{"paper_id":"7ecee3ac-bd14-4196-9acd-7d1a065a0297","body_text":"Genetic testing and diagnostic strategies of fetal skeletal dysplasia: a preliminary study in Wu Han, China ​ | 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 Genetic testing and diagnostic strategies of fetal skeletal dysplasia: a preliminary study in Wu Han, China ​ Wanlu Liu, Jing Cao, Xinwei Shi, Yuqi Li, Fuyuan Qiao, Yuanyuan Wu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2181067/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Oct, 2023 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 4 You are reading this latest preprint version Abstract Background Fetal skeletal dysplasia (FSD) is a diverse group of degenerative diseases of bone and cartilage disorders that can lead to movement disorder and even death. This study aims to deliver prenatal diagnosis through sonographic examination and genetic testing. Methods From September 2015 to April 2021, the study investigated 24 cases with suspected short-limb fetuses, which were obtained from Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. To identify the causative gene, multiple approaches (including karyotype analysis, copy number variations and whole exome sequencing) were performed on these fetuses. And further segregation analysis of the candidate variant was performed in parents by using Sanger sequencing. Results ① Out of 24 cases, likely pathogenic gene variants in FGFR3, FBN2, COL1A2, CUL7 and DYNC2H1 were detected for 6 cases; genetic variants in FGFR3, IMPAD1 and GORAB as possibly lethal mutations were identified in other 6 cases; and gene variants in WNT1, FBN1, OBSL1, COL1A1, DYNC2H1 and NEK1 , known as Variant of Undetermined Significance (VUS), were found in 4 cases. The rest 8 cases showed undetectable mutation in the whole exome sequencing (WES) analysis. ②A genetic diagnosis determined 12 different skeletal dysplasia genotypes in 14/24 (58.3%) cases. The other 10 cases with wild type gene (41.7%) were normal and well developed in one-year follow-up survey after study. Conclusion Genetic testing combining with ultrasound scanning enhances the accurate diagnosis of fatal skeletal dysplasia in utero, and then provides appropriate genetic counseling. fetal skeletal dysplasia genetic testing prenatal diagnosis ultrasound scanning Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Fetal skeletal dysplasia (FSD) is one of the most common fetal malformations, of which the incidence rate is approximately 2.4–4.5 out of 10,000 births [ 1 , 2 ] . It is defined as a group of bone and cartilage disorders with diverse clinical and genetic heterogeneity that can lead to movement disorder and even death. The pathogenicity is closely associated with mutations of the genes encoding collagen (e. g. type I, II, IX, IX, XI collagen) [ 3 ] . Current scientific study reported many pathogenic gene variations in the proband with skeletal dysplasia and variants occurred in causative genes of COL1A1, COL1A2, WNT1, OBSL1, FGFR3, IMPAD1, FBN2 , and GORAB [ 4 – 6 ] . According to 2019 edition of the Nosology, 461 disorders classified within 42 different groups have been described based on radiologic, molecular and biochemical criteria [ 7 ] . The clinical phenotype is broad and ranges from a mild type to a severe type. Genotype and phenotype relationship is unclear. And then an accurate diagnosis of FSD can be challenging due to its rarity and variety of phenotype, especially for fetuses.Therefore, the determination of FSD is challenging due to the diversity of FSD phenotypes, particularly in the diagnosis for prenatal diagnosis. So far, ultrasound is the most common measurement to detect fetal skeletal abnormality in early pregnancy [ 8 ] . However, overlapping features and phenotypic variability of skeletal dyplasias are limited to differentiate FSD and provide a definitive diagnosis via image findings. In addition, phenotypic characteristics of FSD do not manifest until later in pregnancy, which undoubtedly increase the difficulty in definite diagnosis. Recently, with the advance in next-generation sequencing technology, high-throughput sequencing has been considered as an effective method for genetic diagnosis. E.g. whole exome sequencing (WES), is advantageous in identification of De novo and compound heterozygous variants [ 9 , 10 ] . Suggested by the American College of Medical Genetics and Genomics (ACMG), next-generation sequencing can be considered to increase the sensitivity of diagnosis when the tradition gene testing, such as chromosomal microarray analysis, failed to yield a definitive result for the diagnosis. By analyzing the clinical symptoms and gene variation of 24 cases with suspected fetal skeletal dysplasia, this study successfully obtained some solid evidence for prenatal diagnosis of FSD. Ultrasound scanning combining with genetic test in the first or second trimester of gestation enhances the accurate diagnosis of fatal skeletal dysplasia in utero, then provides appropriate genetic counseling. 2. Materials And Methods 2.1 Editorial policies and ethical considerations Our study was approved by the Research Ethics Committee of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. Informed consents were obtained from all the participants in the study. 2.2 Patients information After approval of the Research Ethics Committee of our Hospital, informed consents and samples were obtained from all the participants. Twenty-four cases were collected by the study since all fetuses were detected with suspected short-limb from primary ultrasound scanning in the prenatal diagnosis center (one of prenatal diagnosis referral centers in China) of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology between September 2015 and April 2021. Out of 24 cases, the pregnant women in case 9 and 10 had osteogenesis imperfecta, while the clinical phenotypes of the pregnant women and their spouses of the rest cases (22 cases) were all normal. In addition, case 6 had induced labor previously due to the suspected short limbs of the fetus determined only by ultrasound examination. 2.3 Ultrasound scanning The biometric data of the fetal skeleton (including biparietal diameter (BPD), head circumference (HC), measurements of all long bones (including humerus length (HL), femur length (FL)), assessment of skeletal mineralization), and any other abnormalities were collected and analyzed in comparison with normal values. Out of 24 cases, only cases 6 and 22 were found by ultrasound screening that the values of NT (nuchal translucency) were higher than the normal (NT of case 6: 0.55cm; and NT of case 22: 0.58cm), while the rest of 22 cases were all detected as normal. 2.4 Sample collection Amniotic fluid and blood samples were retrieved from umbilical cord by amniocentesis and cordocentesis individually under ultrasound at second trimester of gestation. For the cases of which the blood or amniotic fluid samples could not be collected, two pieces of fetal muscle tissue (2 ×2 cm, containing the skin) or umbilical cord (about 3 centimeters) were sampled after the termination of pregnancy. 2.5 Fetal karyotype analysis and genetic analysis Karyotype analysis was performed on cultured amniotic fluid cells. Fetal genomic DNA was extracted from amniotic fluid samples or the tissues samples of fetuses using a DNA Extraction Kit (TianGen, Beijing, China) according to the manufacturer's instructions and stored at − 20℃ for further analysis. The genomic DNA of the couples in all cases was extracted from whole blood sample using the same protocol/Kit. The WES was performed for all the DNA samples. After fetal DNA was quantified with Nanodrop 2000 (Thermal Fisher Scientific, DE), 3–5µg DNA was used for sequencing and copy number variations (CNV) test. The sequencing data was used for analyzing likely pathogenic gene variation by the Polyphen and SIFT software. 2.6 Familial validation Once the pathogenic gene variations were detectable in the fetal samples, the coding regions of the mutations were identified and further examined for parents by Sanger sequencing. 3. Results 3.1 Clinical information and ultrasound findings Ultrasound imaging revealed normal amniotic fluid volumes and normal appearance of the brain, heart, liver, or kidneys in all cases, whereas the suspected skeletal malformations were detected. The lengths of humerus and femur in 24 cases were found to be either significantly lower than the reference (Mean ± SD) at the same gestation period according to Hadlock's reference chart. The results of prenatal ultrasound were summarized in Table 1 . Table 1 ultrasound findings in this study No. Age Gestation / Parity （G/P） Gestation (weeks) HL （cm） FL （cm） BPD （cm） HC （cm） Skeletal malformation Value M±SD Value M±SD 1 39 G1P0 30 +2 4.3 5.2-4SD 4.5 5.8-5SD 7.7 27.4 Unseen 2 24 G1P0 17 +5 1.0 2.4-8SD 1.1 2.4-5SD 3.9 14.7 Unseen 3 21 G1P0 32 4.6 5.5-5SD 4.9 6.2-5SD 8.3 29.3 Unseen 4 36 G1P0 33 +4 5.0 5.5-3SD 5.6 6.2-2SD 8.2 28.2 Unseen 5 31 G1P0 23 +2 3.2 3.9-3SD 2.9 4.1-6SD 5.5 21.3 Angle bending of ribs, left lower limb bone and humerus 6 29 G2P0 32 3.7 5.5-10SD 4.5 6.2-7SD 8.8 29.9 Unseen 7 23 G1P0 24 +5 2.9 4.1-6SD 3.7 4.4-3SD 5.1 21 Scoliosis, bipedal varus, bipedal toes continuously hooked, bilateral humerus, tibia, fibula bent 8 29 G1P0 30 4.6 5.1-3SD 4.8 5.8-3SD 8.1 28.4 Bilateral femoral curvature 9 35 G1P0 22+5 3.1 3.6-3SD 3.0 3.9-3SD 5.5 19.8 Right femoral curvature 10 25 G1P0 21 3.5 3.5 3.4 3.4 5.0 18.6 Unseen 11 27 G1P0 22 2.6 3.6-5SD 2.7 3.9-5SD 5.3 19.6 Unseen 12 30 G1P0 32+5 4.3 5.5-6SD 4.3 6.2-7SD 8.9 28.4 Small thorax 13 32 G1P0 32 5.0 5.5-3SD 5.5 6.2-3SD 8.4 29.3 Unseen 14 29 G1P0 25 3.6 4.2-3SD 3.9 4.6-2SD 6.4 23.4 Unseen 15 29 G2P0 33 4.1 5.5-7SD 4.4 6.2-7SD 8.3 29.9 Unseen 16 30 G2P0 38 5.6 6.1-2SD 6.4 7.1-3SD 9.3 32.6 Unseen 17 30 G1P0 40+2 5.0 6.1-5SD 5.1 7.1-8SD 7.3 26.3 Unseen 18 33 G3P0 25+4 3.2 4.2-5SD 3.5 4.6-4SD 5.23 18.62 Scoliosis 19 33 G3P0 34+5 5.4 5.6-2SD 6.1 6.5-2SD 8.8 30.9 Unseen 20 30 G1P0 15+6 1.0 1.8-9SD 1.1 1.8-5SD 3.3 11.7 Small thorax, equinus 21 35 G4P1 36 5.6 5.9-2SD 6.4 6.8-2SD 9.0 32.1 Unseen 22 29 G3P1 16 1.3 2.1-5SD 1.3 2.1-4SD 