Publication Details

Title :

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


Mol Genet Genomic Med.

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Umair M1, Wasif N2, Albalawi AM3, Ramzan K4, Alfadhel M1,5, Ahmad W6, Basit S3.


1 Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia.

2 Institut für Human Genetik, Ulm Universität, Ulm, Germany.

3 Center for Genetics and Inherited Diseases, Taibah University, Medina, Saudi Arabia.

4 Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

5 Division of Genetics, Department of Pediatrics, King Abdullah Specialized Children’s Hospital (KASCH), Riyadh, Saudi Arabia.

6 Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.

Year of Publication:





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.

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.

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.

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.