American Journal of Medical Genetics Part A最新文献

{"title":"A MORC2 Variant Associated With Severe Intellectual Disability and Unusual Phenotype.","authors":"Harry Wilton-Clark, Kati Kämpjärvi, Oksana Suchowersky, Shailly Jain-Ghai","doi":"10.1002/ajmg.a.70307","DOIUrl":"https://doi.org/10.1002/ajmg.a.70307","url":null,"abstract":"<p><p>The microrchidia CW-type zinc finger protein 2 (MORC2) gene encodes an epigenetic regulator, variants in which are often associated with Charcot-Tooth-Marie (CMT) disease type 2Z. In recent years, notable phenotypic variation has been identified in patients with different MORC2 variants. Here, we present a 61-year-old male with a MORC2 c.328C>T, p.(Arg110Cys) variant who displays significant but nonprogressive intellectual disability, hearing loss, retinitis pigmentosa, spasticity, and cerebellar findings, in addition to a mild neuropathy, with follow-up over 12 years. As the oldest reported patient with this variant and phenotype, this case not only expands the phenotypic spectrum of MORC2-related disorders but also provides valuable phenotypic information regarding disease progression in later years, particularly regarding the intellectual disabilities associated with MORC2 variants.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029672","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":"Syndromic Hirschsprung Disease With a Novel De Novo Sense Exonic SVA Insertion of TCF20.","authors":"Briana O'Leary, Aditya Ramanujan, Aria Belle, Nina B Gold, David A Sweetser, Daniel J Pomerantz","doi":"10.1002/ajmg.a.70306","DOIUrl":"https://doi.org/10.1002/ajmg.a.70306","url":null,"abstract":"<p><p>Transcription Co-Activator Factor 20 (TCF20) Associated Neurodevelopmental Disorder (TAND, OMIM: 618430) is a rare autosomal dominant neurodevelopmental disorder most commonly associated with disruptive TCF20 variants and features overlapping Smith-Magenis syndrome (SMS, OMIM: 182290). Here we present a 40-year-old man with Hirschsprung disease (HD), intellectual disability, coarse facial features, sleep disturbances, and recurrent infections in whom whole-exome sequencing revealed a de novo heterozygous SVA retrotransposon insertion at c.1920_1921 in Exon 2 of TCF20 (OMIM: 603107), predicted to disrupt the primary TCF20 transcript (NM_005650.4), consistent with a molecular diagnosis of TAND. This SVA insertion has not been previously reported. The occurrence of congenital, biopsy-confirmed Hirschsprung disease in this patient suggests that intestinal aganglionosis may represent an uncommon extension of the gastrointestinal phenotype associated with TAND, in which chronic constipation and gastrointestinal dysmotility are already recognized. This case also underscores the phenotypic and molecular heterogeneity associated with mobile transposable elements of the human exome, alongside the clinical importance of transposon analysis.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029678","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":"Acute Healthcare Utilization During the First Year After Hospital Discharge in Children With Trisomy 18.","authors":"Aika Matsushima, Sota Iwatani, Satoshi Matsui, Seiji Yoshimoto","doi":"10.1002/ajmg.a.70309","DOIUrl":"https://doi.org/10.1002/ajmg.a.70309","url":null,"abstract":"<p><p>Survival of infants with trisomy 18 (T18) has improved with advances in neonatal intensive care and surgical management, yet postdischarge outcomes remain poorly characterized. This single-center retrospective cohort study included infants with T18 admitted to a Level III neonatal intensive care unit between 2008 and 2022. Survival and survival-to-discharge rates were analyzed by birth era. For patients discharged alive in the most recent era (2018-2022), emergency department (ED) visits and hospital admissions during the first year after discharge were evaluated. Among 87 infants with confirmed outcomes, overall survival and survival-to-discharge rates improved over time. Sixteen patients discharged alive in the late cohort were included in the postdischarge analysis. During the first year after discharge, 13 patients (81%) visited the ED at least once, and 11 (69%) required hospital admission. Respiratory disorders were the most frequent reason for admission, followed by urinary tract infections and gastrointestinal disorders. An exploratory analysis found no significant association between tracheostomy status and ED visits or hospital admissions. Two patients died within 1 year after discharge. Despite improving survival, infants with T18 experience substantial healthcare utilization after discharge, underscoring the need for structured multidisciplinary follow-up and robust home-based care support systems.