Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta

Gandham, SriLakshmi Bhavani and Shah, Hitesh and Shukla, Anju and Katta, Girisha M (2018) Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta. Bone, 368. pp. 368-377.

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Osteogenesis Imperfecta (OI) is a clinically and genetically heterogeneous disorder. Although differential diagnosis is greatly facilitated by next generation sequencing, its availability can vary considerably. In this study, we compared targeted gene panel or exome sequencing with clinical scoring and grouping in a cohort of 50 OI index patients recruited by a single Indian clinical center in an unselected fashion. In 48 patients we observed a total of 24 novelmutations and 24 known OImutations, ofwhich severalwere recurrent. In one patient neither gene panel nor exome sequencing revealed any significant mutation and another patient harbored a class III COL1A1 intronic variant. The percentage of autosomal recessive forms due to mutations in BMP1, FKBP10,LEPRE1, SERPINF1, and WNT1 was unusually high (48%). Grouping according to phenotypic and radiographic features revealed four individuals with Bruck syndrome due to FKBP10 mutations, three patients with hypertrophic callus caused by IFITM5 mutations, and twenty with pronounced bone bowing, of which eight carriedWNT1 mutations.There was a clear correlation between genotype and phenotype severity: IFITM5 = LEPRE1 N WNT1 N SERPINF1 N COL1A1 (qualitative) N BMP1 N FKBP10 N COL1A2 (qualitative) N COL1A1 (quantitative) N COL1A2 (quantitative). In one patient we found heterozygous variants in COL1A1 and COL1A2 inherited from parents without an obvious bone phenotype indicating that both variants might contribute to the phenotype. Our findings demonstrate the clinical utility of gene panel testing for OI, but in caseswith contractures, hypertrophic callus formation, or – to some extent – extensive bowing single gene analysis might still be more cost-effective.

Item Type: Article
Uncontrolled Keywords: Osteogenesis imperfecta; Low bone mineral density; Multiple fractures; Gene panel; Collagen; Exome sequencing
Subjects: Medicine > KMC Manipal > Medical Genetics
Medicine > KMC Manipal > Orthopaedics
Depositing User: KMC Library
Date Deposited: 23 Aug 2018 04:36
Last Modified: 11 May 2022 06:00
URI: http://eprints.manipal.edu/id/eprint/151837

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