American Journal of Medical Genetics Part A最新文献

{"title":"DHX16-Associated Neuromuscular Oculoauditory Syndrome: A Novel Case.","authors":"Sloane Clay, Alejandro Leon, Luke Wall, Regina M Zambrano","doi":"10.1002/ajmg.a.64083","DOIUrl":"https://doi.org/10.1002/ajmg.a.64083","url":null,"abstract":"<p><p>DHX16, a member of the DexD/H-box RNA helicase family, facilitates ATP-dependent unwinding of RNA secondary structures. Pathogenic variants cause poor functioning of the spliceosome complex leading to intron retention in gene transcripts. Clinically, it is associated with neuromuscular oculoauditory syndrome (MIM #618733). To date, there are nine published cases. We report a tenth case: a 3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. An inherited retinal disorder panel identified nondiagnostic variants of uncertain significance. Trio exome sequencing revealed a de novo Likely Pathogenic DHX16 variant, c.692G>C; p.R231P. Published cases of DHX16-related disorders report developmental delay/intellectual disability, seizures, myopathy, retinal anomalies, myopia, nystagmus, and hearing loss. No published variants to date are located upstream of the start of the helicase domain, and little is known about upstream domains. In silico analysis demonstrates evidence of pathogenicity, while Missense3D modeling demonstrates no structural damage to the protein. These findings are consistent with current literature, suggesting a mechanism of pathogenicity that is difficult to assess via modeling. This case illustrates a DHX16 variant in an unknown domain displaying a mild phenotype.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64083"},"PeriodicalIF":1.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958532","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":"Four New Patients of HHAT-Related Multiple Congenital Anomalies Syndrome (Nivelon-Nivelon-Mabille Syndrome) and a Comprehensive Literature Review.","authors":"Ayşe Burcu Doğan Arı, Hasan Arı, Ayberk Türkyılmaz, Kerem Teralı, Gönül Büyükyılmaz, Şenay Savaş Erdeve, Esra Kılıç","doi":"10.1002/ajmg.a.64107","DOIUrl":"https://doi.org/10.1002/ajmg.a.64107","url":null,"abstract":"<p><p>Nivelon-Nivelon-Mabille syndrome (NNMS, #600092) is an extremely rare genetic disorder characterized by microcephaly, central nervous system abnormalities, skeletal anomalies, and 46,XY disorders of sex development. It is caused by biallelic variants in the HHAT gene, which encodes the Hedgehog acyltransferase (HHAT) protein. To date, only eight patients with NNMS have been reported in the literature. In this study, four new patients from two unrelated families were presented, exhibiting distinct phenotypic features including 46,XY gonadal dysgenesis, microcephaly, microphthalmia, ocular coloboma, skeletal dysplasia, and cerebellar vermis hypoplasia. Ptosis and marked visual impairment were present only in the current study. NNMS was considered with the present clinical and radiological findings for four patients, and whole exome analysis revealed three novel variants of the HHAT gene. In silico analyses were performed to provide insights into the structural and functional effects of these genetic variants on the HHAT protein. Accurate diagnosis is crucial for increasing clinical awareness and offering genetic counseling to affected families.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64107"},"PeriodicalIF":1.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951336","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":"Table of Contents, Volume 197A, Number 6, June 2025","authors":"","doi":"10.1002/ajmg.a.63751","DOIUrl":"https://doi.org/10.1002/ajmg.a.63751","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"197 6","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.63751","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904934","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":"In Memoriam: John Bruce Beckwith, MD (1933–2025)","authors":"","doi":"10.1002/ajmg.a.63748","DOIUrl":"https://doi.org/10.1002/ajmg.a.63748","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"197 6","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904936","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":"Broad Exclusion Criteria Increase Rate of Genetic Diagnosis in Neonates","authors":"","doi":"10.1002/ajmg.a.63746","DOIUrl":"https://doi.org/10.1002/ajmg.a.63746","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"197 6","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904935","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":"Trends in the Prevalence of Down Syndrome (Trisomy 21) in Texas by Maternal Race/Ethnicity and Maternal Age Groups, 1999-2020.","authors":"Charles Shumate, Rachel Allred, Ashley Dixon, Dayana Betancourt, Caitlyn Yantz, Rebecca Howell, Henal Gandhi, Madeline Kilburn, Philip J Lupo, A J Agopian","doi":"10.1002/ajmg.a.64109","DOIUrl":"https://doi.org/10.1002/ajmg.a.64109","url":null,"abstract":"<p><p>Down syndrome (DS) is a common chromosomal aneuploidy characterized by intellectual disability. Older maternal age is the strongest known risk factor for DS. The purpose of this study was to describe DS prevalence among major racial/ethnic groups stratified by maternal age, and