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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The identified variants have been submitted to the ClinVar database [Accession numbers: SCV003804323 and SCV003804374].
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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.
This research was funded by Higher Education Commission of Pakistan, Pediatric Genomics Discovery Program, and the Department of Neurology, Columbia University Medical Center.
The authors declare no competing interest.
Written informed consent for presentation and publication of this study was obtained from all the participating members.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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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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