Expanding the phenotypic spectrum of Rauch-Steindl syndrome: A novel NSD2 variant with atrial septal defect in a Chinese patient

Expanding the phenotypic spectrum of Rauch-Steindl syndrome: A novel NSD2 variant with atrial septal defect in a Chinese patient | 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 Case Report Expanding the phenotypic spectrum of Rauch-Steindl syndrome: A novel NSD2 variant with atrial septal defect in a Chinese patient Hui Zhu, Min Du, Lan Zeng, Shuyao Zhu, Jinlin Liu, Jin Wang, Ping Zhou, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7605765/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Jan, 2026 Read the published version in BMC Neurology → Version 1 posted 10 You are reading this latest preprint version Abstract Background Rauch-Steindl syndrome (RSS) is a very rare autosomal dominant disorder caused by pathogenic variants in the NSD2 gene, characterized by dysmorphic facial features, prenatal and postnatal growth retardation, and variable developmental delay. Case presentation : We report the case of a 16-month-old Han Chinese girl who presented with typical features of RSS, including prenatal and postnatal growth failure, low body mass index, global developmental delay, expressive language impairment, infantile feeding difficulties, and distinctive dysmorphic facies (triangular face, broad forehead, high anterior hairline, deep-set eyes, full cheeks, thin and high nasal bridge, thick lower lip vermilion). She also exhibited mildly increased muscular tone in the lower limbs, transient recurrent respiratory infections, and a persistent atrial septal defect (ASD). Whole-exome sequencing identified a novel de novo heterozygous nonsense variant (NM_001042424.3: c.1466C > G, p.Ser489Ter) in exon 6 of the NSD2 gene on chromosome 4, which was classified as pathogenic according to ACMG guidelines. Notably, the patient exhibited an ASD that persisted through follow-up beyond 31 months of age—a feature not previously documented in RSS. Conclusions This case report expands both the phenotypic and genotypic spectrum of NSD2 -associated RSS. Rauch-Steindl syndrome NSD2 growth restriction developmental delay facial gestalt case report Figures Figure 1 Figure 2 Background Rauch–Steindl syndrome (RSS; OMIM #619695) is an extremely rare autosomal dominant genetic disorder caused by heterozygous pathogenic variants in the Nuclear receptor-binding Set Domain-protein 2 ( NSD2 ) gene located at chromosome 4p16.3 [ 1 ]. Its main features comprise dysmorphic facial features, intrauterine growth retardation with all body measurements below the mean, feeding difficulties, mild developmental delay (DD), speech delay, and muscular hypotonia [ 1 ]. The phenotype of the RSS resembles that of mild Wolf-Hirschhorn syndrome (WHS; #194190) and exhibits incomplete penetrance. WHS is a contiguous gene deletion syndrome caused by a heterozygous deletion of multiple genes in the chromosomal region 4p16.3. Recently, molecular cytogenetics studies have identified two genes within the WHS critical region (WHSCR) whose loss-of-function (LoF) variants are associated with a clinical presentation resembling atypical or partial WHS: WHSC1 (also known as NSD2 ), which is only partially located within the WHSCR [ 2 ],, and WHSC2 (also known as Negative Elongation Factor Complex Member A, NELFA ), which lies entirely within this region [ 3 ]. Furthermore, LoF of NSD2 gene has been associated with a distinct phenotype that only partially overlaps with WHS and constitutes a differential diagnosis for WHS [ 1 ]. In this study, we provide a detailed clinical characterization of a Han Chinese girl with RSS caused by a novel de novo heterozygous pathogenic variant (c.1466C > G: p.Ser489Ter) in the NSD2 gene. Our patient exhibited not only the core clinical manifestations of RSS but also an atrial septal defect (ASD) that persisted beyond 31 months of age—a feature not previously documented in this syndrome. Thus, our patient expands both the phenotypic and genotypic spectrum of NSD2 -associated RSS. Case presentation The proband was a 16-month-old Chinese Han girl referred to the pediatric neurology clinic in June 2024 for DD and growth retardation. During the third trimester, a fetal ultrasound at an outside hospital revealed intrauterine growth restriction (IUGR). She was delivered spontaneously at 39 weeks of gestation. Her anthropometric measurements at birth were as follows: weight 1.96 kg (-2.48 SD), length 45 cm (-2.28 SD), and head circumference 31.8 cm (-2.08 SD). The delivery was uneventful. Apgar scores were normal, and there was no history of perinatal asphyxia or need for resuscitation. Her parents are non-consanguineous and both healthy. At the time of their daughter's birth, the mother and father were 26 and 28 years old, respectively. There was no family history of psychomotor retardation or failure to thrive. This was the first pregnancy for the mother, and the couple has no other children. There was no known prenatal exposure to alcohol, recreational drugs, or teratogens. The patient experienced significant feeding difficulties during the first year of life, which improved after 12 months of age. At 5 months she achieved head control, by 9 months sat independently, and at 16 months stood with support and belly-crawled, but had not yet produced meaningful syllables. Physical examination at 16 months revealed the following anthropometric measurements: weight 6.55 kg (-2.86 SD), height 74 cm (-1.63 SD), and head circumference 42.1 cm (-2.62 SD). She had normal eye contact, exhibited context-appropriate emotional responses, recognized familiar people, and used nonverbal cues to communicate basic needs such as hunger, the need to toilet, and dislike. Dysmorphic facial features: triangular face, broad forehead, high anterior hairline, deep-set eyes, full cheeks, thin and high nasal bridge, thick lower lip vermilion. Normal muscle strength in all extremities, slightly increased muscle tone in bilateral lower limbs. By 16 months of age, she had already experienced six episodes of bronchopneumonia and four upper respiratory tract infections. She exhibited neither seizures nor sleep dysfunction, and shows no dysmorphic features—including the "Greek helmet" aspect, cleft lip/palate, coloboma—or visceral (genital and renal), midline, or skeletal anomalies. Hearing, visual acuity, and funduscopic examinations were all normal. At 17 months, a Gesell Development Scale assessment revealed a developmental age of 9.5 months and a developmental quotient (DQ) of 53, consistent with moderate global developmental delay (GDD). The subdomain scores were as follows: gross motor (DQ = 56), fine motor (DQ = 45), adaptive behavior (DQ = 56), language (DQ = 47), and social behavior (DQ = 61). Color Doppler echocardiography revealed an ASD (4.1 mm), trace tricuspid regurgitation, and left ventricular systolic function within the normal range (Fig. 1 ). All laboratory investigations, including complete blood count, serum biochemical profile, serum ammonia, serum lactate, serum ceruloplasmin, blood and urine metabolic screening, serum growth hormone level, and immune function studies (comprising quantitative serum immunoglobulins, lymphocyte subset analysis, and complement system assessment), were within normal limits. Electroencephalogram (EEG) and brain magnetic resonance imaging findings were unremarkable. Given the patient's history of IUGR presenting in the late trimester, birth as a term small-for-gestational-age (SGA) infant with microcephaly, and subsequent postnatal GDD with failure to thrive, a congenital genetic etiology is highly suspected. Therefore, trio-based whole-exome sequencing (Trio-WES) was performed on the proband and her parents using blood-derived DNA to investigate potential genetic etiologies. WES and Sanger sequencing Library preparation was performed using a customized Twist Bioscience OmniSeek® Whole Exome Capture Kit, followed by high-throughput sequencing with a paired-end 150 bp (PE150) read length. The data analysis pipeline was conducted as follows: for the nuclear genome, raw sequencing data underwent quality control (QC) using fastp (v0.23.1); filtered reads were aligned to the reference genome GRCh38/hg38 with BWA (v0.7.17); duplicate reads were marked using GATK (v4.2.4.0); single nucleotide variants (SNVs) and insertions/deletions (InDels) were called with GATK (v4.2.4.0); copy number variations (CNVs) were detected using XHMM (v1.0) and CNVkit (v0.9.9); and variant annotation was performed using Annovar (2022.6.8) and VEP (v105). For the mitochondrial genome, raw data were processed with fastp (v0.23.1) for QC and removal of low-quality reads; clean reads were aligned to the mitochondrial reference genome NC_012920.1 using BWA (v0.7.17); SNVs and InDels were identified using GATK (v4.2.4.0); and detected variants were annotated with VEP (v105.0), incorporating information from specialized databases including Mitomap, MitImpact, and ClinVar. The proband achieved 189.25× mean depth with 99.42% of targets covered ≥ 20×; samples of her father and mother showed 181.42× and 177.78× average depths, covering 99.64% and 99.39% at ≥ 20×, respectively. WES identified a nonsense variant (NM_001042424.3: c.1466C > G, p.Ser489Ter) in exon 6 of the NSD2 gene on chromosome 4 (chr4: 1930681). Sanger sequencing confirmed that this pathogenic variant occurred de novo in the proband, as both parents exhibited wild-type genotypes (Fig. 2 ). According to the American College of Medical Genetics and Genomics (ACMG) guidelines [ 4 ], this variant was classified as pathogenic based on the following criteria: PVS1, PM2_Supporting, and PS2_Supporting. Specifically, PVS1 was applied given the variant (c.1466C > G) is a nonsense mutation inducing LoF, a known disease mechanism for NSD2 -related disorders, and occurs in exon 6/22 of a relevant transcript. PS2_Supporting was assigned based on confirmed de novo origin via parental testing (though potential mosaicism cannot be fully excluded). PM2_Supporting was invoked due to the variant's absence in gnomAD exome and genome cohorts. Furthermore, a candidate variant in the TAP2 gene (NM_001290043.2: Exon4: c.628C > T, p.Arg210Ter) was identified. However, it was excluded as pathogenic due to a combination of the proband's incompatible clinical phenotype and a segregation pattern inconsistent with autosomal recessive inheritance (heterozygous in proband and mother, absent in father). Based on the clinical presentation and genetic sequencing results, the patient met the diagnostic criteria for NSD2 -related RSS. Treatment and follow up The patient's primary management consisted of regular rehabilitation training. Follow-up echocardiography was performed at 6-month intervals. The most recent examination at 31 months of age showed a persistent ASD of approximately 4 mm, which was unchanged from the previous measurement at 16 months of age. Follow-up showed that she achieved independent walking at 20 months and was able to run and jump by 22 months. By the age of 2 years, she could spontaneously produce simple two- to four-word phrases, such as “mama”, “baba”, “don't like”, “I'm hungry”, and “I need to pee”. Her receptive language skills exceeded her expressive abilities; she could understand daily instructions but often relied on gestures to communicate due to limited verbal expression. Her history of recurrent respiratory infections resolved spontaneously after the age of 2. At the last follow-up (31 months of age), her expressive language had improved further to short phrases of 3–5 words. Anthropometric measurements were as follows: height 84 cm (-2.3 SD), weight 8.3 kg (-4.2 SD), head circumference 45.5 cm (-2.1 SD), and body mass index (BMI) 11.7 kg/m² (-5.8 SD). A subsequent Gesell Developmental Scale assessment revealed an overall developmental age of 22.4 months and a DQ of 68, consistent with mild GDD. The subscale scores were as follows: gross motor (DQ = 68), fine motor (DQ = 89), adaptive behavior (DQ = 70), language (DQ = 70), and personal-social (DQ = 67). Discussion The NSD2 gene is located at 4p16.3, comprises 22 exons, and encodes a protein of 1,365 amino acids. This gene product contains four domains commonly found in other developmental proteins: a PWWP domain, an HMG box, a SET domain, and a PHD-type zinc finger, all of which are ubiquitously involved in early development. The gene is situated within the 165 kb critical region of WHS and is involved in chromosomal translocations associated with multiple myeloma. Recent studies have established that pathogenic variants in the NSD2 gene cause a syndrome characterized by mild clinical features that partially overlap with those of WHS, now defined as RSS. Research on NSD2 -related RSS remains limited. To date, only 41 individuals have been reported in the literature [ 1 , 5 – 9 ], the majority as individual case reports, with only one larger cohort study comprising 18 patients [ 1 ]. Therefore, detailed clinical documentation of each new case provides unique value and contributes meaningfully to future research. Herein, we describe a detailed clinical characterization and genotype of a Han Chinese girl with RSS caused by a novel de novo heterozygous pathogenic variant in the NSD2 gene (c.1466C > G; p.Ser489Ter). She presented with a spectrum of clinical features, including prenatal and postnatal growth failure, low BMI, variable GDD, expressive language impairment, feeding difficulties during infancy, and distinctive dysmorphic facial features (triangular face, broad forehead, deep-set eyes, periorbital hyperpigmentation). These manifestations are consistent with previously reported cases of RSS [ 1 ]. NSD2 regulates embryonic development and physical growth, and defects in this gene can lead to growth retardation[ 10 ]. Our patient and some previously reported cases exhibited feeding difficulties during the neonatal period. Studies suggest that NSD2 deficiency may contribute to low BMI due to an inability of body fat to expand during feeding, rather than being a direct consequence of neonatal feeding difficulties [ 1 ]. Although observed in multiple affected individuals, feeding difficulties do not persist in later stages of life. Additionally, she exhibited several features rarely or never previously reported in RSS cases, including mildly increased muscle tone in both lower limbs, transient recurrent respiratory infections, and a persistent ASD. During follow-up, the patient exhibited continuous neurodevelopmental improvement. Her Gesell Developmental Scale score improved from moderate to mild GDD. Despite this classification, clinical assessment identified expressive language delay as the most significant current impairment. Nonverbal cognitive and adaptive behaviors suggested no intellectual disability; however, formal intellectual assessment was not feasible at this young age and requires continued follow-up. NSD2 functions as a histone methyltransferase that catalyzes the methylation of histone H3 at lysine 36 (H3K36). Given the crucial role of histone modification in neurodevelopment, this explains why carriers of NSD2 variants often present with DD [ 1 ]. Mildly increased muscular tone in the bilateral lower limbs was observed in the patient. To our knowledge, only one previous case has reported a similar finding in RSS. However, unlike our case — which consistently presented with hypertonia — the previously reported patient exhibited fluctuating muscle tone, with documented periods of both hypotonia and hypertonia. All other reported cases have consistently described hypotonia. She had a history of recurrent, non-severe respiratory tract infections, which were self-limiting and showed spontaneous resolution after two years of age. All immunological investigations yielded normal results. A candidate variant in the TAP2 gene (NM_001290043.2: Exon4: c.628C > T, p.Arg210Ter), classified as likely pathogenic for MHC class I deficiency type 2, was identified by WES (heterozygous in the proband and her mother, wild-type in the father). However, this variant was excluded as the disease-causing mutation in this case due to both the inconsistent segregation pattern and the significant phenotypic discrepancy. MHC class I deficiency type 2 is an autosomal recessive immunodeficiency disorder characterized by severe, life-threatening, or chronic debilitating infections — features inconsistent with the patient’s mild and self-resolving infectious history, as well as her normal immunological parameters [ 11 ]. Recurrent respiratory infections have been reported only in a minority of previously described RSS cases, and detailed clinical characterization of this feature is lacking. Her ASD (approximately 4 mm in size) persisted. To our knowledge, this represents the first reported case of a definitive ASD in RSS. Cardiac anomalies are rarely documented in RSS, with only two previously reported cases: one describing an unspecified cardiac malformation[ 1 ] and the other noting mitral valve prolapse [ 5 ]. The small ASD in our patient is unlikely to account for her recurrent respiratory infections. No intervention is currently indicated, and continued clinical surveillance is recommended. The patient did not exhibit several typical features of WHS, such as seizures (no abnormalities were observed on EEG) or the "Greek warrior helmet" facial appearance (characterized by a high forehead, broad and depressed nasal bridge, short philtrum, highly arched eyebrows, hypertelorism, and micrognathia). Based on her clinical manifestations and genetic findings, a definitive diagnosis of RSS was established. Currently, there is no specific treatment for this disorder, and management primarily relies on rehabilitative training. Given the limited number of reported cases, the molecular mechanisms, pathogenic pathways, and therapeutic strategies for RSS remain to be elucidated. Conclusion In summary, we report a Han Chinese girl with RSS caused by a novel de novo heterozygous pathogenic variant (c.1466C > G: p.Ser489Ter) in NSD2 gene. In addition to exhibiting the core clinical features consistent with previously reported cases of RSS, she also demonstrates ASD, a feature that has not been documented in prior cases. Therefore, our patient expands both the phenotypic and genotypic spectrum of NSD2 -associated RSS. Abbreviations RSS Rauch–Steindl syndrome NSD2 Nuclear receptor-binding Set Domain-protein 2 DD Developmental delay WHS Wolf-Hirschhorn syndrome WHSCR WHS critical region LoF Loss-of-function NELFA Negative Elongation Factor Complex Member A ASD Atrial septal defect IUGR Intrauterine growth restriction DQ Developmental quotient GDD Global developmental delay EEG Electroencephalogram SGA Small-for-gestational-age Trio-WES Trio-based whole-exome sequencing PE150 Paired-end 150 bp QC Quality control SNVs Single nucleotide variants InDels Insertions/deletions CNVs copy number variations ACMG American College of Medical Genetics and Genomics Declarations Acknowledgments We are grateful to the child and the families for their contributions to this work. Authors ’ contributions HZ designed this study, collected and integrated data, and wrote the article. MD, LZ, SZ, JL, and JW integrated data and interpreted gene reports. PZ and ZL revised the article. All authors read and approved the final manuscript. Funding This study is supported by a grant from the Natural Science Foundation of Sichuan Province (No. 2022NSFSC0784). Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Availability of data and materials The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors. Our pathogenic variant data has been deposited into the ClinVar bank: https://www.ncbi.nlm.nih.gov/clinvar/SUB15653616/. And the accession number: SCV006333412. Declarations Ethics approval and consent to participate This study was reviewed and approved by the hospital’s medical ethics committee of Sichuan Provincial Women’s and Children’s Hospital. Approval Code: 20230807-219. The Approval Date: 10 August 2023. Written informed consent from parents of all participants, and the ethics committee approved this procedure. The study adhered to the Declaration of Helsinki. Consent for publication Written informed consent was obtained from the patient’s parents for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Competing interests The authors declare no competing interests. References Zanoni P, Steindl K, Sengupta D, Joset P, Bahr A, Sticht H, Lang-Muritano M, van Ravenswaaij-Arts CMA, Shinawi M, Andrews M et al : Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype . Genet Med 2021, 23 (8):1474-1483. Derar N, Al-Hassnan ZN, Al-Owain M, Monies D, Abouelhoda M, Meyer BF, Moghrabi N, Alkuraya FS: De novo truncating variants in WHSC1 recapitulate the Wolf-Hirschhorn (4p16.3 microdeletion) syndrome phenotype . Genet Med 2019, 21 (1):185-188. Cyr AB, Nimmakayalu M, Longmuir SQ, Patil SR, Keppler-Noreuil KM, Shchelochkov OA: A novel 4p16.3 microduplication distal to WHSC1 and WHSC2 characterized by oligonucleotide array with new phenotypic features . Am J Med Genet A 2011, 155A (9):2224-2228. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E et al : Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology . Genetics in Medicine 2015, 17 (5):405-424. Wiel LC, Bruno I, Barbi E, Sirchia F: From Wolf-Hirschhorn syndrome to NSD2 haploinsufficiency: a shifting paradigm through the description of a new case and a review of the literature . Ital J Pediatr 2022, 48 (1):72. Popp B, Brugger M, Poschmann S, Bartolomaeus T, Radtke M, Hentschel J, Di Donato N, Rump A, Gburek-Augustat J, Graf E et al : The constitutional gain-of-function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome . Clin Genet 2023, 103 (2):226-230. Popp B, Brugger M, Poschmann S, Bartolomaeus T, Radtke M, Hentschel J, Di Donato N, Rump A, Gburek-Augustat J, Graf E et al : 2022. Nishi E, Yanagi K, Kaname T, Okamoto N: Clinical details of individuals with Rauch-Steindl syndrome due to NSD2 truncating variants . Mol Genet Genomic Med 2024, 12 (2):e2396. Yang Q, Gong D, Yi S, Luo J, Zhang Q: Case report: A de novo NSD2 truncating variant in a child with Rauch-Steindl syndrome . Front Pediatr 2023, 11 :1064783. Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz RJ, Kaneda Y: A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome . Nature 2009, 460 (7252):287-291. Darazam IA, Shahrooei M, Hakamifard A, Olyaei NA, Zerehpoosh FB, Gharehbagh FJ, Hatami F, Lotfollahi L, Mansouri N, Casanova J-L et al : 2022. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 27 Jan, 2026 Read the published version in BMC Neurology → Version 1 posted Editorial decision: Revision requested 17 Dec, 2025 Reviews received at journal 13 Dec, 2025 Reviews received at journal 12 Dec, 2025 Reviewers agreed at journal 29 Nov, 2025 Reviewers agreed at journal 24 Nov, 2025 Reviewers invited by journal 24 Nov, 2025 Editor invited by journal 06 Nov, 2025 Editor assigned by journal 14 Oct, 2025 Submission checks completed at journal 27 Sep, 2025 First submitted to journal 27 Sep, 2025 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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1","display":"","copyAsset":false,"role":"figure","size":105946,"visible":true,"origin":"","legend":"\u003cp\u003eColor Doppler echocardiography revealed an ASD (4.1 mm), trace tricuspid regurgitation, and left ventricular systolic function within the normal range.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7605765/v1/4638b736677968917042b0e7.png"},{"id":97122102,"identity":"e34f54c4-79f7-4e83-a29c-4032df467be2","added_by":"auto","created_at":"2025-12-01 07:55:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":157276,"visible":true,"origin":"","legend":"\u003cp\u003eSanger sequencing chromatograms of the NSD2 variant. The proband carries a heterozygous pathogenic variant c.1466C\u0026gt;G (p.Ser489Ter) in exon 6. This variant was not detected in either parent, confirming its \u003cem\u003ede novo\u003c/em\u003e origin.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7605765/v1/d03bc323ca4e8710120201e2.png"},{"id":101692019,"identity":"dec3339e-6fee-4848-8054-981ef5e1a5b3","added_by":"auto","created_at":"2026-02-02 16:16:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1160429,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7605765/v1/fab71f14-b0ca-4d82-b3ea-930691bc7128.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Expanding the phenotypic spectrum of Rauch-Steindl syndrome: A novel NSD2 variant with atrial septal defect in a Chinese patient","fulltext":[{"header":"Background","content":"\u003cp\u003eRauch\u0026ndash;Steindl syndrome (RSS; OMIM #619695) is an extremely rare autosomal dominant genetic disorder caused by heterozygous pathogenic variants in the Nuclear receptor-binding Set Domain-protein 2 (\u003cem\u003eNSD2\u003c/em\u003e) gene located at chromosome 4p16.3 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Its main features comprise dysmorphic facial features, intrauterine growth retardation with all body measurements below the mean, feeding difficulties, mild developmental delay (DD), speech delay, and muscular hypotonia [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The phenotype of the RSS resembles that of mild Wolf-Hirschhorn syndrome (WHS; #194190) and exhibits incomplete penetrance. WHS is a contiguous gene deletion syndrome caused by a heterozygous deletion of multiple genes in the chromosomal region 4p16.3. Recently, molecular cytogenetics studies have identified two genes within the WHS critical region (WHSCR) whose loss-of-function (LoF) variants are associated with a clinical presentation resembling atypical or partial WHS: WHSC1 (also known as \u003cem\u003eNSD2\u003c/em\u003e), which is only partially located within the WHSCR [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e],, and WHSC2 (also known as Negative Elongation Factor Complex Member A, \u003cem\u003eNELFA\u003c/em\u003e), which lies entirely within this region [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Furthermore, LoF of \u003cem\u003eNSD2\u003c/em\u003e gene has been associated with a distinct phenotype that only partially overlaps with WHS and constitutes a differential diagnosis for WHS [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this study, we provide a detailed clinical characterization of a Han Chinese girl with RSS caused by a novel \u003cem\u003ede novo\u003c/em\u003e heterozygous pathogenic variant (c.1466C\u0026thinsp;\u0026gt;\u0026thinsp;G: p.Ser489Ter) in the \u003cem\u003eNSD2\u003c/em\u003e gene. Our patient exhibited not only the core clinical manifestations of RSS but also an atrial septal defect (ASD) that persisted beyond 31 months of age\u0026mdash;a feature not previously documented in this syndrome. Thus, our patient expands both the phenotypic and genotypic spectrum of \u003cem\u003eNSD2\u003c/em\u003e-associated RSS.