The molecular spectrum of Turkish osteopetrosis and related osteoclast disorders with natural history (including a candidate gene, CCDC120).

Abstract

Osteopetrosis and related osteoclastic disorders are a heterogeneous group of inherited diseases characterized by increased bone density. The aim of this study is to investigate the molecular spectrum and natural history of the clinical and radiological features of these disorders. 28 patients and 20 families were enrolled in the study; 20 of them were followed for a period of 1-16 years. Targeted gene analysis and whole-exome sequencing (WES) were performed. Biallelic mutations in CLCN7 or TCIRG1 were detected in three families, in TNFRSF11A or CA2 in two families, and in SNX10 in one family in the osteopetrosis group. A heterozygous variant of CLCN7 was also found in one family. In the osteopetrosis and related osteoclast disorders group, three different variants of CTSK were detected in five families with pycnodysostosis and the SLC29A3 variant causing dysosteosclerosis was detected in one family. In autosomal recessive osteopetrosis (ARO), a malignant infantile form, four patients died during follow-up, two of whom had undergone hematopoietic stem cell transplantation. Interestingly, all patients had osteopetrorachia of the long bone metaphyses in infancy, typical skeletal features such as Erlenmeyer flask deformity and bone-in-bone appearance that developed toward the end of early childhood. Two siblings with a biallelic missense mutation in CLCN7 and one patient with the compound heterozygous intronic TCIRG1 variant corresponded to the intermediate form of ARO (IARO); there was intrafamilial clinical heterogeneity in the family with the CLCN7 variant. One of two patients with IARO and distal tubular acidosis was found to have a large deletion in CA2. In one family, two siblings with a heterozygous mutation in CLCN7 were affected, whereas the father with the same mutation was asymptomatic. In WES analysis of three brothers from a family without mutations in osteopetrosis genes, a hemizygous missense variant in CCDC120, a novel gene, was found to be associated with high bone mass. This study extended the natural history of the different types of osteopetrosis and also introduced a candidate gene potentially causing osteopetrosis.