Biallelic variant in DACH1, encoding Dachshund Homolog 1, defines a novel candidate locus for recessive postaxial polydactyly type A

• Published in: Genomics (San Diego, Calif.) Calif.), 2021-07, Vol.113 (4), p.2495-2502
• Main Authors: Umair, Muhammad, Palander, Oliva, Bilal, Muhammad, Almuzzaini, Bader, Alam, Qamre, Ahmad, Farooq, Younus, Muhammad, Khan, Amjad, Waqas, Ahmed, Rafeeq, Misbahuddin M, Alfadhel, Majid
• Format: Article
• Language: English
• Subjects: Biochemistry, Molecular Biology; Cilia; DACH1 gene; Eye Proteins - genetics; Fingers; Genomics; Humans; Life Sciences; Limb anomaly; Missense variant; Pedigree; Polydactyly - genetics; Postaxial polydactyly (PAP); Toes; Transcription Factors - genetics; Whole Exome Sequencing
• ISSN: 0888-7543; 1089-8646
• DOI: 10.1016/j.ygeno.2021.05.015

Polydactyly or hexadactyly is characterized by an extra digit/toe with or without a bone. Currently, variants in ten genes have been implicated in the non-syndromic form of polydactyly. DNA from a single affected individual having bilateral postaxial polydactyly was subjected to whole exome sequencing (WES), followed by Sanger sequencing. Homology modeling was performed for the identified variant and advance microscopy imaging approaches were used to reveal the localization of the DACH1 protein at the base of primary cilia. A disease-causing biallelic missense variant (c.563G > A; p.Cys188Tyr; NM_080760.5) was identified in the DACH1 gene segregating perfectly within the family. Structural analysis using homology modeling of the DACH1 protein revealed secondary structure change that might result in loss of function or influence downstream interactions. Moreover, siRNA-mediated depletion of DACH1 showed a key role of DACH1 in ciliogenesis and cilia function. This study provides the first evidence of involvement of the DACH1 gene in digits development in humans and its role in primary cilia. This signifies the importance and yet unexplored role of DACH1. •WES and Sanger sequencing identified a bi-allelic variant in the DACH1 gene associated with PAP type A.•Findings substantiate the role of DACH1 gene in digits development in humans.•This study showed role of DACH1 proteins in ciliogenesis and cilia function.•First evidence that homozygous DACH1 variant might lead to abnormal digit development in humans.