Gheysen\u003c/strong\u003e: conceptualization, methodology, data curation, writing \u0026ndash; original draft, writing \u0026ndash; review and editing, funding acquisition, project administration\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCalder Hamill:\u0026nbsp;\u003c/strong\u003econceptualization, investigation, data curation, visualization\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSusan Fawcett:\u003c/strong\u003e investigation, data curation, writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTenielle Davis:\u003c/strong\u003e investigation, data curation, writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnand Vasudevan:\u003c/strong\u003e writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStefan Kane:\u003c/strong\u003e writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMelissa Graetz:\u003c/strong\u003e investigation, data curation, writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCandice Dao\u003c/strong\u003e investigation, data curation, writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDavid Amor:\u0026nbsp;\u003c/strong\u003econceptualization, supervision, writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMichael Fahey:\u003c/strong\u003e writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKirsten Palmer:\u003c/strong\u003e writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNikki Gelfand:\u003c/strong\u003e investigation, data curation, writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eYael Prawer:\u0026nbsp;\u003c/strong\u003einvestigation, data curation, writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJoanne M. Said:\u003c/strong\u003e writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKate Riley:\u003c/strong\u003e investigation, data curation, writing \u0026ndash; review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLilian Downie:\u003c/strong\u003e review and editing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLisa Hui:\u0026nbsp;\u003c/strong\u003econceptualization, supervision, methodology, data curation, writing \u0026ndash; review and editing, project administration\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by an Innovation Grant provided by the Norman Beischer Medical Research Foundation.\u003c/p\u003e\n\u003cp\u003eInfrastructure support was provided by the Murdoch Children\u0026rsquo;s Research Institute.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCollaborators:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003c/strong\u003eStefan C. Kane,\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDepartment of Maternal Fetal Medicine, Royal Women\u0026rsquo;s Hospital, Parkville, VIC, Australia\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDepartment of Obstetrics, Gynaecology and Newborn Health, The University of Melbourne, Parkville, Victoria, Australia\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eKirsten Palmer\u003cem\u003e, Department of Clinical Genetics, Monash Medical Centre, Clayton, VIC, Australia\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eJoanne M. Said, \u003cem\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDepartment of Maternal Fetal Medicine, Joan Kirner Women\u0026rsquo;s and Children\u0026rsquo;s Hospital, St Albans, VIC, Australia\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDepartment of Obstetrics, Gynaecology and Newborn Health, The University of Melbourne, Parkville, Victoria, Australia\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eLilian Downie,\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDepartment of Perinatal Medicine, Mercy Hospital for Women, Heidelberg, VIC, Australia\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMurdoch Children\u0026rsquo;s Research Institute, Parkville, VIC, Australia\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eUniversity of Melbourne Department of Paediatrics, Royal Children\u0026rsquo;s Hospital, Parkville, VIC, Australia\u003c/em\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAustralian Institute of Health \u0026amp; Welfare. Australia\u0026apos;s mothers and babies. December 2024. (Available from https://www.aihw.gov.au/reports/mothers-babies/australias-mothers-babies).\u003c/li\u003e\n\u003cli\u003eWapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):2175-84.\u003c/li\u003e\n\u003cli\u003ePetrovski S, Aggarwal V, Giordano JL, Stosic M, Wou K, Bier L, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet. 2019;393(10173):758-67.\u003c/li\u003e\n\u003cli\u003eLord J, McMullan DJ, Eberhardt RY, Rinck G, Hamilton SJ, Quinlan-Jones E, et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet. 2019;393(10173):747-57.\u003c/li\u003e\n\u003cli\u003eByrne AB, Arts P, Ha TT, Kassahn KS, Pais LS, O\u0026apos;Donnell-Luria A, et al. Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death. Nat Med. 2023;29(1):180-9.\u003c/li\u003e\n\u003cli\u003eMellis R, Oprych K, Scotchman E, Hill M, Chitty LS. Diagnostic yield of exome sequencing for prenatal diagnosis of fetal structural anomalies: A systematic review and meta-analysis. Prenat Diagn. 2022;42(6):662-85.\u003c/li\u003e\n\u003cli\u003eRamakrishnan R, Mallinson C, Hardy S, Broughan J, Blyth M, Melis G, et al. Implementation of a national rapid prenatal exome sequencing service in England: evaluation of service outcomes and factors associated with regional variation. Front Genet. 2024;15:1485306.\u003c/li\u003e\n\u003cli\u003eMiranda Durkie E-JC, Ian Berry, Martina Owens, Clare Turnbull, Richard H Scott, Robert W Taylor, Zandra C Deans, Sian Ellard, Emma L Baple and Dominic J McMullan. ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2024. 2024 20/02/2024.\u003c/li\u003e\n\u003cli\u003eRichards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24.\u003c/li\u003e\n\u003cli\u003eCristofoli F, Daja M, Maltese PE, Guerri G, Tanzi B, Miotto R, et al. MAGI-ACMG: Algorithm for the Classification of Variants According to ACMG and ACGS Recommendations. Genes (Basel). 2023;14(8).\u003c/li\u003e\n\u003cli\u003eBowman-Smart H, Keogh L, Haining CM, O\u0026apos;Rourke A, de Crespigny L, Savulescu J. \u0026apos;The tabloid test\u0026apos;: a qualitative interview study on the function and purpose of termination of pregnancy review committees in Victoria, Australia. Reprod Health. 2023;20(1):104.\u003c/li\u003e\n\u003cli\u003eRogers A, De Jong L, Waters W, Rawlings LH, Simons K, Gao S, et al. Extending the new era of genomic testing into pregnancy management: A proposed model for Australian prenatal services. Aust N Z J Obstet Gynaecol. 2024.\u003c/li\u003e\n\u003cli\u003eDayman S, Graetz M, Hui L, Downie L. \u0026ldquo;It\u0026apos;s both a terrifying and a powerful position to be in\u0026rdquo;: A qualitative study exploring clinician experiences and perspectives on providing publicly funded fetal exome sequencing. PREPRINT available at Research Square (https://doiorg/1021203/rs3rs-4960652/v1). 2024.\u003c/li\u003e\n\u003cli\u003ePoljak B, Agarwal U, Alfirevic Z, Allen S, Canham N, Higgs J, et al. Prenatal exome sequencing and impact on perinatal outcome: cohort study. Ultrasound Obstet Gynecol. 2023;61(3):339-45.\u003c/li\u003e\n\u003cli\u003eMollison L, O\u0026apos;Daniel JM, Henderson GE, Berg JS, Skinner D. Parents\u0026apos; perceptions of personal utility of exome sequencing results. Genet Med. 2020;22(4):752-7.\u003c/li\u003e\n\u003cli\u003eMcInnes-Dean H, Mellis R, Daniel M, Walton H, Baple EL, Bertoli M, et al. \u0026apos;Something that helped the whole picture\u0026apos;: Experiences of parents offered rapid prenatal exome sequencing in routine clinical care in the English National Health Service. Prenat Diagn. 2024;44(4):465-79.\u003c/li\u003e\n\u003cli\u003eDiderich KEM, Klapwijk JE, van der Schoot V, van den Born M, Wilke M, Joosten M, et al. The role of a multidisciplinary team in managing variants of uncertain clinical significance in prenatal genetic diagnosis. Eur J Med Genet. 2023;66(10):104844.