Variants in EFCAB7 underlie nonsyndromic postaxial polydactyly

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.

Fig. 1. Pedigrees of postaxial polydactyly families MB1, BD547, BD635, and BD727.

Circles represent females and squares males. Filled symbols designate individuals with postaxial polydactyly. An asterisk indicates a DNA sample was obtained from the family member and a blue arrow indicates that the DNA sample underwent exome sequencing. Below every individual with an available DNA sample is shown their genotype for the EFCAB7 variant segregating in the family. A Family MB1 that segregates c.830delG;p.(Gly277Valfs*5). B Family BD547 that segregates c.830delG;p.(Gly277Valfs*5). C Family BD635 that segregates c.830delG;p.(Gly277Valfs*5). D Family BD727 that segregates c.1350_1351delGA;p.(Asn451Phefs*2).

Fig. 2. Photographs of hands and feet of affected pedigree members.

A Hands of affected individual (IV-1) from Family MB1 who has postaxial polydactyly of both hands. B Feet of affected individual (IV-1) from Family MB1 showing postaxial polydactyly. C–E Hands and feet of affected individual (IV-1) from Family BD635 manifesting postaxial polydactyly with bilateral syndactyly in feet only. F–H Affected individual (IV-2) from BD635 exhibiting bilateral postaxial polydactyly in the feet. Extra digits of the hands that were surgically removed are circled in red. I, J Feet of affected individual (IV-3) from Family BD727 manifesting bilateral postaxial polydactyly, polydactyly of the hands was surgically corrected. K Affected individual (IV-2) from Family BD727 exhibiting bilateral postaxial polydactyly in feet only.