Genome-Based Diagnosis of Genetic Disease (Commentary‪)‬

Malignant osteopetrosis or autosomal recessive osteopetrosis (ARO) is characterized by severe osteosclerosis, pathologic fractures, hepatosplenomegaly, and pancytopenia, due to an osteoclast dysfunction that results in inadequate bone resorption. ARO is a severe disease, causing early infantile death if bone marrow is not successfully transplanted. The malignant course of the disease and the often unfavourable outcome of bone marrow transplantation make prenatal diagnosis very important (1). However, prenatal ultrasound examination can be normal for a foetus with osteopetrosis (2). Therefore, molecular analysis provides the best method for making a reliable prenatal diagnosis. ARO can result from mutations in the TCIRG1 gene (T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 protein a isoform 3) (3) the CLCN7 gene (chloride channel 7) (4) the OSTM1 gene (osteopetrosis-associated transmembrane protein 1) (5) the TNFSF11 gene (tumour necrosis factor ligand superfamily, member 11 encoding receptor activator for nuclear factor kappa b ligand, RANKL) (6), the TNFRSF11A gene (tumour necrosis factor ligand superfamily, member 11A encoding receptor activator of nuclear factor-kappa B, RANK) (7) or PLEKHM1 gene (pleckstrin homology domain-containing protein, family M, member) (8) and CA2 gene (carbonic anhydrase II) (9). Most ARO cases have been ascribed to mutations in the TCIRG1 gene and only a few cases have been ascribed to mutations in the CLCN7 gene (10). In this issue, Phadke and colleagues (11) have studied the locus heterogeneity and mutational spectra of eight patients with autosomal recessive infantile malignant osteopetrosis; six patients had mutations in TCIRG1 and two patients harboured mutations in CLCN7. Three of the five different TCIRG1 mutations identified and both CLCN7 mutations were novel mutations. Two patients had history of consanguinity and six have homozygous mutations.