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Stephen, J. and Girisha, K.M. and Dalal, Ashwin and Shukla, A. and Shah, H. and Srivastava, P. and Kornak, U. and Phadke, S.R. (2015) Mutations in patients with osteogenesis imperfecta from consanguineous Indian families. European Journal of Medical Genetics, 58 (1). pp. 21-27. ISSN 1878-0849

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Abstract

Osteogenesis imperfecta (OI) is a spectrum of genetic disorders with decreased bone density and bone fragility. Most of the cases of OI are inherited in autosomal dominant fashion with mutations in COL1A1 or COL1A2 genes. Over last few years, twelve genes for autosomal recessive OI have been identified. In this study we have evaluated seven patients with OI from consanguineous Indian families. Homozygosity mapping using SNP microarray was done and selected candidate genes were sequenced. Candidate genes were identified in four out of seven patients studied. Four mutations, namely; a homozygous non-sense (p.Q178*) and a deletion (p.F277del) mutations in SERPINF1 gene, a missense mutation (p.M101K) in PPIB gene and a nonsense mutation (p.E45*) in CRTAP gene were identified. In three patients for whom the regions of homozygosity did not reveal any known autosomal recessive OI genes, exome sequencing was performed and we identified a known missense mutation (p.G1012S) in COL1A2 gene in one of the patients. As WNT1 gene was not properly covered in exome sequencing in one patient, the gene was sequenced and a homozygous in-frame deletion of four amino acids (p.Phe176_Leu179del) was identified. In one of the three cases the exome sequencing did not reveal a mutation in any known OI genes, suggesting the possibility of mutations in an unidentified gene. The phenotypes of all the cases are described. This work proves the power of homozygosity mapping followed by candidate gene sequencing approach for clinical application in consanguineous families. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Item Type: Article
Uncontrolled Keywords: Autosomal recessive; CRTAP; Consanguinity; Exome sequencing; Homozygosity; India; OI; PPIB; SERPINF1; WNT1
Subjects: Genetics
Molecular Biology
Depositing User: Dr P Divakar
Date Deposited: 15 May 2015 11:57
Last Modified: 24 Sep 2015 06:21
URI: http://cdfd.sciencecentral.in/id/eprint/25

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