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. \u0026nbsp;Clinical characteristics of \u0026lsquo;green\u0026rsquo; approved cases (n=179)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian maternal age in years at time MDT\u003csup\u003e\u0026dagger;\u003c/sup\u003e, (IQR\u003csup\u003e*\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e32 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCountry of birth Australia\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e119 (66%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetropolitan residence\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e137 (77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo interpreter required\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e166 (93%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParity\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e91 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e50 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e22 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e\u0026ge;\u0026nbsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e13 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSEIFA\u003csup\u003e\u0026Dagger;\u003c/sup\u003e Quintiles\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e1 \u0026ndash; Most disadvantaged\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e5 \u0026ndash; Most advantaged\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTiming of exome \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003ePrenatal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003ePost-mortem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* Interquartile range\u003c/p\u003e\n\u003cp\u003e\u0026dagger; Multi-Disciplinary team meeting\u003c/p\u003e\n\u003cp\u003e\u0026Dagger; Socio-Economic Indexes for Areas\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Indications for exome in \u0026lsquo;green\u0026rsquo; approved cohort (n=179)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003eMultisystem anomaly\u003c/p\u003e\n \u003cp\u003eSingle organ system anomaly (total)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e70 (39%)\u003c/p\u003e\n \u003cp\u003e109 (61%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003eOrgan system\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003eBrain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e37 (34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003eSkeletal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e20 (18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003eIncreased nuchal translucency (\u0026gt;5mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e16 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003eHydrops\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e11 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003eCardiac\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e10 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003eRenal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e6 (5.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003eAbdominal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e5 (4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 380px;\"\u003e\n \u003cp\u003eFacial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 196px;\"\u003e\n \u003cp\u003e4 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Results Exome Sequencing total cohort (n=179)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"75%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (n=179)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Prenatal (n=72)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost-mortem (n=107)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eCausative variant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e27 (37.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e41 (38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eSecondary findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e3 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e3 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eVUS\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e3 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e23 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eCarrier status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e2 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e7 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eNo Findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e37 (51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e32 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eNo data\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e1 (1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian Turn Around Time, days\u0026nbsp;(IQR*)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e21 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e125 (87)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eType Testing\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003eTrio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e64 (89%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e19 (18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003eSingle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e5 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e86 (80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003eDuo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e2 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eQuad\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e1 (1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e1 (1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eNo data\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e/\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e1 (1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePregnancy outcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eLivebirth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e31 (43%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e3 (2.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eTermination of Pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e25 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e82 (76.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eNeonatal Death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e2 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e6 (5.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eStillbirth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e3 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e16 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003eMissing data\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e11 (15%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* Interquartile range\u003cbr\u003e\u0026nbsp;\u0026dagger; data unavailable as patients delivered in other hospital \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Diagnostic yield according to indication for testing\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"623\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 167px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnostic yield in prenatal cohort (n=72)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnostic yield in post-mortem cohort (n=107)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnostic yield in total combined cohort (n=179)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIndication for testing\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en/N\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en/N\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u003cstrong\u003en/N\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eMultisystem anomalies \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e11/22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e0.31-0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e16/48\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.22-0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e27/70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.28-0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eBrain\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e5/13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e0.17-0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e7/24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.15-0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e12/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.20-0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eSkeletal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e3/6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e0.19-0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e8/14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.33-0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e11/20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.34-0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eIncreased