to assess trends in prevalence over time in Texas. Cases with DS diagnoses delivered between 1999 and 2020 were identified from the Texas Birth Defects Registry (TBDR). Birth prevalence and crude prevalence ratios (PRs) by maternal race/ethnicity, maternal education, residence along the Texas-Mexico border, and Texas public health region (PHR) were calculated. Trends over time were assessed using Joinpoint. DS prevalence was significantly lower among mothers < 35 years compared to those 35+ years. Hispanic mothers, mothers with less than high school education, and mothers residing along the Texas-Mexico border had consistently higher PRs. Joinpoint analyses revealed significant increases in DS prevalence over time among non-Hispanic Black and Hispanic mothers. These findings identified significant increases in DS prevalence among non-Hispanic Black and Hispanic mothers compared to non-Hispanic White mothers, suggesting a potential widening of racial/ethnic differences in DS occurrence. Further research is needed to explore underlying drivers of these trends and to address differences in DS prevalence.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64109"},"PeriodicalIF":1.7,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963016","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":"Further Delineation of the AUTS2 HX Repeat Domain-Related Phenotype.","authors":"Esin Nur Erdogan, Chi Vicky Cheng, Stefano G Caraffi, Ivan Ivanovski, Gianluca Piatelli, Edoardo Errichiello, Antigone S Papavasiliou, Georgia Vasileiou, André Reis, Bradley Prince, Scott E Hickey, Daniel C Koboldt, Michael C Schneider, Joseph Porrmann, Nataliya Di Donato, Thomas Leis, M Scott Perry, Jennifer Humberson, Joshua Rotenberg, Somayeh Bakhtiari, Helen Magee, Shaydah Kheradmand, Michael C Kruer, Andrew Swale, Astrid Weber, Caren Landes, Orsetta Zuffardi, Livia Garavelli, Arie van Haeringen, Claudia A L Ruivenkamp, Melissa Pauly, Ping Yee Billie Au, William B Dobyns, Kimberly A Aldinger","doi":"10.1002/ajmg.a.64093","DOIUrl":"https://doi.org/10.1002/ajmg.a.64093","url":null,"abstract":"<p><p>Haploinsufficiency of AUTS2 is associated with a neurodevelopmental disorder characterized by intellectual disability, autistic features, and spasticity. AUTS2 protein interacts with p300, encoded by EP300, through the HX repeat domain of AUTS2, thereby activating transcription. We previously reported two de novo variants in the HX repeat domain of AUTS2. These variants disrupt the AUTS2-P300 interaction, resulting in a phenotype resembling Rubinstein-Taybi Syndrome (RSTS) associated with variants in EP300/CREBBP. Here, we expand beyond the initial clinical description to delineate the HX domain-associated phenotype and compare it to the AUTS2-haploinsufficient phenotype. We reviewed clinical data, photographs, and neuroimaging studies to examine genotype-phenotype relationships. Our review of 80 individuals included 14 individuals we present here and 66 individuals with AUTS2 variants presented in the literature. The clinical features for individuals with variants in the HX repeat domain include severe intellectual disability, severe language disability, distinct craniofacial and skeletal dysmorphic features, and neuroimaging findings. Facial dysmorphisms include wide and prominent nasal bridges with complex nasal shapes and dysmorphic eyebrows. Dysmorphisms include digit anomalies: Symphalangism and hypoplasia of distal phalanges, exclusive to the HX domain variant group. Cerebellar anomalies not seen with other AUTS2 variants are seen within this group. Our report delineates a distinct and severe clinical phenotype associated with variants in the AUTS2 HX domain, including an in-depth comparison with the AUTS2 haploinsufficiency phenotype features.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64093"},"PeriodicalIF":1.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963911","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":"Worth the Effort: Lessons for Discovery and Care From an Unusual Case of Gorlin Syndrome.","authors":"V Taliercio, J Zhao, S E Boyden, R Mao, P Bayrak-Toydemir, A Pflaum, J Palumbos, A Andrews, E E Baldwin, C Welt, Mackenzie Fait, L D Botto, D Viskochil","doi":"10.1002/ajmg.a.64108","DOIUrl":"https://doi.org/10.1002/ajmg.a.64108","url":null,"abstract":"<p><p>Gorlin-Goltz Syndrome (GGS) is a rare autosomal dominant genetic disorder encompassing a diverse range of clinical manifestations, including congenital anomalies and predisposition to cancer. Pathogenic variants in PTCH1 and SUFU account for up to 79% and 6% of cases, respectively. Currently, an estimated 15%-27% of individuals with a clinical diagnosis of GGS do not have a pathogenic variant identified in either gene. We report on a 17-year-old female referred to the Undiagnosed Disease Network with a clinical diagnosis of GGS that manifested as both classic and unusual findings, including isolated hypogonadotropic hypogonadism and anosmia (Kallmann syndrome), orofacial cleft, and abnormal semicircular canals (SCC). Prior genetic testing, including a targeted gene panel, genomic microarray, exome sequencing, and genome sequencing, was non-diagnostic, although these studies identified a variant of uncertain significance in CHD7, which may have contributed to elements of the phenotype (e.g., abnormal SCC). Reanalysis of genome sequencing data using research analytic methods, together with karyotyping, FISH, and Sanger sequencing, identified a novel de novo paracentric inversion that truncated PTCH1. These findings underscore the value of in-depth phenotype-guided genomic analysis, including chromosomal structural variants, as well as the occurrence of possible dual genetic diagnoses in the same individuals. Moreover, the definitive diagnosis provided the patient and family with a firmer basis for management and counseling.