3.7 13.5 Bilateral temporal bone depression 23 32 G1P0 22 2.2 3.6-7SD 2.3 3.9-6SD 5.7 21 Unseen 24 30 G1P0 30+5 4.7 5.1-2SD 5.0 5.8-3SD 7.7 29 Unseen 3.2 Abnormalities by karyotype analysis and copy number variations (CNV) The chromosome G band karyotype revealed negative in all 24 cases, while CNV was undetected in 22 cases except of case15 and 23. In the case15, we found a 0.2MB duplication in the chromosome 7 q11,21, considered benign according to the available evidence; In the case 23, a 0.4MB duplication in the chromosome 18p11.31q11.23 was detected and known as VUS. 3.3 Abnormalities Detected by Whole exome sequencing (WES) Out of 24 cases, 6 cases were identified with carrying the likely pathogenic variants in gene FGFR3, FBN2, COL1A2, CUL7 and DYNC2H1 ; 6 other cases were considered to carry likely lethal gene variants and the chromosomes of fetuses were trisomy 13 and trisomy 18, respectively; 3 cases were detected with variants in gene WNT1, FBN1, OBSL1, COL1A1, DYNC2H1 and NEK1 , known as VUS; The rest 8 cases showed negative in WES (Table 2 ), which was further confirmed by Sanger sequencing. Table 2 Variants of the fetuses identified in the study NO. Bone gene encoded Nucleotide mutation Amino-acid change heterogeneity Mutation type Inheritance Inheritance type Pregnancy Outcomes 1 FGFR3 c.1015C > T p. Arg339Ter het Likely pathogenic De novo AD Induced labor 2 WNT1 c.1027G > C p. Glu343Gln het VUS Paternal AR Induced labor 3 FGFR3 c.1144G > A p. Gly282Arg het pathogenic De novo AD Induced labor 4 FBN1 OBSL1 c.7842T > A c.2135-3_2135-2delCA p. Ala2614Ala p.2135-3_2135-2delCA het VUS Biparental AD AR Vaginal delivery 5 COL1A1 c.824G > A p. Gly275Asp het VUS De novo AD Induced labor 6 IMPAD1 c.700G > T CDS4-5del p.E234* CDS4-5 del hom het pathogenic Biparental AR Cesarean Section(death) 7 FBN2 Exon21-25del Exon21-25del het Likely Pathogenic De novo AR Induced labor 8 DYNC2H1 NEK1 c.2641G > T c.859C > G p. Asp881Tyr p. Pro287Ala het VUS Biparental AR Induced labor 9 COL1A2 c.1118G > C p. Gly373Ala het Likely pathogenic Maternal AD Induced labor 10 GORAB c.178C > T p. Arg60* het pathogenic Maternal AR Cesarean section 11 N N N N N N N Cesarean section 12 FGFR3 c. 1138 G > A p. Gly380Arg het pathogenic De novo AD Induced labor 13 N N N N N N N Vaginal delivery 14 N N N N N N N Vaginal delivery 15 CUL7 c.3355 + 5G > A c.3722_3749dup p. V1252Gfs*23 het Likely pathogenic Biparental AR Induced labor 16 N N N N N N N Vaginal delivery 17 N N N N N N N Vaginal delivery 18 DYNC2H1 c.4072C > T p. Arg1358Cys het Likely pathogenic De novo AR Induced labor 19 N N N N N N N Cesarean section 20 FGFR3 c.2420G > C p.*807Sext*101 het Likely pathogenic De novo AD Induced labor 21 N N N N N N N Cesarean section 22 FGFR3 c.1948A > G p. Lys650Glu het pathogenic De novo AD Induced labor 23 FGFR3 c.742C > T p. Arg248Cys het pathogenic De novo AD Induced labor 24 N N N N N N N N “N” in Table 2 means negative findings in this case For the fetus of case 4 carried the c.7842T > A (p. Ala2614Ala) variant in FBN1 gene and the deletion of c.2135-3_2135-2delCA in OBSL1 gene. The Sanger sequencing analysis further revealed that the gene variant was carried by the father and the deletion was carried by the mother ( Fig. 1 ). For the fetus of case 6, we detected the variant of c.700G > T (p.E234*) and the deletion of CDS4-5 in IMPAD1 gene. Both Sanger sequencing and qPCR determined that the heterozygous deletion of CDS4-5 and the homozygous mutation in gene IMPAD1 were inherited from their parents, resulting to a composite heterozygous mutation ( Fig. 2 ). In the case 9 and 10, the two women were diagnosed with osteogenesis imperfecta before pregnancy. Our analysis detected the variant of c.1118G > C (p. Gly373Ala) in COL1A2 gene for the fetus in case 9, and variant of c.178C > T (p. Arg60*) in GORAB gene for the fetus in case 10. The two variants originated from osteogenesis imperfecta and inherited from their mother ( Fig. 3, 4 ). 4. Discussion The prenatal diagnosis of FSD is important at the second trimester of gestation, however, it is still challenging due to diverse clinical and genetic heterogeneity of the disorder. For decades, ultrasound is widely used in the noninvasive detection of FSD. Pajkrt and Chitty [ 11 ] found that FL and HL of the fetuses with skeletal dysplasia were 5% shorter than the normal value. Previous reports in China demonstrated that the diagnosis accuracy of continuous sequential follow-up ultrasound was over 80% and 87.2% in the second trimester of gestation [ 12 ] . In this study, by ultrasound scanning, we found the HL and FL of the fetuses in the 24 cases was either lower or higher than the normal value except of case 10 (the woman with OI (osteogenesis imperfecta) before pregnancy). The BPD and HC of the fetus were normal in all the 24 cases. In one-year follow-up survey, we found the 8 infants (account for 33.3%) were normal in skeletal development after delivery when the HL and FL of these fetuses was 2SD-3SD lower than the mean value. Differently, when the HL and FL of the fetuses was 3SD less or 3SD more, only two newborns (8.33%) were normal. The results of this ultrasound-only dependent approach are inadequate for diagnosing the disorder and impossible to differentiate the complex types of FSD. In recent years, NGS (WES and WGS, Whole exome sequencing and Whole gene sequencing) has been applied in the area of disease diagnosis [ 13 ] . The mutation detection tool needs to optimize since the detection rates of WES could be variable depending on many factors, such as the sample size, the analysis criteria, proband-only or trio WES, and so on [ 10 ] . More importantly, the complex of genetic variants was found to be associated with the diverse pathogenicity of FSD. In case 4, The fetus carried the c.7842T > A (p. Ala2614Ala) variant in the FBN1 gene and the deletion of c.2135-3_2135-2delCA in OBSL1 gene. The mutation is synonymous mutation and the deletion is in the intron. The FBN1 gene variation [ 14 ] is reported to be associated with Weill Marchesani syndrome (clinical manifestations are short limb deformity, secondary glaucoma, short stature, etc.). The OBSL1 gene variation [ 15 ] is related to 3-M syndrome (clinical manifestations include severe intrauterine growth retardation, short stature, recessive spina bifida, compression deformation of long metaphysis). The inheritance patterns of Weill Marchesani syndrome and 3-M syndrome are both AR (autosomal recessive inheritance). The Sanger analysis indicated that the mutation was carried by the father and the deletion was carried by the mother ( Fig. 1 ). The mother of case 4 had natural delivery by vaginal at 39 + 6 weeks of gestation, and the newborn did not show any abnormality of bone development (up to 18-monthes old) at the end of the following-up survey. In case 6, we detected the variant of c.700G > T (p.E234*) and the deletion of CDS4-5 in IMPAD1 gene for the fetus. The heterozygous deletion of CDS4-5 and the homozygous variant in gene IMPAD1 were inherited from their parents, as a compound heterozygote mutation (Fig. 2). IMPAD1 -related chondrodysplasia is an autosomal recessive disease [ 16 ] . The pregnant women had cesarean section at 38 weeks of gestation in this case, and the newborn had typical short limb deformity and died within one month after delivery. In the study, there were two women (case 9 and 10) diagnosed with osteogenesis imperfecta before pregnancy. We detected the variant of c.1118G > C (p. Gly373Ala) in COL1A2 gene for the fetus in case 9, and found the variant of c.178C > T (p. Arg60*) in GORAB gene for the fetus in case 10( Fig. 3, 4 ). The two variants related to osteogenesis imperfecta and inherited from their mother, but one genetic type is autosomal dominant (AD) [ 17 ] and the other is autosomal recessive (AR) [ 18 ] . The fetus of case 9 died before delivery at 35 weeks of gestation, while the newborn of case 10 had no significant abnormality in bone development up to 2-years old in the following-up survey. In the case 2, 5 and 8, we found the WNT1 or COL1A1 -related VUS in osteogenesis imperfecta, and DYNC2H1 and NEK1 -related asphyxiative hypoplasia of thorax. Notably, the fetuses in these cases all had short lower limbs, which was determined after abortion, while the proteins encoded by the gene variants were predicted to be deleterious using the SIFT and Polyphen analysis. Our assumption includes: (1) the limited data depth which failed to achieve 100% coverage of the exon sequences, resulting in the related pathogenic gene variants was dismissed; (2) the unknown gene variation outside the exons, including non-coding region and intron mutation, possibly responsible for the pathogenicity; (3) other environmental factors that have not been found. Furthermore, we had negative findings by WES, and the 8 infants were normal in skeletal development after delivery in the rest 8 cases. 5. Conclusions In sum, skeletal dysplasia is mostly hereditary. Our study has obtained 14/24 (58.3%) cases carrying 12 different skeletal dysplasia genotypes, which will broaden the spectrum of FSD in Chinese patients. Genetic diagnosis combining with ultrasound scanning enhances the accurate diagnosis of FSD in utero, then can provide appropriate genetic counseling. Abbreviations FSD: fetal skeletal dysplasia FGFR3: fibroblast growth factor receptor3 FBN1: Fibrillin-1 FBN2: Fibrillin-2 COL1A1: collagen type I alpha 1 Chain COL1A2: collagen type I alpha 2 Chain CUL7: cullin-7 DYNC2H1: Dynein Cytoplasmic 2 Heavy Chain 1 IMPAD1: Inositol Monophosphatase Domain containing 1 WNT1: Wnt Family Member 1 GORAB: Golgi-associated Rab-binding protein OBSL1: Obscurin Like Cytoskeletal Adaptor 1 NEK1: NIMA (Never-in-mitosis A)-related kinase 1 VUS: variant of undetermined significance WES: whole exome sequencing WGS: whole gene sequencing NIPT: non-invasive prenatal test BPD: biparietal diameter HC: head circumference HL: humerus length FL: femur length NT: nuchal translucency CNV: copy number variations OI: osteogenesis imperfecta NGS: next-generation sequencing AR: autosomal recessive inheritance AD: autosomal dominant inheritance Declarations Ethics approval and consent to participate The study was approved by the Research Ethics Committee of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. The parents provided a signed informed consent prior to intrauterine diagnosis and sample collection in our country. Consent for publication Not applicable. Availability of data and material All data analyzed in our study are available upon reasonable request. Competing interests All authors declare that they have no conflict of interest. Funding This study was supported by The National Key Research and Development Program of China(2018YFC1002904). Acknowledgements We thank all the subjects who participated in this study. Authors' contributions Xinwei Shi was responsible for the conceptualization of the review and literature Search. Jing Cao, Yuqi Li and Fuyuan Qiao provided the included case studies. Wanlu Liu and Yuanyuan Wu were major contributors to the drafting of the manuscript. All authors read and approved the final manuscript. References Liu Y, Wang L, Yang YK, et al. 