Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis

Cédric Le Caignec and colleagues show that truncating mutations in the last exon of NOTCH2 cause Hajdu-Cheney syndrome, a rare disorder marked by facial anomalies, osteoporosis and multiple organ defects. The mutations are predicted to result in an increase in NOTCH2 signaling. Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner.