American Journal of Medical Genetics Part A最新文献

{"title":"Targeted Genetic Testing Uncovers a Novel LRP4 Variant in Cenani–Lenz Syndactyly Syndrome","authors":"Gamze Mutlucan Köseoğlu,&nbsp;Esra Kılıç","doi":"10.1002/ajmg.a.70208","DOIUrl":"10.1002/ajmg.a.70208","url":null,"abstract":"<div>\u0000 \u0000 <p>Cenani–Lenz syndactyly syndrome (CLSS, OMIM 212780) is a rare autosomal recessive disorder characterized by syndactyly and oligodactyly of the digits, fusion of carpal and tarsal bones, and radioulnar synostosis. Craniofacial anomalies and renal malformations have been reported in approximately half of cases, with variable expression. The condition results from homozygous or compound heterozygous mutations in the <i>LRP4</i> gene. We identified a consanguineous family with four individuals affected by CLSS, comprising two brothers and their two maternal male cousins. All patients presented with bilateral complex syndactyly, characterized by absent phalanges, reduced and disorganized metacarpals, and cutaneous toe syndactyly. The 2-year-old proband had a horseshoe kidney, whereas his 6-year-old cousin presented with right renal agenesis. None of the patients exhibited growth and developmental delay, cardiac anomalies, or intellectual disability. Based on the clinical suspicion of CLSS, targeted next-generation sequencing of the <i>LRP4</i> gene was performed. This analysis revealed a biallelic variant, c.3830G&gt;T (NM_002334.3), resulting in the protein change p.Arg1277Leu, which has not been previously described. CLSS is a rare congenital disorder affecting distal limb development and is frequently associated with renal malformations and variable dysmorphic features. In this report, we describe four affected individuals carrying a novel homozygous missense variant in the <i>LRP4</i> gene, thereby broadening the clinical and genetic spectrum of CLSS and highlighting the pathogenic significance of this newly identified variant.</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2273-2278"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De Novo 2.2 Mb 19q13.42–q13.43 Microdeletion Encompassing U2AF2: Support for a Haploinsufficiency Model","authors":"Amanda Toledo,&nbsp;Sarah Araji,&nbsp;Weimin Bi,&nbsp;Seema R. Lalani","doi":"10.1002/ajmg.a.70202","DOIUrl":"10.1002/ajmg.a.70202","url":null,"abstract":"<p>U2 small nuclear RNA auxiliary factor 2 (<i>U2AF2</i>) is an essential pre-mRNA splicing factor involved in the early stages of pre-mRNA splicing. To date, multiple individuals have been reported with predominantly heterozygous missense variants presenting intellectual disability, speech and motor delays, seizures, hypotonia, and thin or hypoplastic corpus callosum. Here, we describe a patient with a de novo 2.2 Mb interstitial deletion involving chromosome 19q13.42–q13.43, encompassing <i>U2AF2</i>, presenting with intellectual disability, epilepsy, corpus callosum hypoplasia, dysmorphic features, and congenital heart disease. The patient's clinical features overlap substantially with those reported in individuals harboring heterozygous <i>U2AF2</i> variants, supporting haploinsufficiency as a plausible disease mechanism. To our knowledge, this represents the first postnatal report of complete <i>U2AF2</i> gene deletion. In addition, this is the first detailed phenotypic characterization of a distal 19q chromosomal interstitial deletion, further delineating the clinical spectrum associated with this genomic region.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2350-2356"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic and Genetic Insights Into CNOT3-Related Intellectual Developmental Disorder of Speech Delay, Autism, and Dysmorphic Faces (IDDSADF) From the First Two Japanese Cases","authors":"Daisuke Ariyasu,&nbsp;Rika Kosaki,&nbsp;Hideo Cho,&nbsp;Moeko Nakashima,&nbsp;Takatoshi Tsuchihashi,&nbsp;Kenjiro Kosaki,&nbsp;Kazuki Yamazawa","doi":"10.1002/ajmg.a.70198","DOIUrl":"10.1002/ajmg.a.70198","url":null,"abstract":"<div>\u0000 \u0000 <p>Intellectual Developmental Disorder with Speech Delay, Autism, and Dysmorphic Faces (IDDSADF) is a rare neurodevelopmental disorder caused by heterozygous variants in <i>CNOT3</i>. Although several cohorts have been documented worldwide, no Japanese patients have been reported to date. Here, we present the first two Japanese cases of IDDSADF, an 8-year-old girl and a 19-year-old boy, both presenting with developmental delay, characteristic facial features, and short stature. Both individuals exhibited a thin, tented upper lip, a morphology that has been rarely reported in other cohorts and may represent an ethnicity-associated trait. Growth impairment was observed either from early childhood or emerging after puberty and may represent an underrecognized aspect of the phenotype. Trio-exome sequencing identified pathogenic <i>CNOT3</i> variants in both patients, including a recurrent frameshift (c.732dup, p.Ser245fs) and a novel splice-site substitution (c.837+1G&gt;A). Our findings expand the phenotypic and mutational spectrum of IDDSADF, highlighting the importance of longitudinal auxological assessment and recognition of potential ethnicity-associated facial traits in its clinical diagnosis and management.