Mutations in NOTCH2 in families with Hajdu-Cheney syndrome

Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Canada.
Human Mutation (Impact Factor: 5.05). 10/2011; 32(10):1114-7. DOI: 10.1002/humu.21546
Source: PubMed

ABSTRACT Hajdu-Cheney syndrome (HCS) is a rare genetic disorder whose hallmark is acro-osteolysis, shortening of terminal phalanges, and generalized osteoporosis. We assembled a cohort of seven families with the condition and performed whole exome resequencing on a selected set of affected patients. One protein-coding gene, NOTCH2, carried heterozygous truncating variants in all patients and their affected family members. Our results replicate recently published studies of HCS and further support this as the causal gene for the disorder. In total, we identified five novel and one previously reported mutation, all clustered near the carboxyl terminus of the gene, suggesting an allele specific genotype-phenotype effect since other mutations in NOTCH2 have been reported to cause a form of Alagille syndrome. Notch-mediated signaling is known to play a role in bone metabolism. Our results support a potential therapeutic role for Notch pathways in treatment of osteoporosis.

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    • "Approaches like the Cohort Allelic Sums Test (CAST) (Morgenthaler and Thilly, 2007) and Combined Multivariate and Collapsing (CMC) method (Li and Leal, 2008) aggregate the rare variants seen within a gene or a pathway to mitigate this, but the applicability of association-based methods remains extremely limited for small cohorts. The alternative approach of prioritizing disease-causing single nucleotide variants (SNVs) based on their population frequency, conservation and the type of change (radical versus conservative amino acid change, introduction of a stop codon, etc.) has been extremely effective at identifying causal non-synonymous mutations in a number of Mendelian disorders, including Charcot– Marie–Tooth neuropathy (Lupski et al., 2010), Hajdu–Cheney syndrome (Majewski et al., 2011a) and Miller syndrome (Ng et al., 2009). In this approach, the variants identified in the genome are filtered to those with low allele frequencies (common variants are unlikely to cause rare disorders) and are sorted based on a 'harmfulness' score generated by tools such as PolyPhen, SIFT or PANTHER (Adzhubei et al., 2010; Ng and Henikoff, 2003; Thomas et al., 2003). "
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