CLCN7 and TCIRG1 mutations in a single family: Evidence for digenic inheritance of osteopetrosis

Osteopetrosis is a monogenic condition with various inheritance patterns, including autosomal dominant, autosomal recessive and X-linked. Several disease-causing genes have been identified and three distinguished types of osteopetrosis have been reported. In the present study, a family with osteopetrosis was investigated. Two novel mutations in chloride voltage-gated channel 7 (CLCN7) and T cell immune regulator 1 (TCIRG1) were identified by exome sequencing, Sanger sequencing and microsatellite marker analysis. The CLCN7 mutation occurred in amino acid R286, the same position as previously reported. The TCIRG1 mutation occurred on a splicing site of exon 15, thereby leading to a truncated transcript. These two mutations were undetected in 496 ethnic-matched controls. To the best of our knowledge, this is the first report of human osteopetrosis involving digenic inheritance in a single family, which has important implications for decisions on clinical therapeutic regimen, prognosis evaluation and antenatal diagnosis.