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eThe proband was a 16-month-old Chinese Han girl referred to the pediatric neurology clinic in June 2024 for DD and growth retardation. During the third trimester, a fetal ultrasound at an outside hospital revealed intrauterine growth restriction (IUGR). She was delivered spontaneously at 39 weeks of gestation. Her anthropometric measurements at birth were as follows: weight 1.96 kg (-2.48 SD), length 45 cm (-2.28 SD), and head circumference 31.8 cm (-2.08 SD). The delivery was uneventful. Apgar scores were normal, and there was no history of perinatal asphyxia or need for resuscitation. Her parents are non-consanguineous and both healthy. At the time of their daughter's birth, the mother and father were 26 and 28 years old, respectively. There was no family history of psychomotor retardation or failure to thrive. This was the first pregnancy for the mother, and the couple has no other children. There was no known prenatal exposure to alcohol, recreational drugs, or teratogens. The patient experienced significant feeding difficulties during the first year of life, which improved after 12 months of age. At 5 months she achieved head control, by 9 months sat independently, and at 16 months stood with support and belly-crawled, but had not yet produced meaningful syllables. Physical examination at 16 months revealed the following anthropometric measurements: weight 6.55 kg (-2.86 SD), height 74 cm (-1.63 SD), and head circumference 42.1 cm (-2.62 SD). She had normal eye contact, exhibited context-appropriate emotional responses, recognized familiar people, and used nonverbal cues to communicate basic needs such as hunger, the need to toilet, and dislike. Dysmorphic facial features: triangular face, broad forehead, high anterior hairline, deep-set eyes, full cheeks, thin and high nasal bridge, thick lower lip vermilion. Normal muscle strength in all extremities, slightly increased muscle tone in bilateral lower limbs. By 16 months of age, she had already experienced six episodes of bronchopneumonia and four upper respiratory tract infections. She exhibited neither seizures nor sleep dysfunction, and shows no dysmorphic features\u0026mdash;including the \"Greek helmet\" aspect, cleft lip/palate, coloboma\u0026mdash;or visceral (genital and renal), midline, or skeletal anomalies. Hearing, visual acuity, and funduscopic examinations were all normal. At 17 months, a Gesell Development Scale assessment revealed a developmental age of 9.5 months and a developmental quotient (DQ) of 53, consistent with moderate global developmental delay (GDD). The subdomain scores were as follows: gross motor (DQ\u0026thinsp;=\u0026thinsp;56), fine motor (DQ\u0026thinsp;=\u0026thinsp;45), adaptive behavior (DQ\u0026thinsp;=\u0026thinsp;56), language (DQ\u0026thinsp;=\u0026thinsp;47), and social behavior (DQ\u0026thinsp;=\u0026thinsp;61). Color Doppler echocardiography revealed an ASD (4.1 mm), trace tricuspid regurgitation, and left ventricular systolic function within the normal range (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). All laboratory investigations, including complete blood count, serum biochemical profile, serum ammonia, serum lactate, serum ceruloplasmin, blood and urine metabolic screening, serum growth hormone level, and immune function studies (comprising quantitative serum immunoglobulins, lymphocyte subset analysis, and complement system assessment), were within normal limits. Electroencephalogram (EEG) and brain magnetic resonance imaging findings were unremarkable.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eGiven the patient's history of IUGR presenting in the late trimester, birth as a term small-for-gestational-age (SGA) infant with microcephaly, and subsequent postnatal GDD with failure to thrive, a congenital genetic etiology is highly suspected. Therefore, trio-based whole-exome sequencing (Trio-WES) was performed on the proband and her parents using blood-derived DNA to investigate potential genetic etiologies.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eWES and Sanger sequencing\u003c/h2\u003e\u003cp\u003eLibrary preparation was performed using a customized Twist Bioscience OmniSeek\u0026reg; Whole Exome Capture Kit, followed by high-throughput sequencing with a paired-end 150 bp (PE150) read length. The data analysis pipeline was conducted as follows: for the nuclear genome, raw sequencing data underwent quality control (QC) using fastp (v0.23.1); filtered reads were aligned to the reference genome GRCh38/hg38 with BWA (v0.7.17); duplicate reads were marked using GATK (v4.2.4.0); single nucleotide variants (SNVs) and insertions/deletions (InDels) were called with GATK (v4.2.4.0); copy number variations (CNVs) were detected using XHMM (v1.0) and CNVkit (v0.9.9); and variant annotation was performed using Annovar (2022.6.8) and VEP (v105). For the mitochondrial genome, raw data were processed with fastp (v0.23.1) for QC and removal of low-quality reads; clean reads were aligned to the mitochondrial reference genome NC_012920.1 using BWA (v0.7.17); SNVs and InDels were identified using GATK (v4.2.4.0); and detected variants were annotated with VEP (v105.0), incorporating information from specialized databases including Mitomap, MitImpact, and ClinVar.\u003c/p\u003e\u003cp\u003eThe proband achieved 189.25\u0026times; mean depth with 99.42% of targets covered\u0026thinsp;\u0026ge;\u0026thinsp;20\u0026times;; samples of her father and mother showed 181.42\u0026times; and 177.78\u0026times; average depths, covering 99.64% and 99.39% at \u0026ge;\u0026thinsp;20\u0026times;, respectively. WES identified a nonsense variant (NM_001042424.3: c.1466C\u0026thinsp;\u0026gt;\u0026thinsp;G, p.Ser489Ter) in exon 6 of the \u003cem\u003eNSD2\u003c/em\u003e gene on chromosome 4 (chr4: 1930681). Sanger sequencing confirmed that this pathogenic variant occurred \u003cem\u003ede novo\u003c/em\u003e in the proband, as both parents exhibited wild-type genotypes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). According to the American College of Medical Genetics and Genomics (ACMG) guidelines [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], this variant was classified as pathogenic based on the following criteria: PVS1, PM2_Supporting, and PS2_Supporting. Specifically, PVS1 was applied given the variant (c.1466C\u0026thinsp;\u0026gt;\u0026thinsp;G) is a nonsense mutation inducing LoF, a known disease mechanism for \u003cem\u003eNSD2\u003c/em\u003e-related disorders, and occurs in exon 6/22 of a relevant transcript. PS2_Supporting was assigned based on confirmed \u003cem\u003ede novo\u003c/em\u003e origin via parental testing (though potential mosaicism cannot be fully excluded). PM2_Supporting was invoked due to the variant's absence in gnomAD exome and genome cohorts. Furthermore, a candidate variant in the \u003cem\u003eTAP2\u003c/em\u003e gene (NM_001290043.2: Exon4: c.628C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.Arg210Ter) was identified. However, it was excluded as pathogenic due to a combination of the proband's incompatible clinical phenotype and a segregation pattern inconsistent with autosomal recessive inheritance (heterozygous in proband and mother, absent in father). Based on the clinical presentation and genetic sequencing results, the patient met the diagnostic criteria for \u003cem\u003eNSD2\u003c/em\u003e-related RSS.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTreatment and follow up\u003c/h3\u003e\n\u003cp\u003eThe patient's primary management consisted of regular rehabilitation training. Follow-up echocardiography was performed at 6-month intervals. The most recent examination at 31 months of age showed a persistent ASD of approximately 4 mm, which was unchanged from the previous measurement at 16 months of age. Follow-up showed that she achieved independent walking at 20 months and was able to run and jump by 22 months. By the age of 2 years, she could spontaneously produce simple two- to four-word phrases, such as \u0026ldquo;mama\u0026rdquo;, \u0026ldquo;baba\u0026rdquo;, \u0026ldquo;don't like\u0026rdquo;, \u0026ldquo;I'm hungry\u0026rdquo;, and \u0026ldquo;I need to pee\u0026rdquo;. Her receptive language skills exceeded her expressive abilities; she could understand daily instructions but often relied on gestures to communicate due to limited verbal expression. Her history of recurrent respiratory infections resolved spontaneously after the age of 2. At the last follow-up (31 months of age), her expressive language had improved further to short phrases of 3\u0026ndash;5 words. Anthropometric measurements were as follows: height 84 cm (-2.3 SD), weight 8.3 kg (-4.2 SD), head circumference 45.5 cm (-2.1 SD), and body mass index (BMI) 11.7 kg/m\u0026sup2; (-5.8 SD). A subsequent Gesell Developmental Scale assessment revealed an overall developmental age of 22.4 months and a DQ of 68, consistent with mild GDD. The subscale scores were as follows: gross motor (DQ\u0026thinsp;=\u0026thinsp;68), fine motor (DQ\u0026thinsp;=\u0026thinsp;89), adaptive behavior (DQ\u0026thinsp;=\u0026thinsp;70), language (DQ\u0026thinsp;=\u0026thinsp;70), and personal-social (DQ\u0026thinsp;=\u0026thinsp;67).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe \u003cem\u003eNSD2\u003c/em\u003e gene is located at 4p16.3, comprises 22 exons, and encodes a protein of 1,365 amino acids. This gene product contains four domains commonly found in other developmental proteins: a PWWP domain, an HMG box, a SET domain, and a PHD-type zinc finger, all of which are ubiquitously involved in early development. The gene is situated within the 165 kb critical region of WHS and is involved in chromosomal translocations associated with multiple myeloma. Recent studies have established that pathogenic variants in the \u003cem\u003eNSD2\u003c/em\u003e gene cause a syndrome characterized by mild clinical features that partially overlap with those of WHS, now defined as RSS. Research on \u003cem\u003eNSD2\u003c/em\u003e-related RSS remains limited. To date, only 41 individuals have been reported in the literature [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], the majority as individual case reports, with only one larger cohort study comprising 18 patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Therefore, detailed clinical documentation of each new case provides unique value and contributes meaningfully to future research.\u003c/p\u003e\u003cp\u003eHerein, we describe a detailed clinical characterization and genotype of a Han Chinese girl with RSS caused by a novel \u003cem\u003ede novo\u003c/em\u003e heterozygous pathogenic variant in the \u003cem\u003eNSD2\u003c/em\u003e gene (c.1466C\u0026thinsp;\u0026gt;\u0026thinsp;G; p.Ser489Ter). She presented with a spectrum of clinical features, including prenatal and postnatal growth failure, low BMI, variable GDD, expressive language impairment, feeding difficulties during infancy, and distinctive dysmorphic facial features (triangular face, broad forehead, deep-set eyes, periorbital hyperpigmentation). These manifestations are consistent with previously reported cases of RSS [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. \u003cem\u003eNSD2\u003c/em\u003e regulates embryonic development and physical growth, and defects in this gene can lead to growth retardation[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Our patient and some previously reported cases exhibited feeding difficulties during the neonatal period. Studies suggest that \u003cem\u003eNSD2\u003c/em\u003e deficiency may contribute to low BMI due to an inability of body fat to expand during feeding, rather than being a direct consequence of neonatal feeding difficulties [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although observed in multiple affected individuals, feeding difficulties do not persist in later stages of life. Additionally, she exhibited several features rarely or never previously reported in RSS cases, including mildly increased muscle tone in both lower limbs, transient recurrent respiratory infections, and a persistent ASD.\u003c/p\u003e\u003cp\u003eDuring follow-up, the patient exhibited continuous neurodevelopmental improvement. Her Gesell Developmental Scale score improved from moderate to mild GDD. Despite this classification, clinical assessment identified expressive language delay as the most significant current impairment. Nonverbal cognitive and adaptive behaviors suggested no intellectual disability; however, formal intellectual assessment was not feasible at this young age and requires continued follow-up. \u003cem\u003eNSD2\u003c/em\u003e functions as a histone methyltransferase that catalyzes the methylation of histone H3 at lysine 36 (H3K36). Given the crucial role of histone modification in neurodevelopment, this explains why carriers of \u003cem\u003eNSD2\u003c/em\u003e variants often present with DD [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMildly increased muscular tone in the bilateral lower limbs was observed in the patient. To our knowledge, only one previous case has reported a similar finding in RSS. However, unlike our case \u0026mdash; which consistently presented with hypertonia \u0026mdash; the previously reported patient exhibited fluctuating muscle tone, with documented periods of both hypotonia and hypertonia. All other reported cases have consistently described hypotonia.\u003c/p\u003e\u003cp\u003eShe had a history of recurrent, non-severe respiratory tract infections, which were self-limiting and showed spontaneous resolution after two years of age. All immunological investigations yielded normal results. A candidate variant in the \u003cem\u003eTAP2\u003c/em\u003e gene (NM_001290043.2: Exon4: c.628C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.Arg210Ter), classified as likely pathogenic for MHC class I deficiency type 2, was identified by WES (heterozygous in the proband and her mother, wild-type in the father). However, this variant was excluded as the disease-causing mutation in this case due to both the inconsistent segregation pattern and the significant phenotypic discrepancy. MHC class I deficiency type 2 is an autosomal recessive immunodeficiency disorder characterized by severe, life-threatening, or chronic debilitating infections \u0026mdash; features inconsistent with the patient\u0026rsquo;s mild and self-resolving infectious history, as well as her normal immunological parameters [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Recurrent respiratory infections have been reported only in a minority of previously described RSS cases, and detailed clinical characterization of this feature is lacking.