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Mutations in the COL1A1 and COL1A2 genes associated with osteogenesis imperfecta (OI) types I or III. Acta Biochim Pol. 2018;65(1):79–86. Yang H, Albiol L, Chan WL, et al. Examining tissue composition, whole-bone morphology and mechanical behavior of Gorab Prx1 mice tibiae: A mouse model of premature aging. J Biomech. 2017;65(10):145–53. Cite Share Download PDF Status: Published Journal Publication published 25 Oct, 2023 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Reviewers agreed at journal 01 Jun, 2023 Reviewers invited by journal 08 Nov, 2022 Editor assigned by journal 04 Nov, 2022 First submitted to journal 31 Oct, 2022 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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Technology\",\"correspondingAuthor\":true,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yuanyuan\",\"middleName\":\"\",\"lastName\":\"Wu\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2022-10-19 03:44:06\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-2181067/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-2181067/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1186/s13023-023-02955-4\",\"type\":\"published\",\"date\":\"2023-10-25T15:02:38+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":28916730,\"identity\":\"3061d7fc-4063-4cae-869f-f777257df1ea\",\"added_by\":\"auto\",\"created_at\":\"2022-11-10 17:55:05\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":209234,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSee image above for figure 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3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":75111,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSee image above for figure legend.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Fig3.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2181067/v1/56db379c3fc34d6fde5cde66.jpg\"},{\"id\":28916615,\"identity\":\"cfdce4cc-4729-4efc-a2ee-61832adf3cee\",\"added_by\":\"auto\",\"created_at\":\"2022-11-10 17:47:05\",\"extension\":\"jpg\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":144705,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSee image above for figure legend.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Fig4.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2181067/v1/c266ab9b8edb3f7702e70f64.jpg\"},{\"id\":45454214,\"identity\":\"3c9ba994-6a62-40c3-9379-6fe3dc1eae64\",\"added_by\":\"auto\",\"created_at\":\"2023-10-30 15:09:13\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":830817,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-2181067/v1/96d8225a-abc5-42e2-8069-406caa3ff2d9.pdf\"}],\"financialInterests\":\"\",\"formattedTitle\":\"Genetic testing and diagnostic strategies of fetal skeletal dysplasia: a preliminary study in Wu Han, China ​\",\"fulltext\":[{\"header\":\"1. Introduction\",\"content\":\"\\u003cp\\u003eFetal skeletal dysplasia (FSD) is one of the most common fetal malformations, of which the incidence rate is approximately 2.4\\u0026ndash;4.5 out of 10,000 births \\u003csup\\u003e[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]\\u003c/sup\\u003e. It is defined as a group of bone and cartilage disorders with diverse clinical and genetic heterogeneity that can lead to movement disorder and even death. The pathogenicity is closely associated with mutations of the genes encoding collagen (e. g. type I, II, IX, IX, XI collagen) \\u003csup\\u003e[\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]\\u003c/sup\\u003e. Current scientific study reported many pathogenic gene variations in the proband with skeletal dysplasia and variants occurred in causative genes of \\u003cem\\u003eCOL1A1, COL1A2, WNT1, OBSL1, FGFR3, IMPAD1, FBN2\\u003c/em\\u003e, and \\u003cem\\u003eGORAB\\u003c/em\\u003e \\u003csup\\u003e[\\u003cspan additionalcitationids=\\\"CR5\\\" citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e]\\u003c/sup\\u003e. According to 2019 edition of the Nosology, 461 disorders classified within 42 different groups have been described based on radiologic, molecular and biochemical criteria\\u003csup\\u003e[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]\\u003c/sup\\u003e. The clinical phenotype is broad and ranges from a mild type to a severe type. Genotype and phenotype relationship is unclear. And then an accurate diagnosis of FSD can be challenging due to its rarity and variety of phenotype, especially for fetuses.Therefore, the determination of FSD is challenging due to the diversity of FSD phenotypes, particularly in the diagnosis for prenatal diagnosis.\\u003c/p\\u003e \\u003cp\\u003eSo far, ultrasound is the most common measurement to detect fetal skeletal abnormality in early pregnancy\\u003csup\\u003e[\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]\\u003c/sup\\u003e. However, overlapping features and phenotypic variability of skeletal dyplasias are limited to differentiate FSD and provide a definitive diagnosis via image findings. In addition, phenotypic characteristics of FSD do not manifest until later in pregnancy, which undoubtedly increase the difficulty in definite diagnosis. Recently, with the advance in next-generation sequencing technology, high-throughput sequencing has been considered as an effective method for genetic diagnosis. E.g. whole exome sequencing (WES), is advantageous in identification of De novo and compound heterozygous variants \\u003csup\\u003e[\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]\\u003c/sup\\u003e. Suggested by the American College of Medical Genetics and Genomics (ACMG), next-generation sequencing can be considered to increase the sensitivity of diagnosis when the tradition gene testing, such as chromosomal microarray analysis, failed to yield a definitive result for the diagnosis.\\u003c/p\\u003e \\u003cp\\u003e By analyzing the clinical symptoms and gene variation of 24 cases with suspected fetal skeletal dysplasia, this study successfully obtained some solid evidence for prenatal diagnosis of FSD. Ultrasound scanning combining with genetic test in the first or second trimester of gestation enhances the accurate diagnosis of fatal skeletal dysplasia in utero, then provides appropriate genetic counseling.\\u003c/p\\u003e\"},{\"header\":\"2. Materials And Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003e2.1 Editorial policies and ethical considerations\\u003c/h2\\u003e\\n\\u003cp\\u003eOur study was approved by the Research Ethics Committee of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. Informed consents were obtained from all the participants in the study.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003e2.2 Patients information\\u003c/h2\\u003e\\n\\u003cp\\u003eAfter approval of the Research Ethics Committee of our Hospital, informed consents and samples were obtained from all the participants. Twenty-four cases were collected by the study since all fetuses were detected with suspected short-limb from primary ultrasound scanning in the prenatal diagnosis center (one of prenatal diagnosis referral centers in China) of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology between September 2015 and April 2021. Out of 24 cases, the pregnant women in case 9 and 10 had osteogenesis imperfecta, while the clinical phenotypes of the pregnant women and their spouses of the rest cases (22 cases) were all normal. In addition, case 6 had induced labor previously due to the suspected short limbs of the fetus determined only by ultrasound examination.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003e2.3 Ultrasound scanning\\u003c/h2\\u003e\\n\\u003cp\\u003eThe biometric data of the fetal skeleton (including biparietal diameter (BPD), head circumference (HC), measurements of all long bones (including humerus length (HL), femur length (FL)), assessment of skeletal mineralization), and any other abnormalities were collected and analyzed in comparison with normal values. Out of 24 cases, only cases 6 and 22 were found by ultrasound screening that the values of NT (nuchal translucency) were higher than the normal (NT of case 6: 0.55cm; and NT of case 22: 0.58cm), while the rest of 22 cases were all detected as normal.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003e2.4 Sample collection\\u003c/h2\\u003e\\n\\u003cp\\u003eAmniotic fluid and blood samples were retrieved from umbilical cord by amniocentesis and cordocentesis individually under ultrasound at second trimester of gestation. For the cases of which the blood or amniotic fluid samples could not be collected, two pieces of fetal muscle tissue (2 \\u0026times;2 cm, containing the skin) or umbilical cord (about 3 centimeters) were sampled after the termination of pregnancy.