Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay

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Melo, Uira Souto ^{[1, 2]} ; Bonner, Devon ^[3] ; Kent Lloyd, Kevin C. ^{[4, 5]} ; Moshiri, Ala ^[6] ; Willis, Brandon ^[4] ; Lanoue, Louise ^[4] ; Bower, Lynette ^[4] ; Leonard, Brian C. ^[7] ; Martins, Davi Jardim ^[8] ; Gomes, Fernando ^[1] ; de Souza Leite, Felipe ^[1] ; Oliveira, Danyllo ^[1] ; Kitajima, Joao Paulo ^[9] ; Monteiro, Fabiola P. ^[9] ; Zatz, Mayana ^[1] ; Menck, Carlos Frederico Martins ^[8] ; Wheeler, Matthew T. ^[10] ; Bernstein, Jonathan A. ^[3] ; Dumas, Kevin ^[11] ; Spiteri, Elizabeth ^[11] ; Di Donato, Nataliya ^[12] ; Jahn, Arne ^[12] ; Hashem, Mais ^[13] ; Alsaif, Hessa S. ^[13] ; Chedrawi, Aziza ^[14] ; Alkuraya, Fowzan S. ^{[13, 15]} ; Kok, Fernando ^{[1, 9]} ; Byers, Heather M. ^[3]

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^[1] Univ Sao Paulo, Biosci Inst, Dept Genet & Evolutionary Biol, Human Genome & Stem Cell Res Ctr, Sao Paulo, SP - Brazil

^[2] Max Planck Inst Mol Genet, RG Dev & Dis, Berlin - Germany

^[3] Stanford Univ, Div Med Genet, Dept Pediat, Sch Med, Stanford, CA - USA

^[4] Univ Calif Davis, Mouse Biol Program, Davis, CA 95616 - USA

^[5] Univ Calif Davis, Sch Med, Dept Surg, Sacramento, CA 95817 - USA

^[6] Univ Calif Davis, Sch Med, Dept Ophthalmol & Vis Sci, Sacramento, CA 95817 - USA

^[7] Univ Calif Davis, Sch Vet Med, Dept Surg & Radiol Sci, Davis, CA - USA

^[8] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Sao Paulo, SP - Brazil

^[9] Mendelics, Sao Paulo, SP - Brazil

^[10] Stanford Univ, Div Cardiovasc Med, Dept Med, Sch Med, Stanford, CA - USA

^[11] Stanford Univ, Sch Med, Dept Pathol, Clin Genom Program, Stanford, CA - USA

^[12] Tech Univ Dresden, Inst Clin Genet, Dresden - Germany

^[13] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh - Saudi Arabia

^[14] King Faisal Specialist Hosp & Res Ctr, Dept Neurosci, Riyadh - Saudi Arabia

^[15] Alfaisal Univ, Coll Med, Riyadh - Saudi Arabia

• Tipo de documento: Artigo Científico
• Fonte: Genetics in Medicine; v. 23, n. 4 JAN 2021.
• Citações Web of Science: 0

Resumo

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. (AU)

• Processo FAPESP: 14/15982-6 - Consequências de deficiências de reparo de lesões no genoma
• Beneficiário: Carlos Frederico Martins Menck
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 16/14517-3 - Identificação de variantes/mecanismos protetores em indivíduos com mutação patogênica no gene SPAST assintomáticos ou levemente afetados
• Beneficiário: Uirá Souto Melo
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado