Exome sequencing revealed a novel loss‐of‐function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly

Abstract

Background Polydactyly is a common genetic limb deformity characterized by the presence of extra fingers or toes. This anomaly may occur in isolation (nonsyndromic) or as part of a syndrome. The disease is broadly divided into preaxial polydactyly (PPD; duplication of thumb), mesoaxial polydactyly (complex polydactyly), and postaxial polydactyly (PAP: duplication of the fifth finger). The extra digits may be present in one or both the limbs. Heterozygous variants in the GLI3 , ZRS / SHH , and PITX1 have been associated with autosomal dominant polydactyly, while homozygous variants in the ZNF141 , IQCE , GLI1 , and FAM92A have been associated with autosomal recessive polydactyly. Pathogenic mutations in the GLI3 gene (glioma‐associated oncogene family zinc finger 3) have been associated with both nonsyndromic and syndromic polydactyly. Methods Here, we report an extended five generation kindred having 12 affected individuals exhibiting nonsyndromic postaxial polydactyly type A condition. Whole‐exome sequencing followed by variant prioritization, bioinformatic studies, Sanger validation, and segregation analysis was performed. Results Using exome sequencing in the three affected individuals, we identified a novel heterozygous frameshift variant (c.3567_3568insG; p.Ala1190Glyfs*57) in the transcriptional activator (TA2) domain of the GLI3 encoding gene. Conclusion To the best of our knowledge, the present study reports on the first familial case of nonsyndromic postaxial polydactyly due to the GLI3 variant in Pakistani population. Our study also demonstrated the important role of GLI3 in causing nonsyndromic postaxial polydactyly.

Genetic overview of postaxial polydactyly: Updated classification

“…As a polydactyly is also involved in hundreds of different syndromic disorders, thus increasing our existing information about newly discovered pathways and their interconnected genes might help in future therapeutic interventions. 50,51 Furthermore, specific pathogenic variants in the causal gene might cause the concerned phenotype, while different variants in modifier genes might explain the phenotypic variability in several cases. The advancement of new technologies such as the NGS approach has been used to figure out diseases associated with Mendelian and non-Mendelian disorders and identify the disease-causing genes.…”

A variant in the LDL receptor‐related protein encoding gene LRP4 underlying polydactyly and phalangeal synostosis in a family of Pakistani origin

“…Shh regulates limb skeletal patterning by modulating Gli3 activity 14 . Variants in GLI3 have been associated with pre and postaxial polydactyly 15,16 …”

“…14 Variants in GLI3 have been associated with pre and postaxial polydactyly. 15,16 Here, we present a heterozygous missense variant [p.(Gly566Ser)] in the LRP4 gene causing a previously unreported combination of complex polydactyly in hands, preaxial polydactyly in feet, and phalangeal synostosis in a Pakistani family segregating the disorder in an autosomal dominant manner.…”

A novel variant of GLI3, p.Asp1514Thrfs*5, is identified in a Chinese family affected by polydactyly

“…PAP can be further sub‐divided into postaxial polydactyly type A (PAPA) and postaxial polydactyly type B (PAPB) based on developmental status, the former of which is characterized by a well‐formed redundant digit, whereas the latter manifests only as a minor protuberance (Malik, 2014 ). It has previously been established that polydactyly is primarily inherited in an autosomal dominant pattern, and that human polydactyly is associated with the GLI family zinc‐finger 3 protein ( GLI3 ; MIM*165240 ) (Al‐Qattan et al, 2017 ; Umair et al, 2019 ; Verma & El‐Harouni, 2015 ). The GLI3 gene has been demonstrated to be one of the three GLI zinc‐finger transcription factors that mediate the SHH‐GLI3 pathway, and has been identified as playing an important role during embryogenesis, particularly with respect to formation of the neural tube, craniofacial structure, and limbs (Motoyama, 2006 ).…”