title: Mutations in NOTCH2 in families with Hajdu-Cheney syndrome.
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.
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Schwartzentruber
authors.forename: Aurore
authors.initials: A
authors.lastname: Caqueret
authors.forename: Lysanne
authors.initials: L
authors.lastname: Patry
authors.forename: Janet
authors.initials: J
authors.lastname: Marcadier
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: Louis-Georges
authors.initials: LG
authors.lastname: Ste-Marie
authors.forename: Fergus E
authors.initials: FE
authors.lastname: McKiernan
authors.forename: Ivo
authors.initials: I
authors.lastname: Marik
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
mesh_terms: D030981:Acro-Osteolysis / Q000000981:diagnostic imaging / Q000235:genetics; D059472:Exome; D005145:Face / Q000002:abnormalities; D005192:Family Health; D005260:Female; D031845:Hajdu-Cheney Syndrome / Q000235:genetics*; D006225:Hand; D006228:Hand Deformities, Congenital / Q000000981:diagnostic imaging; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011859:Radiography; D051883:Receptor, Notch2 / Q000235:genetics*
chemical_list: D051883:Receptor, Notch2