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Exome sequencing revealed a novel loss-of-function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly.
Mol Genet Genomic Med. 2019 07; 7(7):e00627.MG

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.

Authors+Show Affiliations

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.Institut für Human Genetik, Ulm Universität, Ulm, Germany.Center for Genetics and Inherited Diseases, Taibah University, Medina, Saudi Arabia.Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.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. Division of Genetics, Department of Pediatrics, King Abdullah Specialized Children's Hospital (KASCH), Riyadh, Saudi Arabia.Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.Center for Genetics and Inherited Diseases, Taibah University, Medina, Saudi Arabia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31115189

Citation

Umair, Muhammad, et al. "Exome Sequencing Revealed a Novel Loss-of-function Variant in the GLI3 Transcriptional Activator 2 Domain Underlies Nonsyndromic Postaxial Polydactyly." Molecular Genetics & Genomic Medicine, vol. 7, no. 7, 2019, pp. e00627.
Umair M, Wasif N, Albalawi AM, et al. Exome sequencing revealed a novel loss-of-function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly. Mol Genet Genomic Med. 2019;7(7):e00627.
Umair, M., Wasif, N., Albalawi, A. M., Ramzan, K., Alfadhel, M., Ahmad, W., & Basit, S. (2019). Exome sequencing revealed a novel loss-of-function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly. Molecular Genetics & Genomic Medicine, 7(7), e00627. https://doi.org/10.1002/mgg3.627
Umair M, et al. Exome Sequencing Revealed a Novel Loss-of-function Variant in the GLI3 Transcriptional Activator 2 Domain Underlies Nonsyndromic Postaxial Polydactyly. Mol Genet Genomic Med. 2019;7(7):e00627. PubMed PMID: 31115189.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exome sequencing revealed a novel loss-of-function variant in the GLI3 transcriptional activator 2 domain underlies nonsyndromic postaxial polydactyly. AU - Umair,Muhammad, AU - Wasif,Naveed, AU - Albalawi,Alia M, AU - Ramzan,Khushnooda, AU - Alfadhel,Majid, AU - Ahmad,Wasim, AU - Basit,Sulman, Y1 - 2019/05/21/ PY - 2019/01/13/received PY - 2019/02/11/revised PY - 2019/02/11/accepted PY - 2019/5/23/pubmed PY - 2020/6/12/medline PY - 2019/5/23/entrez KW - GLI3 KW - PAPA KW - Sanger sequencing KW - loss-of-function variant KW - polydactyly KW - whole exome sequencing SP - e00627 EP - e00627 JF - Molecular genetics & genomic medicine JO - Mol Genet Genomic Med VL - 7 IS - 7 N2 - 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. SN - 2324-9269 UR - https://www.unboundmedicine.com/medline/citation/31115189/Exome_sequencing_revealed_a_novel_loss_of_function_variant_in_the_GLI3_transcriptional_activator_2_domain_underlies_nonsyndromic_postaxial_polydactyly_ L2 - https://doi.org/10.1002/mgg3.627 DB - PRIME DP - Unbound Medicine ER -