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Variants in EFCAB7 underlie nonsyndromic postaxial polydactyly

European Journal of Human Genetics volume 31, pages 1270–1274 (2023)Cite this article

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Abstract

Polydactyly is the most common limb malformation that occurs in 1.6–10.6 per one thousand live births, with incidence varying with ancestry. The underlying gene has been identified for many of the ~100 syndromes that include polydactyly. While for the more common form, nonsydromic polydactyly, eleven candidate genes have been reported. We investigated the underlying genetic cause of autosomal recessive nonsyndromic postaxial polydactyly in four consanguineous Pakistani families. Some family members with postaxial polydactyly also present with syndactyly, camptodactyly, or clinodactyly. Analysis of the exome sequence data revealed two novel homozygous frameshift deletions in EFCAB7: [c.830delG;p.(Gly277Valfs*5)]; in three families and [c.1350_1351delGA;p.(Asn451Phefs*2)] in one family. Sanger sequencing confirmed that these variants segregated with postaxial polydactyly, i.e., family members with postaxial polydactyly were found to be homozygous while unaffected members were heterozygous or wild type. EFCAB7 displays expressions in the skeletal muscle and on the cellular level in cilia. IQCE-EFCAB7 and EVC-EVC2 are part of the heterotetramer EvC complex, which is a positive regulator of the Hedgehog (Hh) pathway, that plays a key role in limb formation. Depletion of either EFCAB7 or IQCE inhibits induction of Gli1, a direct Hh target gene. Variants in IQCE and GLI1 have been shown to cause nonsyndromic postaxial polydactyly, while variants in EVC and EVC2 underlie Ellis van Creveld and Weyers syndromes, which include postaxial polydactyly as a phenotype. This is the first report of the involvement of EFCAB7 in human disease etiology.

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Fig. 1: Pedigrees of postaxial polydactyly families MB1, BD547, BD635, and BD727.
Fig. 2: Photographs of hands and feet of affected pedigree members.

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Data availability

The identified variants have been submitted to the ClinVar database [Accession numbers: SCV003804323 and SCV003804374].

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Acknowledgements

We are highly obliged to members of the families for their cooperation and participation in this study. Muhammad Bilal, Hammal Khan and Muhammad Javed Khan were supported by Indigenous PhD and IRSIP fellowships from Higher Education Commission (HEC), Islamabad, Pakistan.

Funding

This research was funded by Higher Education Commission of Pakistan, Pediatric Genomics Discovery Program, and the Department of Neurology, Columbia University Medical Center.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

    Muhammad Bilal, Kifayat Ullah & Wasim Ahmad

  2. Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan

    Hammal Khan & Hamid Ali

  3. Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY, USA

    Hammal Khan, Khurram Liaqat, Thashi Bharadwaj, Anushree Acharya, Isabelle Schrauwen & Suzanne M. Leal

  4. Institute of Biochemistry, University of Balochistan, Quetta, Pakistan

    Muhammad Javed Khan, Sohail Ahmed & Muhammad Sharif Hasni

  5. Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

    Tobias B. Haack, Rebecca Buchert & Susana Peralta

  6. National Centre for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan

    Najumuddin

  7. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Asmat Ullah

  8. Taub Institute for Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA

    Suzanne M. Leal

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  1. Muhammad Bilal
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Contributions

MB, HK, and MJK performed the laboratory experiments, analyzed the genomic data, and drafted the manuscript. IS, KL, AA, TB, N, HA, SA, KU, MSH, and AU collected samples and analyzed clinical and genomic data. WA and SML designed the project, analyzed the data, edited the manuscript, and provided funds for the study.

Corresponding author

Correspondence to Suzanne M. Leal.

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Bilal, M., Khan, H., Khan, M.J. et al. Variants in EFCAB7 underlie nonsyndromic postaxial polydactyly. Eur J Hum Genet 31, 1270–1274 (2023). https://doi.org/10.1038/s41431-023-01450-5

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