A novel de novo COL1A1 mutation in a Thai boy with osteogenesis imperfecta born to consanguineous parents.

Siraprapa Tongkobpetch,Thantrira Porntaveetus,Kanya Suphapeetiporn,Noppachart Limpaphayom,Vorasuk Shotelersuk,Apiruk Sangsin

doi:10.1590/1678-4685-gmb-2016-0033

Abstract

Osteogenesis imperfecta (OI) is genetically heterogeneous. Mutations in COL1A1 and COL1A2 are responsible for at least 90% of the cases, which are transmitted in an autosomal dominant manner or are de novo events. We identified a Thai boy with OI whose parents were first cousins. Because the proband was the product of a consanguineous marriage, we hypothesized that he might be homozygous for a mutation in a known gene causing a recessive form of OI. Using whole exome sequencing (WES), we did not find any pathogenic mutations in any known gene responsible for an autosomal recessive form of OI. Instead, we identified a COL1A1 frameshift mutation, c.1290delG (p.Gly431Valfs*110) in heterozygosis. By Sanger sequencing, the mutation was confirmed in the proband, and not detected in his parents, indicating that it was a de novo mutation. These findings had implication for genetic counseling. In conclusion, we expanded the mutational spectrum of COL1A1 and provided another example of a de novo pathogenic mutation in heterozygosis in a patient born to consanguineous parents.

Highlights

Osteogenesis imperfecta (OI), or brittle bone disease, is a disorder characterized by low bone mass, bone fragility and often short stature
Several novel causative genes were subsequently reported by generation sequencing (NGS), including the most recently identified X-linked gene for OI, MBTPS2 (Lindert et al, 2016)
We looked for variants located in the coding regions of known skeletal dysplasia genes for all potential pathogenic Single-nucleotide variants (SNVs) and Indels

Summary

Introduction

Osteogenesis imperfecta (OI), or brittle bone disease, is a disorder characterized by low bone mass, bone fragility and often short stature. About 90% of OI patients carry mutations in the COL1A1 or COL1A2 genes, which are de novo events or transmitted in an autosomal dominant manner due to parental mosaicism. (Seoul, South Korea), Figure 1 - Clinical and radiographic features of the patient with osteogenesis imperfecta.

Results

Conclusion