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003e2.5 Fetal karyotype analysis and genetic analysis\\u003c/h2\\u003e\\n\\u003cp\\u003eKaryotype analysis was performed on cultured amniotic fluid cells. Fetal genomic DNA was extracted from amniotic fluid samples or the tissues samples of fetuses using a DNA Extraction Kit (TianGen, Beijing, China) according to the manufacturer's instructions and stored at \\u0026minus;\\u0026thinsp;20℃ for further analysis. The genomic DNA of the couples in all cases was extracted from whole blood sample using the same protocol/Kit. The WES was performed for all the DNA samples. After fetal DNA was quantified with Nanodrop 2000 (Thermal Fisher Scientific, DE), 3\\u0026ndash;5\\u0026micro;g DNA was used for sequencing and copy number variations (CNV) test. The sequencing data was used for analyzing likely pathogenic gene variation by the Polyphen and SIFT software.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003e2.6 Familial validation\\u003c/h2\\u003e\\n\\u003cp\\u003eOnce the pathogenic gene variations were detectable in the fetal samples, the coding regions of the mutations were identified and further examined for parents by Sanger sequencing.\\u003c/p\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"3. Results\",\"content\":\"\\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003e3.1 Clinical information and ultrasound findings\\u003c/h2\\u003e\\n\\u003cp\\u003eUltrasound imaging revealed normal amniotic fluid volumes and normal appearance of the brain, heart, liver, or kidneys in all cases, whereas the suspected skeletal malformations were detected. The lengths of humerus and femur in 24 cases were found to be either significantly lower than the reference (Mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;SD) at the same gestation period according to Hadlock's reference chart. The results of prenatal ultrasound were summarized in Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e.\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" width=\\\"728\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\"\\u003e\\u003ccaption\\u003e\\n\\u003cp\\u003eTable 1\\u003c/p\\u003e\\n\\u003cp\\u003eultrasound findings in this study\\u003c/p\\u003e\\n\\u003c/caption\\u003e\\n\\u003ctbody\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd rowspan=\\\"3\\\" width=\\\"5.509641873278237%\\\"\\u003e\\n\\u003cp\\u003eNo.\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"3\\\" width=\\\"6.74931129476584%\\\"\\u003e\\n\\u003cp\\u003eAge\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"3\\\" width=\\\"8.264462809917354%\\\"\\u003e\\n\\u003cp\\u003eGestation /\\u0026nbsp;Parity\\u0026nbsp;（G/P）\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"3\\\" width=\\\"8.264462809917354%\\\"\\u003e\\n\\u003cp\\u003eGestation\\u003c/p\\u003e\\n\\u003cp\\u003e(weeks)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd colspan=\\\"2\\\" width=\\\"16.52892561983471%\\\"\\u003e\\n\\u003cp\\u003eHL\\u0026nbsp;（cm）\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd colspan=\\\"2\\\" width=\\\"17.90633608815427%\\\"\\u003e\\n\\u003cp\\u003eFL\\u0026nbsp;（cm）\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"3\\\" width=\\\"7.851239669421488%\\\"\\u003e\\n\\u003cp\\u003eBPD\\u003c/p\\u003e\\n\\u003cp\\u003e（cm）\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"3\\\" width=\\\"7.300275482093664%\\\"\\u003e\\n\\u003cp\\u003eHC\\u003c/p\\u003e\\n\\u003cp\\u003e（cm）\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"3\\\" width=\\\"21.62534435261708%\\\"\\u003e\\n\\u003cp\\u003eSkeletal malformation\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"0%\\\" 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width=\\\"0%\\\" height=\\\"55\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"5.502063273727648%\\\"\\u003e\\n\\u003cp\\u003e4\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"6.740027510316368%\\\"\\u003e\\n\\u003cp\\u003e36\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003eG1P0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003e33\\u003csup\\u003e+4\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.4277854195323245%\\\"\\u003e\\n\\u003cp\\u003e5.0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"9.21595598349381%\\\"\\u003e\\n\\u003cp\\u003e5.5-3SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.702888583218707%\\\"\\u003e\\n\\u003cp\\u003e5.6\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"10.178817056396149%\\\"\\u003e\\n\\u003cp\\u003e6.2-2SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.8404401650618984%\\\"\\u003e\\n\\u003cp\\u003e8.2\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.290233837689134%\\\"\\u003e\\n\\u003cp\\u003e28.2\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"21.595598349381017%\\\"\\u003e\\n\\u003cp\\u003eUnseen\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"0%\\\" height=\\\"49\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"5.502063273727648%\\\"\\u003e\\n\\u003cp\\u003e5\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"6.740027510316368%\\\"\\u003e\\n\\u003cp\\u003e31\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003eG1P0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003e23\\u003csup\\u003e+2\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.4277854195323245%\\\"\\u003e\\n\\u003cp\\u003e3.2\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"9.21595598349381%\\\"\\u003e\\n\\u003cp\\u003e3.9-3SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.702888583218707%\\\"\\u003e\\n\\u003cp\\u003e2.9\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"10.178817056396149%\\\"\\u003e\\n\\u003cp\\u003e4.1-6SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.8404401650618984%\\\"\\u003e\\n\\u003cp\\u003e5.5\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.290233837689134%\\\"\\u003e\\n\\u003cp\\u003e21.3\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"21.595598349381017%\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAngle\\u003c/strong\\u003e bending of ribs, left lower limb bone and humerus\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"0%\\\"\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"5.502063273727648%\\\"\\u003e\\n\\u003cp\\u003e6\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"6.740027510316368%\\\"\\u003e\\n\\u003cp\\u003e29\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003eG2P0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003e32\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.4277854195323245%\\\"\\u003e\\n\\u003cp\\u003e3.7\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"9.21595598349381%\\\"\\u003e\\n\\u003cp\\u003e5.5-10SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.702888583218707%\\\"\\u003e\\n\\u003cp\\u003e4.5\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"10.178817056396149%\\\"\\u003e\\n\\u003cp\\u003e6.2-7SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.8404401650618984%\\\"\\u003e\\n\\u003cp\\u003e8.8\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.290233837689134%\\\"\\u003e\\n\\u003cp\\u003e29.9\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"21.595598349381017%\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eUnseen\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"0%\\\"\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"5.502063273727648%\\\"\\u003e\\n\\u003cp\\u003e7\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"6.740027510316368%\\\"\\u003e\\n\\u003cp\\u003e23\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003eG1P0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003e24\\u003csup\\u003e+5\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.4277854195323245%\\\"\\u003e\\n\\u003cp\\u003e2.9\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"9.21595598349381%\\\"\\u003e\\n\\u003cp\\u003e4.1-6SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.702888583218707%\\\"\\u003e\\n\\u003cp\\u003e3.7\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"10.178817056396149%\\\"\\u003e\\n\\u003cp\\u003e4.4-3SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.8404401650618984%\\\"\\u003e\\n\\u003cp\\u003e5.1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.290233837689134%\\\"\\u003e\\n\\u003cp\\u003e21\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"21.595598349381017%\\\"\\u003e\\n\\u003cp\\u003eScoliosis, bipedal varus, bipedal toes continuously hooked, bilateral humerus, tibia, fibula bent\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"0%\\\"\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"5.502063273727648%\\\"\\u003e\\n\\u003cp\\u003e8\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"6.740027510316368%\\\"\\u003e\\n\\u003cp\\u003e29\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003eG1P0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003e30\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.4277854195323245%\\\"\\u003e\\n\\u003cp\\u003e4.6\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"9.21595598349381%\\\"\\u003e\\n\\u003cp\\u003e5.1-3SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.702888583218707%\\\"\\u003e\\n\\u003cp\\u003e4.8\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"10.178817056396149%\\\"\\u003e\\n\\u003cp\\u003e5.8-3SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.8404401650618984%\\\"\\u003e\\n\\u003cp\\u003e8.1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.290233837689134%\\\"\\u003e\\n\\u003cp\\u003e28.4\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"21.595598349381017%\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eBilateral\\u0026nbsp;\\u003c/strong\\u003efemoral curvature\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"0%\\\"\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"5.502063273727648%\\\"\\u003e\\n\\u003cp\\u003e9\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"6.740027510316368%\\\"\\u003e\\n\\u003cp\\u003e35\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003eG1P0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003e22+5\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.4277854195323245%\\\"\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e3.1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"9.21595598349381%\\\"\\u003e\\n\\u003cp\\u003e3.6-3SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.702888583218707%\\\"\\u003e\\n\\u003cp\\u003e3.0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"10.178817056396149%\\\"\\u003e\\n\\u003cp\\u003e3.9-3SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.8404401650618984%\\\"\\u003e\\n\\u003cp\\u003e5.5\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.290233837689134%\\\"\\u003e\\n\\u003cp\\u003e19.8\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"21.595598349381017%\\\"\\u003e\\n\\u003cp\\u003eRight