1. ¹Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
2. ²Department of Obstetrics and Gynecology, Centro Hospitalar Conde S. Januario, Macau, China
3. ³Prenatal Diagnosis and Counseling Department, Tsan Yuk Hospital, Hong Kong, China
4. ⁴Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Correspondence: Ching-Wan Lam, Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China. E-mail: ching-wanlam@cuhk.edu.hk

Received 3 June 2006; Accepted 21 September 2006; Published online 11 October 2007.

Abstract

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. This 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.