\u003c/p\u003e\u003cp\u003eHer ASD (approximately 4 mm in size) persisted. To our knowledge, this represents the first reported case of a definitive ASD in RSS. Cardiac anomalies are rarely documented in RSS, with only two previously reported cases: one describing an unspecified cardiac malformation[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] and the other noting mitral valve prolapse [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The small ASD in our patient is unlikely to account for her recurrent respiratory infections. No intervention is currently indicated, and continued clinical surveillance is recommended.\u003c/p\u003e\u003cp\u003eThe patient did not exhibit several typical features of WHS, such as seizures (no abnormalities were observed on EEG) or the \"Greek warrior helmet\" facial appearance (characterized by a high forehead, broad and depressed nasal bridge, short philtrum, highly arched eyebrows, hypertelorism, and micrognathia). Based on her clinical manifestations and genetic findings, a definitive diagnosis of RSS was established. Currently, there is no specific treatment for this disorder, and management primarily relies on rehabilitative training.\u003c/p\u003e\u003cp\u003eGiven the limited number of reported cases, the molecular mechanisms, pathogenic pathways, and therapeutic strategies for RSS remain to be elucidated.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, we report a Han Chinese girl with RSS caused by a novel \u003cem\u003ede novo\u003c/em\u003e heterozygous pathogenic variant (c.1466C\u0026thinsp;\u0026gt;\u0026thinsp;G: p.Ser489Ter) in \u003cem\u003eNSD2\u003c/em\u003e gene. In addition to exhibiting the core clinical features consistent with previously reported cases of RSS, she also demonstrates ASD, a feature that has not been documented in prior cases. Therefore, our patient expands both the phenotypic and genotypic spectrum of \u003cem\u003eNSD2\u003c/em\u003e-associated RSS.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRSS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRauch\u0026ndash;Steindl syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNSD2\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNuclear receptor-binding Set Domain-protein 2\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDevelopmental delay\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eWHS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWolf-Hirschhorn syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eWHSCR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWHS critical region\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLoF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLoss-of-function\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNELFA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNegative Elongation Factor Complex Member A\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eASD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAtrial septal defect\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIUGR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIntrauterine growth restriction\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDQ\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDevelopmental quotient\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGDD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGlobal developmental delay\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEEG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eElectroencephalogram\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSGA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSmall-for-gestational-age\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTrio-WES\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTrio-based whole-exome sequencing\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePE150\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePaired-end 150 bp\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eQC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eQuality control\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSNVs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSingle nucleotide variants\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eInDels\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInsertions/deletions\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCNVs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecopy number variations\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eACMG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAmerican College of Medical Genetics and Genomics\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to the child and the families for their contributions to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u003c/strong\u003e\u003cstrong\u003e\u0026rsquo;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHZ designed this study, collected and integrated data, and wrote the article. MD, LZ, SZ, JL, and JW integrated data and interpreted gene reports. PZ and ZL revised the article. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is supported by a grant from the Natural Science Foundation of Sichuan Province (No. 2022NSFSC0784).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors. Our pathogenic variant data has been deposited into\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ethe ClinVar bank: \u0026nbsp;https://www.ncbi.nlm.nih.gov/clinvar/SUB15653616/. And the accession number: SCV006333412.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was reviewed and approved by the hospital\u0026rsquo;s medical ethics committee of Sichuan Provincial Women\u0026rsquo;s and Children\u0026rsquo;s Hospital. Approval Code: 20230807-219. The Approval Date: 10 August 2023. Written informed consent from parents of all participants, and the ethics committee approved this procedure. The study adhered to the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient\u0026rsquo;s parents for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZanoni P, Steindl K, Sengupta D, Joset P, Bahr A, Sticht H, Lang-Muritano M, van Ravenswaaij-Arts CMA, Shinawi M, Andrews M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eLoss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype\u003c/strong\u003e. \u003cem\u003eGenet Med \u003c/em\u003e2021, \u003cstrong\u003e23\u003c/strong\u003e(8):1474-1483.