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149011759","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":"First Report of Uniparental Isodisomy of Chromosome 15 Revealing Angelman Syndrome and Microphthalmia Associated With a Novel Homozygous ALDH1A3 Variant.","authors":"Gabriela Roldão Correia-Costa, Joana Rosa Marques Prota, Antonia Paula Marques-de-Faria, Carlos Eduardo Steiner, Társis Paiva Vieira","doi":"10.1002/ajmg.a.70305","DOIUrl":"https://doi.org/10.1002/ajmg.a.70305","url":null,"abstract":"<p><p>Paternal isodisomy of chromosome 15 (iUPD15) is a recognized cause of Angelman syndrome (AS), accounting for approximately 2%-5% of cases. Additionally, another recognized consequence of iUPD is the unmasking of autosomal recessive disorders. However, reports of recessive disorders resulting from iUPD15 remain scarce in the literature. Here, we report a Brazilian male patient with paternal iUPD15 who presented with clinical features consistent with AS and bilateral microphthalmia, the latter attributable to a novel homozygous likely pathogenic variant in ALDH1A3 (NM_000693.4:c.3G>A:p.(Met1?)) unmasked by the isodisomy. Comprehensive molecular investigation, including chromosomal microarray, microsatellite marker analysis, and whole exome sequencing, was essential to elucidate this diagnosis. To the best of our knowledge, this is the first case reported of Angelman syndrome and ALDH1A3-related microphthalmia due to paternal iUPD15. This case highlights the importance of considering UPD in the context of imprinting disorders as well as a mechanism for unveiling recessive diseases.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987574","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":"L-Cysteine and N-Acetylcysteine Supplementation Improves Clinical Outcome in a Patient With COXPD10.","authors":"Nishitha R Pillai, Sara A Elsbecker, Grace Bronken McCarthy, Kaitlin Weisshappel, Peter Karachunski, Fernando Scaglia","doi":"10.1002/ajmg.a.70299","DOIUrl":"https://doi.org/10.1002/ajmg.a.70299","url":null,"abstract":"<p><p>MTO1 is a nuclear gene that encodes a mitochondrial protein essential for modifying mitochondrial transfer RNAs (tRNAs) and stabilizing codon-anticodon interactions to ensure accurate and efficient mitochondrial protein synthesis and oxidative phosphorylation. Mitochondrial tRNA translation optimization 1 (MTO1) plays an important role in the mitochondrial tRNA taurinomethylation modification by using the amino acid taurine, obtained from cysteine metabolism, at the wobble position U34 of the anticodon loop. Biallelic pathogenic variants in MTO1 cause combined oxidative phosphorylation deficiency 10 (COXPD10) (OMIM#614702). In the severe end of the spectrum, COXPD10 is characterized by infantile-onset hypertrophic cardiomyopathy and lactic acidosis with perinatal mortality when associated with nonsense and frameshift variants. The extra cardiac phenotypes include muscle hypotonia, feeding difficulties, psychomotor delay, optic atrophy, encephalopathy, and seizures. Currently, there is no targeted treatment for this condition aside from supportive care. Herein, we report a 22-month-old child, diagnosed early with a genotype predictive of severe COXPD10, who was initiated on treatment with L-cysteine and N-acetylcysteine (NAC) early in life and did not develop cardiac manifestations. This outcome suggests a potential benefit and improved clinical outcome with early disease-specific treatment initiation.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987648","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":"ADNP-Related Helsmoortel-Van der Aa Syndrome: A Review of the Literature and Clinical Recommendations for Assessment and Monitoring.","authors":"Jarrett Fastman, Ana Kolevzon, Paige Siper, Tess Levy, Jeffrey M Saland, Yitzchak Frank, Robert Rapaport, Kayla Kupietzky, William E Bennett, Bruce Gelb, Sandra Bedrosian Sermone, Alexander Kolevzon","doi":"10.1002/ajmg.a.70288","DOIUrl":"https://doi.org/10.1002/ajmg.a.70288","url":null,"abstract":"<p><p>ADNP-related Helsmoortel-Van der Aa syndrome (ADNP-related HVDAS) is a single gene form of autism spectrum disorder (ASD) caused by pathogenic sequence variants in the activity-dependent neuroprotective protein (ADNP) gene. In addition to ASD, ADNP-related HVDAS is associated with a wide range of cognitive, behavioral, and physical health features that may lead to profound impairment in functioning and significantly impact