femoral curvature\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"0%\\\"\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"5.502063273727648%\\\"\\u003e\\n\\u003cp\\u003e10\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"6.740027510316368%\\\"\\u003e\\n\\u003cp\\u003e25\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003eG1P0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003e21\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.4277854195323245%\\\"\\u003e\\n\\u003cp\\u003e3.5\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd valign=\\\"top\\\" width=\\\"9.21595598349381%\\\"\\u003e\\n\\u003cp\\u003e3.5\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.702888583218707%\\\"\\u003e\\n\\u003cp\\u003e3.4\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd valign=\\\"top\\\" width=\\\"10.178817056396149%\\\"\\u003e\\n\\u003cp\\u003e3.4\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.8404401650618984%\\\"\\u003e\\n\\u003cp\\u003e5.0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.290233837689134%\\\"\\u003e\\n\\u003cp\\u003e18.6\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"21.595598349381017%\\\"\\u003e\\n\\u003cp\\u003eUnseen\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"0%\\\"\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"5.502063273727648%\\\"\\u003e\\n\\u003cp\\u003e11\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"6.740027510316368%\\\"\\u003e\\n\\u003cp\\u003e27\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003eG1P0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd 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width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003e36\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.4277854195323245%\\\"\\u003e\\n\\u003cp\\u003e5.6\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd valign=\\\"top\\\" width=\\\"9.21595598349381%\\\"\\u003e\\n\\u003cp\\u003e5.9-2SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.702888583218707%\\\"\\u003e\\n\\u003cp\\u003e6.4\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd valign=\\\"top\\\" width=\\\"10.178817056396149%\\\"\\u003e\\n\\u003cp\\u003e6.8-2SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.8404401650618984%\\\"\\u003e\\n\\u003cp\\u003e9.0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.290233837689134%\\\"\\u003e\\n\\u003cp\\u003e32.1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"21.595598349381017%\\\"\\u003e\\n\\u003cp\\u003eUnseen\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"0%\\\"\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"5.502063273727648%\\\"\\u003e\\n\\u003cp\\u003e22\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"6.740027510316368%\\\"\\u003e\\n\\u003cp\\u003e29\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003eG3P1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003e16\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.4277854195323245%\\\"\\u003e\\n\\u003cp\\u003e1.3\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd valign=\\\"top\\\" width=\\\"9.21595598349381%\\\"\\u003e\\n\\u003cp\\u003e2.1-5SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.702888583218707%\\\"\\u003e\\n\\u003cp\\u003e1.3\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd valign=\\\"top\\\" width=\\\"10.178817056396149%\\\"\\u003e\\n\\u003cp\\u003e2.1-4SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.8404401650618984%\\\"\\u003e\\n\\u003cp\\u003e3.7\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.290233837689134%\\\"\\u003e\\n\\u003cp\\u003e13.5\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"21.595598349381017%\\\"\\u003e\\n\\u003cp\\u003eBilateral temporal bone depression\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"0%\\\" height=\\\"33\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"5.502063273727648%\\\"\\u003e\\n\\u003cp\\u003e23\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"6.740027510316368%\\\"\\u003e\\n\\u003cp\\u003e32\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003eG1P0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003e22\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.4277854195323245%\\\"\\u003e\\n\\u003cp\\u003e2.2\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd valign=\\\"top\\\" width=\\\"9.21595598349381%\\\"\\u003e\\n\\u003cp\\u003e3.6-7SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.702888583218707%\\\"\\u003e\\n\\u003cp\\u003e2.3\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd valign=\\\"top\\\" width=\\\"10.178817056396149%\\\"\\u003e\\n\\u003cp\\u003e3.9-6SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.8404401650618984%\\\"\\u003e\\n\\u003cp\\u003e5.7\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.290233837689134%\\\"\\u003e\\n\\u003cp\\u003e21\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"21.595598349381017%\\\"\\u003e\\n\\u003cp\\u003eUnseen\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"0%\\\" height=\\\"29\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"5.502063273727648%\\\"\\u003e\\n\\u003cp\\u003e24\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"6.740027510316368%\\\"\\u003e\\n\\u003cp\\u003e30\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003eG1P0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"8.253094910591471%\\\"\\u003e\\n\\u003cp\\u003e30+5\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.4277854195323245%\\\"\\u003e\\n\\u003cp\\u003e4.7\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd valign=\\\"top\\\" width=\\\"9.21595598349381%\\\"\\u003e\\n\\u003cp\\u003e5.1-2SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.702888583218707%\\\"\\u003e\\n\\u003cp\\u003e5.0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd valign=\\\"top\\\" width=\\\"10.178817056396149%\\\"\\u003e\\n\\u003cp\\u003e5.8-3SD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.8404401650618984%\\\"\\u003e\\n\\u003cp\\u003e7.7\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"7.290233837689134%\\\"\\u003e\\n\\u003cp\\u003e29\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"21.595598349381017%\\\"\\u003e\\n\\u003cp\\u003eUnseen\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"0%\\\" height=\\\"20\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003e3.2 Abnormalities by karyotype analysis and copy number variations (CNV)\\u003c/h2\\u003e\\n\\u003cp\\u003eThe chromosome G band karyotype revealed negative in all 24 cases, while CNV was undetected in 22 cases except of case15 and 23. In the case15, we found a 0.2MB duplication in the chromosome 7 q11,21, considered benign according to the available evidence; In the case 23, a 0.4MB duplication in the chromosome 18p11.31q11.23 was detected and known as VUS.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003e3.3 Abnormalities Detected by Whole exome sequencing (WES)\\u003c/h2\\u003e\\n\\u003cp\\u003eOut of 24 cases, 6 cases were identified with carrying the likely pathogenic variants in gene \\u003cem\\u003eFGFR3, FBN2, COL1A2, CUL7\\u003c/em\\u003e and \\u003cem\\u003eDYNC2H1\\u003c/em\\u003e; 6 other cases were considered to carry likely lethal gene variants and the chromosomes of fetuses were trisomy 13 and trisomy 18, respectively; 3 cases were detected with variants in gene \\u003cem\\u003eWNT1, FBN1, OBSL1, COL1A1, DYNC2H1\\u003c/em\\u003e and \\u003cem\\u003eNEK1\\u003c/em\\u003e, known as VUS; The rest 8 cases showed negative in WES (Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e), which was further confirmed by Sanger sequencing.\\u003c/p\\u003e\\n\\u003cdiv class=\\\"gridtable\\\"\\u003e\\n\\u003ctable id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e\\u003ccaption\\u003e\\n\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e\\n\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\n\\u003cp\\u003eVariants of the fetuses identified in the study\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003c/caption\\u003e\\n\\u003cthead\\u003e\\n\\u003ctr\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNO.\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eBone gene encoded\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNucleotide mutation\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAmino-acid change\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eheterogeneity\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMutation type\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInheritance\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInheritance type\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePregnancy Outcomes\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/thead\\u003e\\n\\u003ctbody\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eFGFR3\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.1015C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. Arg339Ter\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eLikely pathogenic\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDe novo\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e2\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eWNT1\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.1027G\\u0026thinsp;\\u0026gt;\\u0026thinsp;C\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. Glu343Gln\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eVUS\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePaternal\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAR\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e3\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eFGFR3\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.1144G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. Gly282Arg\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003epathogenic\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDe novo\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e4\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eFBN1\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eOBSL1\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.7842T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e\\n\\u003cp\\u003ec.2135-3_2135-2delCA\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. Ala2614Ala\\u003c/p\\u003e\\n\\u003cp\\u003ep.2135-3_2135-2delCA\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eVUS\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eBiparental\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAD\\u003c/p\\u003e\\n\\u003cp\\u003eAR\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eVaginal delivery\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e5\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eCOL1A1\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.824G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. Gly275Asp\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eVUS\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDe novo\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e6\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eIMPAD1\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.700G\\u0026thinsp;\\u0026gt;\\u0026thinsp;T CDS4-5del\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep.E234* CDS4-5 del\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehom\\u003c/p\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003epathogenic\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eBiparental\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAR\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eCesarean\\u003c/p\\u003e\\n\\u003cp\\u003eSection(death)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e7\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eFBN2\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eExon21-25del\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eExon21-25del\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eLikely Pathogenic\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDe novo\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAR\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e8\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eDYNC2H1\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eNEK1\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.2641G\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\n\\u003cp\\u003ec.859C\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. Asp881Tyr\\u003c/p\\u003e\\n\\u003cp\\u003ep. Pro287Ala\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eVUS\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eBiparental\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAR\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e9\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eCOL1A2\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.1118G\\u0026thinsp;\\u0026gt;\\u0026thinsp;C\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. Gly373Ala\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eLikely pathogenic\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMaternal\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e10\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eGORAB\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.178C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. Arg60*\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003epathogenic\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMaternal\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAR\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eCesarean section\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e11\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eN\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eCesarean section\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e12\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eFGFR3\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec. 1138 G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. Gly380Arg\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003epathogenic\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDe novo\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e13\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eN\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eVaginal delivery\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e14\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eN\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eVaginal delivery\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e15\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eCUL7\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.3355\\u0026thinsp;+\\u0026thinsp;5G\\u0026thinsp;\\u0026gt;\\u0026thinsp;A\\u003c/p\\u003e\\n\\u003cp\\u003ec.3722_3749dup\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. V1252Gfs*23\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eLikely pathogenic\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eBiparental\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAR\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e16\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eN\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eVaginal delivery\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e17\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eN\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eN\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eN\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eN\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eVaginal delivery\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e18\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eDYNC2H1\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.4072C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. Arg1358Cys\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eLikely pathogenic\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDe novo\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAR\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e19\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eN\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eCesarean section\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e20\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eFGFR3\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.2420G\\u0026thinsp;\\u0026gt;\\u0026thinsp;C\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep.*807Sext*101\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eLikely pathogenic\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDe novo\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e21\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eN\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eCesarean section\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e22\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eFGFR3\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.1948A\\u0026thinsp;\\u0026gt;\\u0026thinsp;G\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. Lys650Glu\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003epathogenic\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDe novo\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e23\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eFGFR3\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ec.742C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep. Arg248Cys\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ehet\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003epathogenic\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDe novo\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAD\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInduced labor\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e24\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eN\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eN\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tbody\\u003e\\n\\u003ctfoot\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"9\\\"\\u003e\\u0026ldquo;N\\u0026rdquo; in Table \\u003cspan class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e means negative findings in this case\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tfoot\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cp\\u003eFor the fetus of case 4 carried the c.7842T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A (p. Ala2614Ala) variant in \\u003cem\\u003eFBN1\\u003c/em\\u003e gene and the deletion of c.2135-3_2135-2delCA in \\u003cem\\u003eOBSL1\\u003c/em\\u003e gene. The Sanger sequencing analysis further revealed that the gene variant was carried by the father and the deletion was carried by the mother (\\u003cstrong\\u003eFig.\\u0026nbsp;1\\u003c/strong\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eFor the fetus of case 6, we detected the variant of c.700G\\u0026thinsp;\\u0026gt;\\u0026thinsp;T (p.E234*) and the deletion of CDS4-5 in \\u003cem\\u003eIMPAD1\\u003c/em\\u003e gene. Both Sanger sequencing and qPCR determined that the heterozygous deletion of CDS4-5 and the homozygous mutation in gene \\u003cem\\u003eIMPAD1\\u003c/em\\u003e were inherited from their parents, resulting to a composite heterozygous mutation (\\u003cstrong\\u003eFig.\\u0026nbsp;2\\u003c/strong\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003eIn the case 9 and 10, the two women were diagnosed with osteogenesis imperfecta before pregnancy. Our analysis detected the variant of c.1118G\\u0026thinsp;\\u0026gt;\\u0026thinsp;C (p. Gly373Ala) in \\u003cem\\u003eCOL1A2\\u003c/em\\u003e gene for the fetus in case 9, and variant of c.178C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T (p. Arg60*) in \\u003cem\\u003eGORAB\\u003c/em\\u003e gene for the fetus in case 10. The two variants originated from osteogenesis imperfecta and inherited from their mother (\\u003cstrong\\u003eFig.\\u0026nbsp;3, 4\\u003c/strong\\u003e).