\u003c/li\u003e\n\u003cli\u003eDerar N, Al-Hassnan ZN, Al-Owain M, Monies D, Abouelhoda M, Meyer BF, Moghrabi N, Alkuraya FS: \u003cstrong\u003eDe novo truncating variants in WHSC1 recapitulate the Wolf-Hirschhorn (4p16.3 microdeletion) syndrome phenotype\u003c/strong\u003e. \u003cem\u003eGenet Med \u003c/em\u003e2019, \u003cstrong\u003e21\u003c/strong\u003e(1):185-188.\u003c/li\u003e\n\u003cli\u003eCyr AB, Nimmakayalu M, Longmuir SQ, Patil SR, Keppler-Noreuil KM, Shchelochkov OA: \u003cstrong\u003eA novel 4p16.3 microduplication distal to WHSC1 and WHSC2 characterized by oligonucleotide array with new phenotypic features\u003c/strong\u003e. \u003cem\u003eAm J Med Genet A \u003c/em\u003e2011, \u003cstrong\u003e155A\u003c/strong\u003e(9):2224-2228.\u003c/li\u003e\n\u003cli\u003eRichards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eStandards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology\u003c/strong\u003e. \u003cem\u003eGenetics in Medicine \u003c/em\u003e2015, \u003cstrong\u003e17\u003c/strong\u003e(5):405-424.\u003c/li\u003e\n\u003cli\u003eWiel LC, Bruno I, Barbi E, Sirchia F: \u003cstrong\u003eFrom Wolf-Hirschhorn syndrome to NSD2 haploinsufficiency: a shifting paradigm through the description of a new case and a review of the literature\u003c/strong\u003e. \u003cem\u003eItal J Pediatr \u003c/em\u003e2022, \u003cstrong\u003e48\u003c/strong\u003e(1):72.\u003c/li\u003e\n\u003cli\u003ePopp B, Brugger M, Poschmann S, Bartolomaeus T, Radtke M, Hentschel J, Di Donato N, Rump A, Gburek-Augustat J, Graf E\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eThe constitutional gain-of-function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome\u003c/strong\u003e. \u003cem\u003eClin Genet \u003c/em\u003e2023, \u003cstrong\u003e103\u003c/strong\u003e(2):226-230.\u003c/li\u003e\n\u003cli\u003ePopp B, Brugger M, Poschmann S, Bartolomaeus T, Radtke M, Hentschel J, Di Donato N, Rump A, Gburek-Augustat J, Graf E\u003cem\u003e et al\u003c/em\u003e: 2022.\u003c/li\u003e\n\u003cli\u003eNishi E, Yanagi K, Kaname T, Okamoto N: \u003cstrong\u003eClinical details of individuals with Rauch-Steindl syndrome due to NSD2 truncating variants\u003c/strong\u003e. \u003cem\u003eMol Genet Genomic Med \u003c/em\u003e2024, \u003cstrong\u003e12\u003c/strong\u003e(2):e2396.\u003c/li\u003e\n\u003cli\u003eYang Q, Gong D, Yi S, Luo J, Zhang Q: \u003cstrong\u003eCase report: A de novo NSD2 truncating variant in a child with Rauch-Steindl syndrome\u003c/strong\u003e. \u003cem\u003eFront Pediatr \u003c/em\u003e2023, \u003cstrong\u003e11\u003c/strong\u003e:1064783.\u003c/li\u003e\n\u003cli\u003eNimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz RJ, Kaneda Y: \u003cstrong\u003eA histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome\u003c/strong\u003e. \u003cem\u003eNature \u003c/em\u003e2009, \u003cstrong\u003e460\u003c/strong\u003e(7252):287-291.\u003c/li\u003e\n\u003cli\u003eDarazam IA, Shahrooei M, Hakamifard A, Olyaei NA, Zerehpoosh FB, Gharehbagh FJ, Hatami F, Lotfollahi L, Mansouri N, Casanova J-L\u003cem\u003e et al\u003c/em\u003e: 2022.\u003c/li\u003e\n\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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Rauch-Steindl syndrome, NSD2, growth restriction, developmental delay, facial gestalt, case report","lastPublishedDoi":"10.21203/rs.3.rs-7605765/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7605765/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eRauch-Steindl syndrome (RSS) is a very rare autosomal dominant disorder caused by pathogenic variants in the \u003cem\u003eNSD2\u003c/em\u003e gene, characterized by dysmorphic facial features, prenatal and postnatal growth retardation, and variable developmental delay.\u003c/p\u003e\u003ch2\u003eCase presentation\u003c/h2\u003e\u003cp\u003e: We report the case of a 16-month-old Han Chinese girl who presented with typical features of RSS, including prenatal and postnatal growth failure, low body mass index, global developmental delay, expressive language impairment, infantile feeding difficulties, and distinctive dysmorphic facies (triangular face, broad forehead, high anterior hairline, deep-set eyes, full cheeks, thin and high nasal bridge, thick lower lip vermilion). She also exhibited mildly increased muscular tone in the lower limbs, transient recurrent respiratory infections, and a persistent atrial septal defect (ASD). Whole-exome sequencing identified a novel \u003cem\u003ede novo\u003c/em\u003e heterozygous nonsense variant (NM_001042424.3: c.1466C\u0026thinsp;\u0026gt;\u0026thinsp;G, p.Ser489Ter) in exon 6 of the \u003cem\u003eNSD2\u003c/em\u003e gene on chromosome 4, which was classified as pathogenic according to ACMG guidelines. Notably, the patient exhibited an ASD that persisted through follow-up beyond 31 months of age\u0026mdash;a feature not previously documented in RSS.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThis case report expands both the phenotypic and genotypic spectrum of \u003cem\u003eNSD2\u003c/em\u003e-associated RSS.\u003c/p\u003e","manuscriptTitle":"Expanding the phenotypic spectrum of Rauch-Steindl syndrome: A novel NSD2 variant with atrial septal defect in a Chinese patient","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 07:55:04","doi":"10.21203/rs.3.rs-7605765/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-17T08:06:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-13T18:30:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-12T20:58:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"198522919911379945549803726843206244424","date":"2025-11-29T13:26:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"19657541347018637841192680403442886975","date":"2025-11-24T20:37:47+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-24T06:05:07+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-06T07:01:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-14T21:19:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-27T17:34:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2025-09-27T10:28:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"85c82523-b4b8-489b-b688-f361226f80b9","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-02T16:11:42+00:00","versionOfRecord":{"articleIdentity":"rs-7605765","link":"https://doi.org/10.1186/s12883-026-04649-3","journal":{"identity":"bmc-neurology","isVorOnly":false,"title":"BMC Neurology"},"publishedOn":"2026-01-27 15:58:06","publishedOnDateReadable":"January 27th, 2026"},"versionCreatedAt":"2025-12-01 07:55:04","video":"","vorDoi":"10.1186/s12883-026-04649-3","vorDoiUrl":"https://doi.org/10.1186/s12883-026-04649-3","workflowStages":[]},"version":"v1","identity":"rs-7605765","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7605765","identity":"rs-7605765","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}