quality of life for affected individuals, their families, and caregivers. However, because it remains rare, most clinicians are not familiar with the syndrome and lack knowledge to guide assessment and monitoring. The goals of this study are to (1) provide an updated systematic review of the clinical manifestations of ADNP-related HVDAS, (2) establish recommendations for assessment and monitoring that can be used by caregivers when advocating for their children, and (3) be applied practically by clinicians caring for affected individuals. A literature review was conducted by searching PubMed, PsycInfo, and Embase databases using \"ADNP\", \"ADNP Syndrome,\" and \"Helsmoortel-Van der Aa Syndrome\" through July 18, 2026. Articles were included if they reported on clinical manifestations of ADNP-related HVDAS and were excluded if they did not describe at least one individual with the diagnosis. A total of 28 publications met inclusion criteria including case reports, case series, and small cohort studies; data were extracted for 209 cases and organized by clinical domain. A formal risk of bias assessment was not performed, and results were limited by the rarity of ADNP-related HVDAS and thus small sample sizes, as well as variability in symptom reporting. Our updated review highlights the complex symptomatology of ADNP-related HVDAS and the importance of early diagnosis, comprehensive evaluations, and individualized treatment planning.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987587","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":"Moebius-Plus Phenotype With Positive RCEM Episignature May Indicate Broader Embryologic Malformation Spectrum Detectable by Methylation Profiling.","authors":"Hannah Peck, Laura A Krueger, Ethan D Sperry, Ryan Monsberger, Shaindy Grunwald, Daniel T Swarr, Robert J Hopkin, Amelle Shillington","doi":"10.1002/ajmg.a.70300","DOIUrl":"https://doi.org/10.1002/ajmg.a.70300","url":null,"abstract":"<p><p>Moebius syndrome (OMIM #157900) is a rare congenital cranial dysinnervation disorder characterized by abducens (CN VI) and facial (CN VII) nerve palsies with variable craniofacial and limb anomalies. Despite advances in genomic testing, the majority of patients remain genetically unexplained. Episignature testing, which detects syndrome-specific DNA methylation patterns, has emerged as a complementary diagnostic tool for conditions with shared developmental mechanisms. We describe an 8-month-old male born prematurely with bilateral clubfoot, craniofacial dysmorphism, feeding difficulty requiring gastrostomy tube placement, and respiratory failure requiring tracheostomy. Neuroimaging demonstrated absence of bilateral abducens and facial nerves with pontocerebellar hypoplasia, supporting a clinical diagnosis of Moebius syndrome. Extensive genetic evaluation, including genome sequencing and targeted testing for hypotonia and hypoventilation syndromes, was nondiagnostic. Episignature analysis revealed a moderately positive methylation signature consistent with a recurrent constellation of embryonic malformation (RCEM), concordant with two of three previously validated RCEM classifier models. To our knowledge, this is the first report of a patient with a positive RCEM episignature and Moebius syndrome, suggesting a common embryologic pathway. Episignature testing may represent a valuable diagnostic tool in patients with Moebius syndrome and related craniofacial-limb malformation spectra when conventional genomic testing is unrevealing.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987637","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":"Mechanisms of Aging in Phenylketonuria (PKU).","authors":"John Bassett, Neve Cufflin, Iain Hargreaves, Chris Murgatroyd, Alison Woodall, Anita MacDonald, Nenad Blau, Emma Vardy, Karolina M Stepien","doi":"10.1002/ajmg.a.70301","DOIUrl":"https://doi.org/10.1002/ajmg.a.70301","url":null,"abstract":"<p><p>Phenylketonuria (PKU) is an autosomal recessive inherited metabolic disorder (IMD) characterized by elevated phenylalanine (Phe) levels, requiring a low-protein diet and low-Phe amino acid supplementation from birth to prevent cognitive impairment. Despite early and continuous treatment, emerging evidence indicates that adults with PKU may experience subtle cognitive deficits and features consistent with accelerated aging. This narrative review synthesizes the current evidence on accelerated aging in PKU, describes its clinical manifestations, and explores potential underlying mechanisms. Adults with PKU exhibit greater cardiovascular aging, including arterial