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Title: Novel mutation G324C in WNT1 mapped in a large Pakistani family with severe recessively inherited Osteogenesis Imperfecta
Authors: Kausar, Mehran
Saima Siddiqi
Muhammad Yaqoob
Sajid Mansoor
Makitie, Outi
Asif Mir
Khor, Chiea Chuen
Foo, Jia Nee
Anees, Mariam
Keywords: Whole-exome Sequencing
WNT Signaling
Issue Date: 2018
Source: Kausar, M., Saima Siddiqi., Muhammad Yaqoob., Sajid Mansoor., Makitie, O., Asif Mir., . . . Anees, M. (2018). Novel mutation G324C in WNT1 mapped in a large Pakistani family with severe recessively inherited Osteogenesis Imperfecta. Journal of Biomedical Science, 25(1), 82-. doi:10.1186/s12929-018-0481-x
Series/Report no.: Journal of Biomedical Science
Abstract: Introduction: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disease with skeletal fragility and variable extra-skeletal manifestations. To date several point mutations in 18 different genes causing different types of OI have been identified. Mutations in WNT1 compromise activity of the osteoblasts leading to disturbed bone mass accrual, fragility fractures and progressive skeletal abnormalities. The present study was conducted to determine the underlying genetic cause of an autosomal recessive skeletal dysplasia in a large consanguineous family from Chinute, Pakistan.Materials and methods: Blood was collected from 24 individuals of affected family along with clinical data. Homozygosity mapping was performed to confirm consanguinity. SNPs were identified, followed by whole exome and Sanger sequencing. In silico characterization of WNT1 mutation was performed using multiple platforms. Results:Nine affected family members exhibited severe bone deformities, recurrent fractures, short stature and low bone mineral density. SNP array data revealed homozygous segments > 1 Mb in length accounting for 2.1–12.7% of the genome in affected individuals and their siblings and a single 6,344,821 bp homozygous region in all affected individuals on chromosome 12q12-q13. This region includes two potential OI candidate genes WNT1 and VDR. We did whole-exome sequencing for both genes in two patients and identified a novel damaging missense mutation in exon 4 of WNT1: c.1168G > T (NM_005430) resulting in p.G324C. Sanger sequencing confirmed segregation of mutation with the disease in family.Conclusion:We report a novel mutation responsible for OI and our investigation expands the spectrum of disease-causing WNT1 mutations and the resulting OI phenotypes.
ISSN: 1021-7770
DOI: 10.1186/s12929-018-0481-x
Rights: © 2018 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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