{"title":"Identification of a Novel TRIT1 Mutation in a Consanguineous Iranian–Azeri–Turkish Family With Global Developmental Delay","authors":"Fatemeh Beyad, Mortaza Bonyadi, Mohammad Barzegar","doi":"10.1002/jdn.70053","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>Global developmental delay (GDD) and intellectual disability (ID) affect up to 3% of the paediatric population, with a multifactorial aetiology that complicates genetic identification. To date, over 400 genes have been implicated in GDD. Here, we report a novel homozygous splice acceptor variant, NC_000001.11(NM_017646.6):c.1235-3C>G, in the <i>TRIT1</i> gene, classified as ‘likely pathogenic’ through bioinformatics analysis. The proband, a 5-year-old male from a consanguineous family, presented with severe GDD, microcephaly, progressive spasticity, contractures, dysmorphic features (low-set ears, high-arched palate, simian creases and hypospadias), and refractory seizures (focal motor clonic, generalized myoclonic, and tonic) since 6 months of age. Brain MRI revealed nonspecific atrophy, while metabolic, laboratory and electrophysiological evaluations were unremarkable. To further assess the variant's frequency, we screened 430 healthy individuals from the same ethnic group and found no occurrences of the variant. Notably, this variant has not been documented in any published population databases, including gnomAD, the 1000 Genomes Project, Genome Asia, GME Variome and Iranome, despite coverage of the locus in these databases. Taken together, these findings strongly support the potential pathogenicity of the variant. In addition, the prenatal diagnosis results from the subsequent pregnancy in this family showed that the embryo was heterozygous for the mutation. The baby was born, and follow-up studies indicated that she was healthy, with no clinical manifestations observed in her affected brother. This further supports the classification of the variant as ‘likely pathogenic.’ This study expands the phenotypic spectrum of <i>TRIT1</i>-related disorders.</p>\n </div>","PeriodicalId":13914,"journal":{"name":"International Journal of Developmental Neuroscience","volume":"85 6","pages":""},"PeriodicalIF":1.6000,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Developmental Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jdn.70053","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"DEVELOPMENTAL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Global developmental delay (GDD) and intellectual disability (ID) affect up to 3% of the paediatric population, with a multifactorial aetiology that complicates genetic identification. To date, over 400 genes have been implicated in GDD. Here, we report a novel homozygous splice acceptor variant, NC_000001.11(NM_017646.6):c.1235-3C>G, in the TRIT1 gene, classified as ‘likely pathogenic’ through bioinformatics analysis. The proband, a 5-year-old male from a consanguineous family, presented with severe GDD, microcephaly, progressive spasticity, contractures, dysmorphic features (low-set ears, high-arched palate, simian creases and hypospadias), and refractory seizures (focal motor clonic, generalized myoclonic, and tonic) since 6 months of age. Brain MRI revealed nonspecific atrophy, while metabolic, laboratory and electrophysiological evaluations were unremarkable. To further assess the variant's frequency, we screened 430 healthy individuals from the same ethnic group and found no occurrences of the variant. Notably, this variant has not been documented in any published population databases, including gnomAD, the 1000 Genomes Project, Genome Asia, GME Variome and Iranome, despite coverage of the locus in these databases. Taken together, these findings strongly support the potential pathogenicity of the variant. In addition, the prenatal diagnosis results from the subsequent pregnancy in this family showed that the embryo was heterozygous for the mutation. The baby was born, and follow-up studies indicated that she was healthy, with no clinical manifestations observed in her affected brother. This further supports the classification of the variant as ‘likely pathogenic.’ This study expands the phenotypic spectrum of TRIT1-related disorders.
期刊介绍:
International Journal of Developmental Neuroscience publishes original research articles and critical review papers on all fundamental and clinical aspects of nervous system development, renewal and regeneration, as well as on the effects of genetic and environmental perturbations of brain development and homeostasis leading to neurodevelopmental disorders and neurological conditions. Studies describing the involvement of stem cells in nervous system maintenance and disease (including brain tumours), stem cell-based approaches for the investigation of neurodegenerative diseases, roles of neuroinflammation in development and disease, and neuroevolution are also encouraged. Investigations using molecular, cellular, physiological, genetic and epigenetic approaches in model systems ranging from simple invertebrates to human iPSC-based 2D and 3D models are encouraged, as are studies using experimental models that provide behavioural or evolutionary insights. The journal also publishes Special Issues dealing with topics at the cutting edge of research edited by Guest Editors appointed by the Editor in Chief. A major aim of the journal is to facilitate the transfer of fundamental studies of nervous system development, maintenance, and disease to clinical applications. The journal thus intends to disseminate valuable information for both biologists and physicians. International Journal of Developmental Neuroscience is owned and supported by The International Society for Developmental Neuroscience (ISDN), an organization of scientists interested in advancing developmental neuroscience research in the broadest sense.