</p>\u0000 </div>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2363-2369"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct Neuropsychiatric Profiles Associated With 17p11.2 Deletions and RAI1 Variants in Smith–Magenis Syndrome","authors":"Albin Blanc,&nbsp;Christophe Nemos,&nbsp;Céline Bonnet,&nbsp;Mathilde Renaud,&nbsp;Sandra Chapuis,&nbsp;Pauline Boiroux,&nbsp;Marie-Noëlle Babinet,&nbsp;Caroline Demily","doi":"10.1002/ajmg.a.70205","DOIUrl":"10.1002/ajmg.a.70205","url":null,"abstract":"<p>Smith–Magenis syndrome (SMS) results from either a recurrent 17p11.2 deletion or pathogenic variants in the <i>retinoic acid induced 1</i> gene (<i>RAI1</i>). While neurodevelopmental impairment and behavioral dysregulation are well recognized, systematic genotype-stratified analyses across psychiatric domains remain limited. We conducted a retrospective genotype-stratified study of 52 individuals with molecularly confirmed SMS (43 with 17p11.2 deletions; 9 with pathogenic <i>RAI1</i> variants) evaluated at the French national coordinating Reference Center for Rare Diseases specializing in psychiatric manifestations (CRMR GénoPsy, Lyon, France). Standardized neurodevelopmental and psychiatric data were extracted and compared using Fisher's exact tests. Intellectual disability was observed in 37/43 deletion carriers (86.0%) and in none of the individuals with <i>RAI1</i> variants (0/9; OR = 109.6, 95% CI [5.66–2122.3], <i>p</i> = 1.3 × 10^-6). Extended deletions were associated with maximal severity. Deletion carriers also exhibited prominent externalizing dysregulation, including self-injurious behavior (34/43 vs. 5/9) and hetero-aggressiveness (28/43 vs. 4/9). Dystonia was observed in 5/43 deletion carriers (11.6%), including 2/2 individuals with extended deletions, and in 0/9 individuals with <i>RAI1</i> variants (<i>p</i> = 0.573; OR = 3.09; 95% CI [0.16–60.6]; Haldane correction). In contrast, <i>RAI1</i> variants demonstrated relative cognitive preservation, with some individuals achieving normal-range IQ, but showed increased internalizing vulnerability, including anxiety (5/9 [55.6%] vs. 5/43 [11.6%]; OR = 0.11, 95% CI [0.02–0.53], <i>p</i> = 0.008) and social withdrawal (4/9 [44.4%] vs. 4/43 [9.3%]; OR = 0.13, 95% CI [0.02–0.68], <i>p</i> = 0.023). Across genotypes, ADHD and sleep–circadian disturbances were highly prevalent. This study refines genotype–phenotype correlations in SMS by delineating two partially divergent neuropsychiatric trajectories. 17p11.2 deletions are associated with pronounced developmental burden and externalizing dysregulation, whereas <i>RAI1</i> variants are characterized by relatively preserved cognition and heightened internalizing vulnerability. Shared ADHD and sleep–circadian disturbances highlight cross-genotypic targets for genotype-informed clinical management.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2320-2330"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70205","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Streamlining Diagnosis of Bardet–Biedl Syndrome: New Diagnostic Algorithm With Updated Criteria","authors":"Jeremy J. Pomeroy,&nbsp;Jesse Richards,&nbsp;Brooke R. Sweeney,&nbsp;Seema Kumar,&nbsp;Katie E. Queen,&nbsp;Joshua Zaritsky,&nbsp;Carl H. Cramer,&nbsp;Elias I. Traboulsi,&nbsp;Brittni A. Scruggs,&nbsp;Erica E. Davis,&nbsp;Ekaterina Keifer,&nbsp;Emma McGibbon,&nbsp;Timothy Ogden,&nbsp;Bendert De Graaf,&nbsp;Tonia Hymers,&nbsp;Elizabeth Forsythe,&nbsp;Philip Beales","doi":"10.1002/ajmg.a.70199","DOIUrl":"10.1002/ajmg.a.70199","url":null,"abstract":"<p>Considerable advances have been made in our understanding of Bardet–Biedl syndrome (BBS), particularly in its core clinical features and molecular genetics, warranting an update to the existing diagnostic criteria framework. Using a rigorous, evidence-based, and consensus-driven process, a multidisciplinary group of international experts and patient-led organizations developed an updated diagnostic algorithm. This algorithm provides practical, updated guidance for clinicians, including a pathway for accurately incorporating genetic findings into the diagnostic process. We recommend that a clinical diagnosis requires either 4 major criteria or 3 major and 2 minor criteria. Revised major criteria are retinal dystrophy, obesity (or overweight in individuals &lt; 2 years old), congenital anomalies of the kidney and urinary tract or chronic kidney disease, hypogonadism/genital anomalies, neurodevelopmental/neurocognitive manifestations, and postaxial polydactyly. The diagnosis can also be established with a positive genetic testing result in patients exhibiting ≥ 1 major criterion, provided that genetic findings should be interpreted in the context of the patient's clinical presentation, age, family history, and overlap with related ciliopathies. These consensus criteria offer a simple algorithm incorporating updated definitions for major and minor criteria and genetic testing to support a timely and accurate diagnosis of patients with BBS, inform genetic counseling, and potentially facilitate earlier access to treatment.</p><p>\u0000 <b>Trial Registration:</b> CRIBBS Registry; ClinicalTrials.gov: NCT02329210</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2181-2198"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70199","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Table of Contents, Volume 200A, Number 10, October 2026","authors":"","doi":"10.1002/ajmg.a.70292","DOIUrl":"https://doi.org/10.1002/ajmg.a.70292","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2177-2180"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70292","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148871952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin Levels in 89 Individuals With Smith Magenis Syndrome","authors":"Wiebe Braam,&nbsp;Ann C. M. Smith","doi":"10.1002/ajmg.a.70167","DOIUrl":"10.1002/ajmg.a.70167","url":null,"abstract":"<p>In patients with Smith–Magenis syndrome (SMS), an inverted circadian rhythm of melatonin (MT) contributes to the sleep disturbance. Standard treatment of sleep disturbance with MT often leads to extremely high daytime MT levels, resulting in even more sleep disorders. We therefore retrospectively evaluated the MT data of 89 SMS patients. Mean MT levels in participants on exogenous MT were significantly higher than in participants that did not use MT (<i>p</i> = &lt; 0.0001). In 9 participants with very high MT levels, these dropped significantly after discontinuation of exogenous MT (<i>p</i> = 0.0037). In 12 participants, MT levels were significantly higher after MT therapy start compared to MT levels before MT start (<i>p</i> = 0.028). MT is catabolized principally by the CYP1A2 enzyme, with a half-life of about 40 min. <i>CYP1A2</i> genotyping was performed in five participants with high MT levels during MT use. Although clinically suspected to be a poor CYP1A2 metabolizer, all five turned out to have haplotype <i>CYP1A2*1F</i>, which is associated with increased enzyme activity. This shows that genotyping of <i>CYP1A2</i> is not suitable to estimate the level of CYP1A2 enzyme activity. When prescribing MT, it is strongly recommended to measure a MT level prior to treatment in order to determine the dose to be given. Checks of the MT level during treatment are necessary due to the frequent occurrence of poor CYP1A2 metabolism. Since <i>CYP1A2</i> genotyping does not provide adequate information about the level of CYP1A2 enzyme activity, we propose a simple way to determine <i>CYP1A2</i> phenotype.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"200 10","pages":"2260-2272"},"PeriodicalIF":1.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.70167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Evaluation of Molecular Genetics and Clinical Manifestations in Patients With LZTR1-Associated Noonan Syndrome: A Retrospective Chart Review and Review of Literature.","authors":"Hager Jaouadi, Şakir Hicazi, Carolyn R Raski, Lindsey Aschbacher-Smith, Ghada Hijazi, Amy E Roberts, Carlos E Prada, K Nicole Weaver","doi":"10.1002/ajmg.a.70297","DOIUrl":"https://doi.org/10.1002/ajmg.a.70297","url":null,"abstract":"<p><p>Pathogenic variants in LZTR1 are an established cause of Noonan syndrome (NS) and uniquely exhibit both autosomal dominant (AD) and autosomal recessive (AR) inheritance. However, the phenotypic spectrum and genotype-phenotype correlations remain incompletely defined. We conducted a multi-center retrospective chart review of patients diagnosed with LZTR1-NS evaluated at three tertiary care centers. Clinical, molecular, and imaging data were systematically collected. A comprehensive literature review (2015-2025) identified 100 additional individuals meeting inclusion criteria. Comparative analyses were performed to evaluate phenotypic patterns by inheritance. Among 21 previously unreported patients aged 6 months to 49 years, 15 had AD NS and 6 had AR NS. Clinical features were largely consistent with prior reports, including high prevalence of craniofacial dysmorphism, neurodevelopmental and multisystem involvement. Cardiac manifestations were frequent, with pulmonary valve stenosis as the most common lesion. Hypertrophic cardiomyopathy appeared more prominent among AR NS. Notably, lymphatic abnormalities were observed at a higher frequency than previously reported. Compared to the literature, our cohort highlights novel findings, including the co-occurrence of AD LZTR1-NS with 22q11.2 deletion and two patients with AR NS with features suggestive of schwannomatosis. These findings expand the clinical spectrum of LZTR1-NS and have important implications for diagnosis, surveillance, and genetic counseling.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exome Sequencing Uncovers Phenotypic and Genotypic Heterogeneity in 196 Indian Families Evaluated for Autoinflammatory Disorders.","authors":"Vaishnavi Ashok Badiger, Periyasamy Radhakrishnan, Suma Balan, Anand P Rao, Prajna Udupa, Karthik Vijay Nair, Bhagesh Hunakunti, Adarsh Pooradan Prasannakumar, Sanket Limaye, Huzail Gani Shaikh, Rohit Naik, Mahesh Janarthanan, Sudharshan Sridharan, Vishal Sondhi, Sheela Nampoothiri, Hitesh Shah, Sabrinath Mahadevan, Mahabaleshwar Mamadapur, Devang Pandya, Katta Mohan Girisha, Abhay Shivpuri, Amita Moirangthem, Jyothi Raghuram, Gandham Sri Lakshmi Bhavani, Sachin Jeevanagi, Girish Subramaniam, Amita Aggarwal, Anju Shukla, Dhanya Lakshmi Narayanan","doi":"10.1002/ajmg.a.70275","DOIUrl":"10.1002/ajmg.a.70275","url":null,"abstract":"<p><p>Autoinflammatory disorders (AIDs) are a clinically heterogeneous group of inborn errors of immunity primarily caused by dysregulation in the innate immune system. Clinical diagnosis is often challenging due to clinical heterogeneity and the overlapping phenotypes with other inborn errors of immunity and monogenic conditions that mimic AIDs. Worldwide, and especially in India, there is a lack of systematic large cohort studies employing genomic testing early in the course of evaluation for individuals with autoinflammatory disease. Herein, we describe our experience using exome sequencing as a first-tier investigation in evaluating 202 individuals from 196 unrelated families with possible monogenic AIDs. Consanguinity was noted in 19% of the families. Recurrent fever was the most common manifestation (90%), frequently associated with arthritis (54%), skin lesions (38%), hepatosplenomegaly (23%), oral ulcers (21%) and lymphadenopathy (21%). Exome sequencing could identify a molecular diagnosis in 50 of 196 (25%) families of whom 30 (60%) had variants in genes associated with monogenic AIDs, 10 (20%) had other distinct inborn errors of immunity and 10 (20%) had monogenic conditions with phenotypic overlap with AIDs. We identified 21 variants in genes associated with monogenic AIDs, of which 20 (95%) were single nucleotide variants and one (5%) was a copy number variant. Notably, seven (33%) of the 21 variants were novel. This study highlights the diagnostic challenges posed by phenotypic overlap in this group of disorders and demonstrates the utility of exome sequencing in enabling a timely diagnosis, including conditions that mimic AIDs thereby facilitating targeted therapy and genetic counseling.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the Genotypic and Phenotypic Spectrum of Vissers-Bodmer Syndrome.","authors":"Kyle Harris, Tauras Vucianis, Eyad Bouso, Amelle Shillington, Yaning Wu","doi":"10.1002/ajmg.a.70284","DOIUrl":"https://doi.org/10.1002/ajmg.a.70284","url":null,"abstract":"<p><p>Vissers-Bodmer Syndrome (VIBOS) is a rare autosomal dominant neurodevelopmental disorder caused by variants in the CNOT1 gene. Affected individuals present with a broad clinical spectrum of developmental delays, intellectual disability, seizures, hypotonia, and behavioral challenges. Most affected individuals also have nonspecific dysmorphic facial features but no recognizable gestalt. We report a de novo pathogenic CNOT1 variant in a 6-month-old male patient who was evaluated for imperforate anus, partial agenesis of the corpus callosum, macrocephaly, hydronephrosis, overlapping toes, and fifth nail hypoplasia. Clinical trio exome sequencing identified a de novo heterozygous CNOT1 nonsense variant (c.4918C>T, p.(Arg1640*)) that has not been previously reported. The patient is now 3 years old and has no growth or developmental concerns in clinical follow-up. This case highlights a novel pathogenic CNOT1 variant and extends the clinical spectrum of VIBOS to include age-appropriate growth and neurodevelopment and the previously unreported presentation of imperforate anus. Recognition of these additional findings may facilitate earlier diagnosis and enhance understanding of the phenotypic variability associated with VIBOS.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}