NT* (\u0026gt; 5mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e4/15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e0.11-0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e1/1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.21-1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e5/16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.14-0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eHydrops\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e3/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e0.31-0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e4/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.25-0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e7/11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.35-0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eCardiac\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e0.00-0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e2/6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.10-0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e2/10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.06-0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eFacial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e1/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e0.05-0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e0/0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e1/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.05-0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eAbdominal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e0.00-0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e0/1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.00-0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e0/5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.00-0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003eRenal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e0/0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003e0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e3/6\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.19-0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e3/6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.19-0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 97px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOTAL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e27/72\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 40px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e37.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.27-0.49\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e41/107\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.30-0.48\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e68/179\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 55px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.31-0.45\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e*Nuchal translucency\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5. Perinatal outcomes in the antenatal cohort by exome result (n=72)\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePerinatal outcomes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCausative variants (n=27)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo findings\u0026nbsp;\u003cbr\u003e\u0026nbsp;(n=36)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSecondary findings (n=3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVUS\u0026nbsp;\u003cbr\u003e\u0026nbsp;(n=3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCarrier status (n=2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eTermination of pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e18* (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e6 \u0026dagger; (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eLivebirths\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e7 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e21 (58%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eNeonatal Deaths\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e1 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e1 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eStillbirths\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e2 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e1 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e6 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* In 3 cases TOP was requested prior to the return of the exome result\u003c/p\u003e\n\u003cp\u003e\u0026dagger; in 3 cases TOP was requested prior to the return of the exome result\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Murdoch Children's Research Institute","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"prenatal diagnosis, exome sequencing, congenital abnormalities, post-mortem exome sequencing","lastPublishedDoi":"10.21203/rs.3.rs-6302126/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6302126/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Congenital anomalies are a leading cause of perinatal mortality, with many having a genetic basis. Exome sequencing (ES) has transformed the diagnostic approach in the prenatal and post-mortem work-up of fetal congenital anomalies. Despite its benefits, population-based implementation programs that address equity and clinical consistency are scarce.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To analyze perinatal cases referred for funding from the state government clinical sequencing initiative for patient eligibility, diagnostic yield, and clinical utility of ES.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A retrospective analysis was conducted on prospectively collected data for 195 cases referred for perinatal ES from 2018 to 2022 in Victoria, Australia. All cases underwent eligibility review against the published criteria for funding by one of 3 multidisciplinary teams (MDT) with members drawn from 4 tertiary fetal medicine units. Descriptive statistics of eligibility assessment, indication for referral, results, diagnostic yield, turn-around time, and pregnancy outcomes were performed. Subgroup analysis was performed for prenatal and post-mortem cases. Differences in proportions were analyzed with the z-test, with p\u0026lt;0.05 considered significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Of the 195 referred cases, 179 (93%) were deemed eligible for publicly funded ES. The most frequent indications for ES were multisystem anomalies, brain anomalies, and skeletal abnormalities. The overall diagnostic yield was 38% (95% Confidence Interval (CI) [0.31-0.45]), with causative genes identified in 37.5% (95% CI [0.27-0.49]) of prenatal and 38% (95% CI [0.30-0.48]) of post-mortem cases. Prenatal ES had demonstrable clinical utility: the termination of pregnancy rate was significantly higher in cases with a causative finding on ES compared with those without (67% vs 17%, P\u0026lt; 0.0001). The average turnaround time was 21 calendar days for prenatal cases and 125 days for post-mortem cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e In conclusion, this study provides a model for a multicenter, MDT-led framework for perinatal ES that achieves high consistency regarding referrals, clinical utility, and diagnostic yield. Supported by public funding, this model serves as a benchmark for integrating ES into maternal fetal medicine services, ensuring equitable access and informed reproductive decision-making. Future research should focus on the long-term impact of ES on subsequent pregnancies and refine strategies to reduce turnaround times.\u003c/p\u003e","manuscriptTitle":"Population-based, government-funded exome sequencing for fetal abnormalities: a state-wide implementation model for equity and clinical consistency","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-26 10:00:04","doi":"10.21203/rs.3.rs-6302126/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8ba76a25-844f-40c6-9f78-9e16472d9c21","owner":[],"postedDate":"March 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":46177110,"name":"Maternal \u0026 Fetal Medicine"}],"tags":[],"updatedAt":"2025-03-26T10:00:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-26 10:00:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6302126","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6302126","identity":"rs-6302126","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}