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

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.

Nonsense mutations of the CYBB gene in two Thai families with X-linked chronic granulomatous disease.

X-linked chronic granulomatous disease (X-CGD) is an immunodeficiency disorder characterized by defective intracellular killing of microorganisms due to the neutrophils' inability to generate superoxide ions. Although it is always caused by mutations in the CYBB gene, clinical and molecular characteristics vary in different ethnic backgrounds. Two unrelated Thai boys presented with severe persistent pulmonary infections at the age of two months. Their abnormal dihydrorhodamine (DHR) flow cytometry assays supported the diagnosis of X-CGD. Mutation analysis was performed by polymerase chain reaction (PCR) amplification and sequencing of the entire coding regions of CYBB. Mutations identified were confirmed by restriction enzyme analyses. PCR-sequencing of the entire coding regions of CYBB identified nonsense mutations, 271C>T (R91X) in exon 4 and 456T>A (Y152X) in exon 5, in probands of each family. Both of the patients' mothers were found to be carriers. This observation supports that CYBB is the gene responsible for X-CGD across different populations and nonsense mutations are associated with severe phenotypes.