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

Julia Mrosk, Gandham Sri Lakshmi Bhavani, Hitesh Shah, Jochen Hecht, Ulrike Krüger, Anju Shukla, Uwe Kornak, Katta Mohan Girisha

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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 novel mutations and 24 known OI mutations, of which several were 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 carried WNT1 mutations. There was a clear correlation between genotype and phenotype severity: IFITM5 = LEPRE1 > WNT1 > SERPINF1 > COL1A1 (qualitative) > BMP1 > FKBP10 > COL1A2 (qualitative) > COL1A1 (quantitative) > 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 cases with contractures, hypertrophic callus formation, or – to some extent – extensive bowing single gene analysis might still be more cost-effective.

Original languageEnglish
Pages (from-to)368-377
Number of pages10
JournalBone
Volume110
DOIs
Publication statusPublished - 01-05-2018

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Osteogenesis Imperfecta
Genetic Association Studies
Mutation
Exome
Bony Callus
Genes
Phenotype
Bone and Bones
Contracture
Differential Diagnosis
Parents
Costs and Cost Analysis

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

Mrosk, Julia ; Bhavani, Gandham Sri Lakshmi ; Shah, Hitesh ; Hecht, Jochen ; Krüger, Ulrike ; Shukla, Anju ; Kornak, Uwe ; Girisha, Katta Mohan. / Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta. In: Bone. 2018 ; Vol. 110. pp. 368-377.
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abstract = "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 novel mutations and 24 known OI mutations, of which several were 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 carried WNT1 mutations. There was a clear correlation between genotype and phenotype severity: IFITM5 = LEPRE1 > WNT1 > SERPINF1 > COL1A1 (qualitative) > BMP1 > FKBP10 > COL1A2 (qualitative) > COL1A1 (quantitative) > 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 cases with contractures, hypertrophic callus formation, or – to some extent – extensive bowing single gene analysis might still be more cost-effective.",
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Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta. / Mrosk, Julia; Bhavani, Gandham Sri Lakshmi; Shah, Hitesh; Hecht, Jochen; Krüger, Ulrike; Shukla, Anju; Kornak, Uwe; Girisha, Katta Mohan.

In: Bone, Vol. 110, 01.05.2018, p. 368-377.

Research output: Contribution to journalArticle

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