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

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.

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Fig. 1: Family pedigrees, clinical pictures and UBE4A pathogenic variants of individuals from four unrelated families.
Fig. 2: Gene and protein expression.
Fig. 3: Ube4aC425Ffs* mice have mild cataracts.
Fig. 4: Phenotype assessment tests conducted on homozygous Ube4aC425Ffs* and wild-type (WT) mice.

Data availability

Data and materials are available upon request.

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Acknowledgements

We thank the patients and families for their support and participation. This study was supported by a grant from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (CEPID number 2013/08028-1, 2014/15982-6) and by a grant from the National Institutes of Health (NIH) Office of the Director (U42OD012210). U.S.M. was fellow of FAPESP (2016/14517-3). We also thank Euna Koo for the image in Figure S3.

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Authors

Contributions

Conceptualization: U.S.M., D.B., F.K., H.M.B. Funding acquisition: U.S.M., M.Z., F.K., H.M.B. Methodology: U.S.M., D.B., J.A.B., K.D., J.P.K., F.K., H.M.B. Project administration: U.S.M., F.K., H.M.B. Resources: K.C.K.L., M.Z., C.F.M.M., E.S., N.D.D., F.S.A., F.K., H.M.B. Validation: B.W., L.B., B.C.L., D.J.M., F.G., F.d.S.L., D.O., F.P.M., M.T.W., A.J., M.H., H.S.A., A.C. Visualization: U.S.M., D.B., A.M., L.L. Writing—original draft: U.S.M, D.B., F.K., H.M.B. Writing—review & editing: U.S.M, D.B., F.K., H.M.B.

Corresponding authors

Correspondence to Uirá Souto Melo PhD or Heather M. Byers MD.

Ethics declarations

Ethics declaration

Studies were independently approved by the review boards of the participating institutions and performed according to local laws: family A: University of Sao Paulo CAAE 77680117.0.0000.5464; family B: Stanford University, IRB 28362; family C: King Faisal Specialist Hospital and Research Centre (KFSHRC) RAC 2121053; family D: German Gene Diagnostic Act (Gendiagnostikgesetz), EK 273072018. Written informed consent was obtained from parents or legal guardians to participate in these studies, giving permission to use patients’ (1) DNA samples for genomic sequencing, (2) blood or skin fibroblasts for establishing cell lines, and (3) photos for research publications and presentations. Mouse Model: All animal use was conducted in accordance with the Animal Welfare Act and the 2013 American Veterinary Medical Association (AVMA) Guidelines on Euthanasia. All studies were done consistent with the Institute for Laboratory Animal Research (ILAR) 8th Revision to the Guide for the Care and Use of Laboratory Animals and in compliance with and with prior approval from the University of California–Davis institutional animal care and use committee (IACUC).

Competing interests

The authors declare no competing interests.

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Melo, U.S., Bonner, D., Kent Lloyd, K.C. et al. Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay. Genet Med 23, 661–668 (2021). https://doi.org/10.1038/s41436-020-01047-z

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