stiffness and dyslipidaemia, alongside higher rates of obesity, diabetes, and hypertension compared to adults without PKU. They also tend to demonstrate lower bone mineral density, more extensive white matter changes, and poorer cognitive performance alongside a higher prevalence of mood disorders and reduced quality of life, despite treatment. These physiological differences are thought to be primarily driven by oxidative stress (OS), which appears to be inherent to the pathophysiology of PKU. OS leads to secondary mitochondrial dysfunction and DNA damage, which are also implicated in accelerated aging in PKU, along with epigenetic changes. This review explores in detail the mechanisms implicated in premature aging in PKU and proposes potential aging biomarkers and treatment targets.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975377","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":"Dual Aberrant Splicing Caused by an Apparently Missense CHD7 Variant, c.5273A>G (p.Asp1758Gly), in CHARGE Syndrome.","authors":"Takashi Okuno, Tatsuto Shimizu, Aiko Igarashi, Kazumi Ikeda, Masamichi Ikawa, Sumihito Togi, Hiroki Ura, Yo Niida, Katsutsugu Umeda","doi":"10.1002/ajmg.a.70302","DOIUrl":"https://doi.org/10.1002/ajmg.a.70302","url":null,"abstract":"<p><p>CHARGE syndrome is a rare congenital disorder primarily attributed to heterozygous pathogenic variants of the CHD7 gene. Most pathogenic CHD7 variants are loss-of-function (LoF) variants, whereas the interpretation of missense variants remains challenging in the absence of functional evidence for their pathogenicity. We report a female infant presenting with clinical features characteristic of CHARGE syndrome. Targeted sequencing identified a heterozygous CHD7 variant (NM_017780.4:c.5273A>G), initially annotated as a missense substitution p.Asp1758Gly. This variant has been previously reported and registered with conflicting pathogenicity classifications; however, its transcript-level consequences remain unclear. Long-PCR-based RNA sequencing of total RNA from peripheral blood mononuclear cells revealed two aberrant splicing patterns associated with the variant: a predominant transcript carrying a 28-bp deletion due to cryptic donor splice-site activation, and a minor transcript with partial intron 24 retention. Both transcripts were predicted to result in premature termination codons. These findings demonstrate that c.5273A>G functions as a LoF variant through dual aberrant splicing rather than a simple missense substitution. This case underscores the importance of RNA-level splicing analysis for the accurate interpretation and classification of CHD7 missense variants.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148962795","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":"Expansion of the Clinical and Molecular Spectrum of LINS1-Associated Disease.","authors":"Ayman Y Ibrahim, Erika Levine, Ayuko Iverson, Sangeeta Sharma, Lisa Forman, Christina Cuccia, Mafalda Barbosa","doi":"10.1002/ajmg.a.70304","DOIUrl":"https://doi.org/10.1002/ajmg.a.70304","url":null,"abstract":"<p><p>LINS1 gene plays a role in cognition and brain development. Mutations in this gene have been identified as the cause of a neurodevelopmental disorder as well as dysmorphisms, motor symptoms, behavioral problems, seizures, microcephaly, mitral valve prolapse, and Q-T prolongation. We recruited two related families with a total of four children affected by LINS1-associated neurodevelopmental disorder. All four subjects have global developmental delay. Congenital heart disease is prominent: Tetralogy of Fallot in two (one with a discontinuous left pulmonary artery), left-sided cardiac hypoplasia with bicuspid aortic valve and membranous VSD in one, and transient aortic dilation with residual mild annular dilation and a small coronary fistula in one. Hyperopia is present in three; the fourth, younger than 2 years, is not yet tested. Dysmorphic features include a long face in two, midface hypoplasia in one, and frontal bossing with prominent eyes in one. All subjects are homozygous for a canonical splice acceptor variant in LINS1 (NM_001040616.3:c.490-1G>C); parents are heterozygous carriers. We extend the phenotypic spectrum of LINS1-associated neurodevelopmental disorder to include significant structural cardiac anomalies and refractive errors. These observations support consideration of cardiac and ophthalmologic evaluation in individuals with biallelic pathogenic LINS1 variants.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148962845","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}