Variants in EFCAB7 underlie nonsyndromic postaxial polydactyly

Area of Science:

• Genetics
• Developmental Biology
• Human Disease Etiology

Background:

• Polydactyly is a common limb malformation with known genetic underpinnings for many syndromic forms.
• Nonsyndromic polydactyly, while more common, has had fewer identified causative genes, with eleven candidates reported previously.

Purpose of the Study:

• To investigate the genetic cause of autosomal recessive nonsyndromic postaxial polydactyly in four consanguineous Pakistani families.
• To identify novel genetic variants associated with this limb malformation.

Main Methods:

• Exome sequencing was performed on affected individuals from four Pakistani families.
• Novel homozygous frameshift deletions in the EFCAB7 gene were identified.
• Sanger sequencing was used to confirm variant segregation within families.

Main Results:

• Two novel homozygous frameshift deletions in EFCAB7 (c.830delG and c.1350_1351delGA) were found in three and one family, respectively.
• These EFCAB7 variants segregated with the postaxial polydactyly phenotype.
• EFCAB7 is expressed in skeletal muscle and cilia and is part of the EvC complex, a regulator of the Hedgehog pathway crucial for limb development.

Conclusions:

• This study is the first to report the involvement of EFCAB7 in human disease etiology, specifically nonsyndromic postaxial polydactyly.
• Mutations in EFCAB7 disrupt limb development pathways, contributing to this congenital anomaly.
• Further research into EFCAB7 function can elucidate mechanisms of limb formation and polydactyly.