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64108"},"PeriodicalIF":1.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962862","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":"A Novel Presentation and Variable Phenotypic Spectrum of Homozygous Start-Loss Variant in LYRM7-Associated Mitochondrial Complex III Deficiency.","authors":"Noel Deep Luke, Aditya Vijayakrishnan Nair, Ajith Sivadasan, Karthik Muthusamy, Maya Mary Thomas, Sangeetha Yoganathan, Rekha Aaron, Anitha Jasper, Pavithra Mannam, Roshan Daniel, Sumita Danda","doi":"10.1002/ajmg.a.64105","DOIUrl":"https://doi.org/10.1002/ajmg.a.64105","url":null,"abstract":"<p><p>LYRM7-associated mitochondrial complex III deficiency has classically been described in the literature as a childhood-onset episodic leukoencephalopathy with neuroimaging findings of cavitating periventricular and subcortical white matter loss. We describe the heterogeneous clinical and neuroimaging profile of six individuals from south India with the specific homozygous pathogenic variant in the LYRM7 gene (c.2T>C, (p.Met1?)). This is a retrospective case series featuring six cases (four pediatric, one adult, and one adolescent-onset) with the pathogenic start loss LYRM7 variant. The spectrum of neurologic manifestations and brain imaging findings documented over multiple clinic visits was analyzed and described. Vision loss and lactic acidosis were seen in all but one individual. A novel phenotype with adult-onset isolated bilateral simultaneous optic neuropathy was noted. Characteristic cavitating leukoencephalopathy in supratentorial white matter was seen in the brain MRI of three out of six individuals. A comprehensive description of our cases along with the previously published cases is provided in the table highlighting the clinical and imaging variability and the disease course. The phenotype of adult-onset isolated acute optic neuropathy can be a manifestation of LYRM7-related mitochondrial disorder. LYRM7-associated Mitochondrial Complex III deficiency should be considered in the differential diagnosis of para- and post-infectious demyelinating/inflammatory disorders, especially if there is a background of variable developmental delay, recurrence of the episodes, family history, cystic changes in cerebral white matter on imaging, or poor response to immunomodulation. The case series also exemplifies the intra-and inter-familial variability seen with this rare disorder.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64105"},"PeriodicalIF":1.7,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952152","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":"Mosaicism for Genome Wide Homozygosity Identified as an Incidental Finding in Two Apparently Healthy Pregnant Women.","authors":"Gloria T Haskell, S Hussain Askree, Laura Kline, Linda Hasadsri, Huong Cabral, Inder Gadi, Stuart Schwartz","doi":"10.1002/ajmg.a.64106","DOIUrl":"https://doi.org/10.1002/ajmg.a.64106","url":null,"abstract":"<p><p>Uniparental Disomy (UPD) occurs when both copies of a chromosome or chromosomal segment originate from only one parent. Mosaic genome-wide UPD (mos gwUPD) is typically identified in cases of fetal demise and placental dysplasia or in prenatal cases, where imprinting effects are associated with abnormal ultrasound findings. Children with mos gwUPD and clinical features due to UPD-associated imprinting effects (especially Beckwith-Wiedemann syndrome) have been reported; however, reports of adults with mos gwUPD are rare. Here we describe mos gwUPD in two apparently healthy pregnant adult women. Carrier testing noted variants with skewed allelic ratios outside of the normal heterozygous range, prompting further testing. Single nucleotide polymorphism (SNP) microarray identified mosaicism for gwUPD in both individuals, present at 85% and 90%, respectively, in blood, with varying percentages in other tissues. Neither woman displayed clinical features that would be expected with gwUPD at the time of testing, although retrospective careful personal history was consistent. Both women had uneventful pregnancies and delivered full-term healthy infants. These two cases demonstrate that mos gwUPD can be an incidental finding identified in apparently healthy adult women. Clinical follow-up is important for tumor monitoring, genetic counseling, and monitoring of future pregnancies due to mos gwUPD in the maternal endometrial tissue.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64106"},"PeriodicalIF":1.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951992","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}