Standardization of molecular investigations of genetic diseases due to consanguinity: DNA-based diagnosis of genetic diseases by whole-genome scan using a single-nucleotide polymorphism microarray

Ching-Wan Lam
The Chinese University of Hong Kong, Department of Chemical Pathology, Prince of Wales Hospital, Hong Kong, China

Malignant osteopetrosis, a severe disease causing early infantile death in humans, is caused by mutations in the TCIRG1, CLCN7, or OSTM1 genes. We have established the molecular basis of malignant osteopetrosis in a Chinese family by means of whole-genome scans based on high-density single-nucleotide polymorphism (SNP) microarrays. Because the parents were consanguineous, the disease-causing locus should be located in an autozygous chromosomal region. Mapping revealed that among the three possible causal loci, only the CLCN7 gene was located in an autozygous region. Mutational analysis of the CLCN7 gene showed that the proband was homozygous for a novel missense mutation, p.I261F. p.I261 is located in helix F of the chloride channel, near a critical site for gating of the channel. This mapping study prepares the ground for future mutation studies by decreasing the burden of completely sequencing all possible loci for this disease. We have generalized this approach to diagnosis of other genetic diseases in consanguineous families. Our data showed that presence of consangunity may not be known among the familiy members. This effective approach can be used to standardize molecular investigations of genetic diseases due to consanguinity to a whole-genome scan and subsequent sequencing of the mapped disease gene.