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A biallelic variant of DCAF13 implicated in a neuromuscular disorder in humans

European Journal of Human Genetics volume 31, pages 629–637 (2023)Cite this article

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Abstract

Neuromuscular disorders encompass a broad range of phenotypes and genetic causes. We investigated a consanguineous family in which multiple patients had a neuromuscular disorder characterized by a waddling gait, limb deformities, muscular weakness and facial palsy. Exome sequencing was completed on the DNA of three of the four patients. We identified a novel missense variant in DCAF13, ENST00000612750.5, NM_015420.7, c.907 G > A;p.(Asp303Asn), ENST00000616836.4, NM_015420.6, c.1363 G > A:p.(Asp455Asn) (rs1209794872) segregating with this phenotype; being homozygous in all four affected patients and heterozygous in the unaffected individuals. The variant was extremely rare in the public databases (gnomAD allele frequency 0.000007081); was absent from the DNA of 300 ethnically matched controls and affected an amino acid which has been conserved across 1–2 billion years of evolution in eukaryotes. DCAF13 contains three WD40 domains and is hypothesized to have roles in both rRNA processing and in ubiquitination of proteins. Analysis of DCAF13 with the p.(Asp455Asn) variant predicted that the amino acid change is deleterious and affects a β-hairpin turn, within a WD40 domain of the protein which may decrease protein stability. Previously, a heterozygous variant of DCAF13 NM_015420.6, c.20 G > C:p.(Trp7Ser) with or without a heterozygous missense variant in CCN3, was suggested to cause inherited cortical myoclonic tremor with epilepsy. In addition, a heterozygous DCAF13 variant has been associated with autism spectrum disorder. Our study indicates a potential role of biallelic DCAF13 variants in neuromuscular disorders. Screening of additional patients with similar phenotype may broaden the allelic and phenotypic spectrum due to DCAF13 variants.

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Fig. 1: Pedigree RDHR-03, phenotype, sequence traces, and depiction of DCAF13 with the encoded protein.
Fig. 2: Conservation of DCAF13 Asp303 in a sampling of eukaryote species.

Data availability

Data supporting manuscript findings is available from corresponding author on reasonable request.

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Acknowledgements

We express our gratitude to all members of the family RDHR-03 for participating in this study. The study was funded by the Higher Education Commission, Pakistan (award #2877).

Funding

The study was supported by grant no. 2877 awarded to SN from the Higher Education Commission, Pakistan.

Author information

Author notes

  1. Humera Manzoor

    Present address: Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore, Pakistan

  2. These authors contributed equally: Humera Manzoor, Hafsa Zahid.

Authors and Affiliations

  1. School of Biological Sciences, University of the Punjab, Quaid-e-Azam Campus, Lahore, 54590, Pakistan

    Humera Manzoor, Hafsa Zahid, Hafiz Muhammad Jafar Hussain & Sadaf Naz

  2. Biology Department, Reedley College, Reedley, CA, 93654, USA

    Christopher A. Emerling

  3. Molecular Medicine Laboratory and Department of Neurology, Concord Repatriation General Hospital, Concord Clinical School Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

    Kishore R. Kumar

  4. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

    Kishore R. Kumar

  5. 3billion inc, Seoul, South Korea

    Go Hun Seo

  6. Department of Zoology, University of Okara, Punjab, Pakistan

    Muhammad Wajid

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Contributions

Research Idea and Study design: SN; Sample collection and clinical analyses: HM, HZ, KRK, HMJ, MW; Data Collection,Analysis and Interpretation: HM, HZ, CAE, GS, SN; Manuscript preparation: HM, HZ, CAE, SN; Final manuscript: All authors. Each author contributed to this work and verifies integrity of this research.

Corresponding author

Correspondence to Sadaf Naz.

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Competing interests

GHS is an employee of 3billion inc, Seoul, South Korea. All authors declare no conflict of interest.

Ethical approval

This study was approved by the Institutional Review Board of School of Biological Sciences, (IRB# 00005281, FWA 00010252), University of the Punjab, Lahore, Pakistan.

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Manzoor, H., Zahid, H., Emerling, C.A. et al. A biallelic variant of DCAF13 implicated in a neuromuscular disorder in humans. Eur J Hum Genet 31, 629–637 (2023). https://doi.org/10.1038/s41431-023-01319-7

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