\\u003c/p\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"4. Discussion\",\"content\":\"\\u003cp\\u003eThe prenatal diagnosis of FSD is important at the second trimester of gestation, however, it is still challenging due to diverse clinical and genetic heterogeneity of the disorder. For decades, ultrasound is widely used in the noninvasive detection of FSD. Pajkrt and Chitty \\u003csup\\u003e[\\u003cspan class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]\\u003c/sup\\u003e found that FL and HL of the fetuses with skeletal dysplasia were 5% shorter than the normal value. Previous reports in China demonstrated that the diagnosis accuracy of continuous sequential follow-up ultrasound was over 80% and 87.2% in the second trimester of gestation \\u003csup\\u003e[\\u003cspan class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]\\u003c/sup\\u003e. In this study, by ultrasound scanning, we found the HL and FL of the fetuses in the 24 cases was either lower or higher than the normal value except of case 10 (the woman with OI (osteogenesis imperfecta) before pregnancy). The BPD and HC of the fetus were normal in all the 24 cases. In one-year follow-up survey, we found the 8 infants (account for 33.3%) were normal in skeletal development after delivery when the HL and FL of these fetuses was 2SD-3SD lower than the mean value. Differently, when the HL and FL of the fetuses was 3SD less or 3SD more, only two newborns (8.33%) were normal. The results of this ultrasound-only dependent approach are inadequate for diagnosing the disorder and impossible to differentiate the complex types of FSD.\\u003c/p\\u003e\\n\\u003cp\\u003eIn recent years, NGS (WES and WGS, Whole exome sequencing and Whole gene sequencing) has been applied in the area of disease diagnosis \\u003csup\\u003e[\\u003cspan class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]\\u003c/sup\\u003e. The mutation detection tool needs to optimize since the detection rates of WES could be variable depending on many factors, such as the sample size, the analysis criteria, proband-only or trio WES, and so on \\u003csup\\u003e[\\u003cspan class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]\\u003c/sup\\u003e. More importantly, the complex of genetic variants was found to be associated with the diverse pathogenicity of FSD.\\u003c/p\\u003e\\n\\u003cp\\u003eIn case 4, The fetus carried the c.7842T\\u0026thinsp;\\u0026gt;\\u0026thinsp;A (p. Ala2614Ala) variant in the \\u003cem\\u003eFBN1\\u003c/em\\u003e gene and the deletion of c.2135-3_2135-2delCA in \\u003cem\\u003eOBSL1\\u003c/em\\u003e gene. The mutation is synonymous mutation and the deletion is in the intron. The \\u003cem\\u003eFBN1\\u003c/em\\u003e gene variation \\u003csup\\u003e[\\u003cspan class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]\\u003c/sup\\u003e is reported to be associated with Weill Marchesani syndrome (clinical manifestations are short limb deformity, secondary glaucoma, short stature, etc.). The \\u003cem\\u003eOBSL1\\u003c/em\\u003e gene variation \\u003csup\\u003e[\\u003cspan class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]\\u003c/sup\\u003e is related to 3-M syndrome (clinical manifestations include severe intrauterine growth retardation, short stature, recessive spina bifida, compression deformation of long metaphysis). The inheritance patterns of Weill Marchesani syndrome and 3-M syndrome are both AR (autosomal recessive inheritance). The Sanger analysis indicated that the mutation was carried by the father and the deletion was carried by the mother (\\u003cstrong\\u003eFig.\\u0026nbsp;1\\u003c/strong\\u003e). The mother of case 4 had natural delivery by vaginal at 39\\u003csup\\u003e+\\u0026thinsp;6\\u003c/sup\\u003eweeks of gestation, and the newborn did not show any abnormality of bone development (up to 18-monthes old) at the end of the following-up survey.\\u003c/p\\u003e\\n\\u003cp\\u003eIn case 6, we detected the variant of c.700G\\u0026thinsp;\\u0026gt;\\u0026thinsp;T (p.E234*) and the deletion of CDS4-5 in \\u003cem\\u003eIMPAD1\\u003c/em\\u003e gene for the fetus. The heterozygous deletion of CDS4-5 and the homozygous variant in gene \\u003cem\\u003eIMPAD1\\u003c/em\\u003e were inherited from their parents, as a compound heterozygote mutation (Fig.\\u0026nbsp;2). \\u003cem\\u003eIMPAD1\\u003c/em\\u003e-related chondrodysplasia is an autosomal recessive disease \\u003csup\\u003e[\\u003cspan class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]\\u003c/sup\\u003e. The pregnant women had cesarean section at 38 weeks of gestation in this case, and the newborn had typical short limb deformity and died within one month after delivery.\\u003c/p\\u003e\\n\\u003cp\\u003eIn the study, there were two women (case 9 and 10) diagnosed with osteogenesis imperfecta before pregnancy. We detected the variant of c.1118G\\u0026thinsp;\\u0026gt;\\u0026thinsp;C (p. Gly373Ala) in \\u003cem\\u003eCOL1A2\\u003c/em\\u003e gene for the fetus in case 9, and found the variant of c.178C\\u0026thinsp;\\u0026gt;\\u0026thinsp;T (p. Arg60*) in \\u003cem\\u003eGORAB\\u003c/em\\u003e gene for the fetus in case 10(\\u003cstrong\\u003eFig.\\u0026nbsp;3, 4\\u003c/strong\\u003e). The two variants related to osteogenesis imperfecta and inherited from their mother, but one genetic type is autosomal dominant (AD) \\u003csup\\u003e[\\u003cspan class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e]\\u003c/sup\\u003e and the other is autosomal recessive (AR) \\u003csup\\u003e[\\u003cspan class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]\\u003c/sup\\u003e. The fetus of case 9 died before delivery at 35 weeks of gestation, while the newborn of case 10 had no significant abnormality in bone development up to 2-years old in the following-up survey.\\u003c/p\\u003e\\n\\u003cp\\u003eIn the case 2, 5 and 8, we found the \\u003cem\\u003eWNT1\\u003c/em\\u003eor \\u003cem\\u003eCOL1A1\\u003c/em\\u003e-related VUS in osteogenesis imperfecta, and \\u003cem\\u003eDYNC2H1\\u003c/em\\u003e and \\u003cem\\u003eNEK1\\u003c/em\\u003e-related asphyxiative hypoplasia of thorax. Notably, the fetuses in these cases all had short lower limbs, which was determined after abortion, while the proteins encoded by the gene variants were predicted to be deleterious using the SIFT and Polyphen analysis. Our assumption includes: (1) the limited data depth which failed to achieve 100% coverage of the exon sequences, resulting in the related pathogenic gene variants was dismissed; (2) the unknown gene variation outside the exons, including non-coding region and intron mutation, possibly responsible for the pathogenicity; (3) other environmental factors that have not been found. Furthermore, we had negative findings by WES, and the 8 infants were normal in skeletal development after delivery in the rest 8 cases.\\u003c/p\\u003e\"},{\"header\":\"5. Conclusions\",\"content\":\"\\u003cp\\u003eIn sum, skeletal dysplasia is mostly hereditary. Our study has obtained 14/24 (58.3%) cases carrying 12 different skeletal dysplasia genotypes, which will broaden the spectrum of FSD in Chinese patients. Genetic diagnosis combining with ultrasound scanning enhances the accurate diagnosis of FSD in utero, then can provide appropriate genetic counseling.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eFSD:\\u003c/strong\\u003e fetal skeletal dysplasia\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFGFR3: \\u003c/strong\\u003efibroblast growth factor receptor3\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFBN1:\\u003c/strong\\u003e Fibrillin-1\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFBN2:\\u003c/strong\\u003e Fibrillin-2\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCOL1A1:\\u003c/strong\\u003e collagen type I alpha 1 Chain\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCOL1A2: \\u003c/strong\\u003ecollagen type I alpha 2 Chain\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCUL7:\\u003c/strong\\u003e cullin-7\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eDYNC2H1:\\u003c/strong\\u003e Dynein Cytoplasmic 2 Heavy Chain 1\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eIMPAD1:\\u003c/strong\\u003e Inositol Monophosphatase Domain containing 1\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eWNT1:\\u003c/strong\\u003e Wnt Family Member 1\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eGORAB:\\u003c/strong\\u003e Golgi-associated Rab-binding protein\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eOBSL1:\\u003c/strong\\u003e Obscurin Like Cytoskeletal Adaptor 1\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eNEK1:\\u003c/strong\\u003e NIMA (Never-in-mitosis A)-related kinase 1\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eVUS:\\u003c/strong\\u003e variant of undetermined significance\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eWES:\\u003c/strong\\u003e whole exome sequencing\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eWGS:\\u003c/strong\\u003e whole gene sequencing\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eNIPT:\\u003c/strong\\u003e non-invasive prenatal test\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eBPD: \\u003c/strong\\u003ebiparietal diameter\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eHC: \\u003c/strong\\u003ehead circumference\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eHL: \\u003c/strong\\u003ehumerus length\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFL: \\u003c/strong\\u003efemur length\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eNT: \\u003c/strong\\u003enuchal translucency\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCNV: \\u003c/strong\\u003ecopy number variations\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eOI:\\u003c/strong\\u003e osteogenesis imperfecta\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eNGS:\\u003c/strong\\u003e next-generation sequencing\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAR:\\u003c/strong\\u003e autosomal recessive inheritance\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAD:\\u003c/strong\\u003e autosomal dominant inheritance\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study was approved by the Research Ethics Committee of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. The parents provided a signed informed consent prior to intrauterine diagnosis and sample collection in our country.