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Genome-based diagnosis of genetic disease.

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.

Consanguinity of parents is common in patients with ARO (3,4,10,12). In our previous study, we were able to prioritize the CLCN7 loci for mutational analysis based on the history of consanguinity, by performing a whole genome scan for homozygous chromosomal regions,using single-nucleotidepolymorphism(SNP) microarrays (13,14). The loci of malignant osteopetrosis should fall on a homozygous chromosomal region because the parents are consanguineous. The genetic mapping study is essential in preparing the ground for the mutation study by decreasing the burden of completely sequencing all possible loci for this disease. For ARO, there are at least 7 disease-causing genes located on 7 different chromosomes; TCIRG1 is located on chromosome 11. CLCN7 is located on chromosome 16, OSTM1 on chromosome 6, TNFSF11 on chromosome 13, TNFRSF11A on chromosome 18, PLEKHM1 on chromosome 17, and CA2 on chromosome 8 (OMIM database). The results of the mapping study and the mutation study proved to be consistent, validating this approach and saving us a considerable amount of effort and time. We have also applied this technique to locate the disease-causing gene out of 8 known disease-causing genes in a patient with xeroderma pigmentosum. With future reductions in the cost of SNP genotyping, whole-genome scans will become the method of choice for diagnosis of inherited disease exhibiting locus heterogeneity in consanguineous families (13-15).


(1.) Villa A, Guerrini MM, Cassani B, Pangrazio A, Sobacchi C. Infantile malignant, autosomal recessive osteopetrosis: the rich and the poor. Calcif Tissue Int 2009; 84 : 1-12.

(2.) Shalev H, Mishori-Dery A, Kapelushnik J, Moser A, Sheffield VC, McClain A, et al. Prenatal diagnosis of malignant osteopetrosis in Bedouin families by linkage analysis. Prenat Diagn 2001; 21 : 183-6.

(3.) Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, et al. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 2000; 25 : 343-6.

(4.) Kornak U, Kasper D, Bosl MR, Kaiser E, Schweizer M, Schulz A, et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 2001; 104 : 205-15.

(5.) Chalhoub N, Benachenhou N, Rajapurohitam V, Pata M, Ferron M, Frattini A, et al. Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Mew 2003; 9 : 399-406.

(6.) Sobacchi C, Frattini A, Guerrini MM, Abinun M, Pangrazio A, Susani L, et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet 2007; 39 : 960-2.

(7.) Guerrini MM, Sobacchi C, Cassani B, Abinun M, Kilic SS, Pangrazio A, et al. Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet 2008; 83 : 64-76.

(8.) Van Wesenbeeck L, Odgren PR, Coxon FP, Frattini A, Moens P, Perdu B, et al. Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans. J Clin Invest 2007; 117 : 919-30.

(9.) Borthwick KJ, Kandemir N, Topaloglu R, Kornak U, Bakkaloglu A, Yordam N, et al. A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis. J Med Genet 2003; 40 : 115-21.

(10.) Cleiren E, Benichou O, Van Hul E, Gram J, Bollerslev J, Singer FR, et al. Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet 2001; 10 : 2861-7.

(11.) Phadke AR, Fischer B, Gupta N, Ranganath P, Kabra M, Kornak U. Novel mutations in Indian patients with autosomal recessive infantile malignant osteopetrosis. Indian J Med Res 2010; 131 : 508-14.

(12.) Pangrazio A, Pusch M, Caldana E, Frattini A, Lanino E, Tamhankar PM, et al. Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations. Hum Mutat 2010; 31 : E1071-80.

(13.) Lam CW, Tong SF, Wong K, Luo YF, Tang HY, Ha SY, et al. DNA-based diagnosis of malignant osteopetrosis by whole-genome scan using a single-nucleotide polymorphism microarray: standardization of molecular investigations of genetic diseases due to consanguinity. J Hum Genet 2007; 52 : 98-101.

(14.) Lau KC, Mak CM, Leung KY, Tsoi TH, Tang HY, Lee P, et al. A fast modified protocol for random-access ultra-high density whole-genome scan: a tool for personalized genomic medicine, positional mapping, and cytogenetic analysis. Clin Chim Acta 2009; 406 : 31-5.

(15.) Lam CW, Cheung KK, Luk NM, Chan SW, Lo KK, Tong SF. DNA-based diagnosis of xeroderma pigmentosum group C by whole-genome scan using single-nucleotide polymorphism microarray. J Invest Dermatol 2005; 124 : 87-91.

Ching-Wan Lam

Department of Pathology

The University of Hong Kong

Queen Mary Hospital

Hong Kong, China
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Title Annotation:Commentary
Author:Lam, Ching-Wan
Publication:Indian Journal of Medical Research
Geographic Code:9CHIN
Date:Apr 1, 2010
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