Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay
| Autor: | Mais Hashem, Jonathan A. Bernstein, Carlos Frederico Martins Menck, Brandon J. Willis, Aziza Chedrawi, Heather M. Byers, Matthew T. Wheeler, Arne Jahn, Danyllo Oliveira, João Paulo Kitajima, Fowzan S. Alkuraya, Lynette Bower, Elizabeth Spiteri, Fabíola Paoli Monteiro, Mayana Zatz, Hessa S. Alsaif, Brian C. Leonard, Uirá Souto Melo, Nataliya Di Donato, Devon Bonner, Ala Moshiri, Fernando Kok, Louise Lanoue, Kevin Dumas, Kevin C K Lloyd, Fernando Ribeiro Gomes, Felipe de Souza Leite, Davi Jardim Martins |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
VARIAÇÃO GENÉTICA Developmental Disabilities Ubiquitin-Protein Ligases Neurological function Dwarfism 030105 genetics & heredity Bioinformatics Short stature Mice 03 medical and health sciences Intellectual Disability Exome Sequencing Intellectual disability Animals Humans Medicine Global developmental delay Child Genetics (clinical) Exome sequencing Loss function business.industry Syndrome medicine.disease Human genetics Hypotonia Phenotype 030104 developmental biology Muscle Hypotonia medicine.symptom business |
| Zdroj: | GENETICS IN MEDICINE Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1098-3600 |
| Popis: | Purpose To identify novel genes associated with intellectual disability (ID) in four unrelated families. Methods Here, through exome sequencing and international collaboration, we report eight individuals from four unrelated families of diverse geographic origin with biallelic loss-of-function variants in UBE4A. Results Eight evaluated individuals presented with syndromic intellectual disability and global developmental delay. Other clinical features included hypotonia, short stature, seizures, and behavior disorder. Characteristic features were appreciated in some individuals but not all; in some cases, features became more apparent with age. We demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioral abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals. Conclusion These data indicate that biallelic loss-of-function variants in UBE4A cause a novel intellectual disability syndrome, suggesting that UBE4A enzyme activity is required for normal development and neurological function. |
| Databáze: | OpenAIRE |
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