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and material\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll data analyzed in our study are available upon reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll authors declare that they have no conflict of interest.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was supported by The National Key Research and Development Program of China(2018YFC1002904).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe thank all the subjects who participated in this study.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthors\\u0026apos; contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eXinwei Shi was responsible for the conceptualization of the review and literature Search. Jing Cao, Yuqi Li and Fuyuan Qiao provided the included case studies. Wanlu Liu and Yuanyuan Wu were major contributors to the drafting of the manuscript. All authors read and approved the final manuscript.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eLiu Y, Wang L, Yang YK, et al. Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases. Diagn Pathol. 2019;14(1):76\\u0026ndash;89.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKrakow D, Rimoin DL. The skeletal dysplasias. Genet Med. 2010;12(1):327\\u0026ndash;41.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFranzone JM, Shah SA, Wallace MJ, Kruse RW. Osteogenesis Imperfecta: A Pediatric Orthopedic Perspective. Orthop Clin North Am. 2019;50(2):193\\u0026ndash;209.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eXu Y, Li L, Wang C, et al. Clinical and Molecular Characterization and Discovery of Novel Genetic Mutations of Chinese Patients with COL2A1-related Dysplasia. Int J Biol Sci. 2020;16(5):859\\u0026ndash;68.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eZheng C, Lin X, Xu X, et al. Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias. EBio Med. 2019;40(2):695\\u0026ndash;709.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eCao YJ, Zhang H, Zhang ZL. Novel mutations in the WNT1, TMEM38B, P4HB, and PLS3 genes in four unrelated chinese families with osteogenesis imperfecta. Endocr Pract. 2019;25(3):230\\u0026ndash;41.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMortier GR, Cohn DH, Cormier-Daire V, et al. Nosology and classification of genetic skeletal disorders: 2019 revision. Am J Med Genet Part A. 2019;179:2393\\u0026ndash;419.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKai Yang M, Shen Y. Yan, et al. Genetic Analysis in Fetal Skeletal Dysplasias by Trio Whole-Exome Sequencing. Biomed Res Int. 2019;3(10):1155\\u0026ndash;64.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFu F, Li R, Li Y, et al. Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities. Ultrasound in Obstetrics \\u0026amp; Gynecology. 2018;51(4):493\\u0026ndash;502.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eChandler N, Best S, Hayward J, et al. Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management. Genet Med. 2018;20(11):1430\\u0026ndash;7.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePajkrt E, Chitty LS. A sonographic approach to the prenatal diagnosis of skeletal dysplasias. Prenat Diagn. 2019;39(9):701\\u0026ndash;19.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWang L, Takai Y, Baba K, et al. Can biparietal diameter-to-femur length ratio be a useful sonographic marker for screening thanatophoric dysplasia since the first trimester? A literature review of case reports and a retrospective study based on 10,293 routine fetal biometry measurements. Taiwan J Obstet Gynecol. 2017;56(3):374\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHan J, Yang YD, He Y, et al. Rapid prenatal diagnosis of skeletal dysplasia using medical trio exome sequencing: benefit for prenatal counseling and pregnancy management. Prenat Diagn. 2020;40(5):577\\u0026ndash;84.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNewell K, Smith W, Ghoshhajra B, et al. Cervical artery dissection expands the cardiovascular phenotype in FBN1-related Weill-Marchesani syndrome. Am J Med Genet A. 2017;173(9):2551\\u0026ndash;6.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eIsik E, Arican D, Atik T, et al. A rare cause of syndromic short stature: 3M syndrome in three families. Am J Med Genet A. 2021;185(2):461\\u0026ndash;8.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRosario M, Venselaar H, Knoll U, et al. Chondrodysplasia and abnormal joint development associated with mutations in IMPAD1, encoding the Golgi-resident nucleotide phosphatase, gPAPP. Am J Hum Genet. 2011;88(5):608\\u0026ndash;15.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAugusciak-Duma A, Witecka J, Sieron AL. J et al. \\u003cem\\u003eMutations\\u003c/em\\u003e in the COL1A1 and COL1A2 genes associated with osteogenesis imperfecta (OI) types I or III. Acta Biochim Pol. 2018;65(1):79\\u0026ndash;86.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eYang H, Albiol L, Chan WL, et al. Examining tissue composition, whole-bone morphology and mechanical behavior of Gorab \\u003csup\\u003ePrx1\\u003c/sup\\u003e mice tibiae: A mouse model of premature aging. J Biomech. 2017;65(10):145\\u0026ndash;53.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":true,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"orphanet-journal-of-rare-diseases\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"ojrd\",\"sideBox\":\"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/ojrd/default.aspx\",\"title\":\"Orphanet Journal of Rare Diseases\",\"twitterHandle\":\"@bmc\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC/SO AJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"fetal skeletal dysplasia, genetic testing, prenatal diagnosis, ultrasound scanning\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-2181067/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-2181067/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eFetal skeletal dysplasia (FSD) is a diverse group of degenerative diseases of bone and cartilage disorders that can lead to movement disorder and even death. This study aims to deliver prenatal diagnosis through sonographic examination and genetic testing.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eFrom September 2015 to April 2021, the study investigated 24 cases with suspected short-limb fetuses, which were obtained from Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. To identify the causative gene, multiple approaches (including karyotype analysis, copy number variations and whole exome sequencing) were performed on these fetuses. And further segregation analysis of the candidate variant was performed in parents by using Sanger sequencing.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003e \\u003cb\\u003e①\\u003c/b\\u003e Out of 24 cases, likely pathogenic gene variants in \\u003cem\\u003eFGFR3, FBN2, COL1A2, CUL7\\u003c/em\\u003e and \\u003cem\\u003eDYNC2H1\\u003c/em\\u003e were detected for 6 cases; genetic variants in \\u003cem\\u003eFGFR3, IMPAD1\\u003c/em\\u003e and \\u003cem\\u003eGORAB\\u003c/em\\u003e as possibly lethal mutations were identified in other 6 cases; and gene variants in \\u003cem\\u003eWNT1, FBN1, OBSL1, COL1A1, DYNC2H1\\u003c/em\\u003e and \\u003cem\\u003eNEK1\\u003c/em\\u003e, known as Variant of Undetermined Significance (VUS), were found in 4 cases. The rest 8 cases showed undetectable mutation in the whole exome sequencing (WES) analysis. ②A genetic diagnosis determined 12 different skeletal dysplasia genotypes in 14/24 (58.3%) cases. The other 10 cases with wild type gene (41.7%) were normal and well developed in one-year follow-up survey after study.\\u003c/p\\u003e\\u003ch2\\u003eConclusion\\u003c/h2\\u003e \\u003cp\\u003eGenetic testing combining with ultrasound scanning enhances the accurate diagnosis of fatal skeletal dysplasia in utero, and then provides appropriate genetic counseling.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Genetic testing and diagnostic strategies of fetal skeletal dysplasia: a preliminary study in Wu Han, China ​\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2022-11-10 17:47:00\",\"doi\":\"10.21203/rs.3.rs-2181067/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"reviewerAgreed\",\"content\":\"\",\"date\":\"2023-06-01T15:28:02+00:00\",\"index\":0,\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2022-11-08T09:35:17+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2022-11-04T07:40:32+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Orphanet Journal of Rare Diseases\",\"date\":\"2022-10-31T04:57:35+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"orphanet-journal-of-rare-diseases\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"ojrd\",\"sideBox\":\"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://www.editorialmanager.com/ojrd/default.aspx\",\"title\":\"Orphanet Journal of Rare Diseases\",\"twitterHandle\":\"@bmc\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"BMC/SO AJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"acf272a4-3614-4f3c-807a-3d99884aec1e\",\"owner\":[],\"postedDate\":\"November 10th, 2022\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2023-10-30T15:08:46+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-2181067\",\"link\":\"https://doi.org/10.1186/s13023-023-02955-4\",\"journal\":{\"identity\":\"orphanet-journal-of-rare-diseases\",\"isVorOnly\":false,\"title\":\"Orphanet Journal of Rare Diseases\"},\"publishedOn\":\"2023-10-25 15:02:38\",\"publishedOnDateReadable\":\"October 25th, 2023\"},\"versionCreatedAt\":\"2022-11-10 17:47:00\",\"video\":\"\",\"vorDoi\":\"10.1186/s13023-023-02955-4\",\"vorDoiUrl\":\"https://doi.org/10.1186/s13023-023-02955-4\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-2181067\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-2181067\",\"identity\":\"rs-2181067\",\"version\":[\"v1\"]},\"buildId\":\"rHA-KDH7Qsr4HCuvH75dn\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}