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

Author(s):Show less -

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]

Affiliation:Show less -

^[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

• Document type: Journal article
• Source: Genetics in Medicine; v. 23, n. 4 JAN 2021.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 14/15982-6 - Consequences of repair deficiencies in damaged genome
• Grantee: Carlos Frederico Martins Menck
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 16/14517-3 - Search for "protective" modifying variants/mechanisms in asymptomatic or very mildly affected individuals with pathogenic mutation in SPAST gene
• Grantee: Uirá Souto Melo
• Support Opportunities: Scholarships in Brazil - Post-Doctoral