NOTCH2 – Hajdu-Cheney Syndrome

Hajdu-Cheney syndrome (HCS) is an ultra-rare autosomal dominant skeletal disorder characterized by progressive acro-osteolysis, wormian bones and severe osteoporosis. Heterozygous truncating mutations in exon 34 of NOTCH2 upstream of the PEST domain have been repeatedly identified as the genetic cause of HCS (PMID:21681853, PMID:21378989).

Genetic studies including whole-exome resequencing of seven multigenerational families and six unrelated probands established NOTCH2 as the causal gene for HCS, with a total of 41 affected individuals in 14 unrelated families showing co-segregation of truncating variants with disease phenotype (PMID:21681853, PMID:23401378). De novo and familial inheritance patterns confirm autosomal dominant transmission with full penetrance.

The variant spectrum is dominated by nonsense and frameshift mutations clustering in the last coding exon, notably c.6667C>T (p.Gln2223Ter) and c.6449_6450del (p.Pro2150fs), yielding truncated NOTCH2 proteins lacking the PEST degradation motif and escaping nonsense-mediated decay (PMID:21378989). Phenotypic variability within and between families underscores a gain-of-function mechanism rather than haploinsufficiency.

Functional assays demonstrate that mutant NOTCH2 proteins are stable and signal-competent, leading to enhanced osteoclastogenesis. A knock-in mouse model harboring an exon 34 truncation replicates the human skeletal phenotype, with increased osteoclast surface and bone resorption that is abrogated by anti-NOTCH2 antibodies (PMID:31371452). These data confirm a gain-of-NOTCH2-function pathogenic mechanism driving bone loss.

No studies have refuted the NOTCH2–HCS association. Comprehensive clinical and genetic data over >10 years ascertain NOTCH2 testing as a robust diagnostic tool. Targeted therapies modulating NOTCH2 signaling may offer future therapeutic avenues.

Key Take-home: NOTCH2 truncating mutations are definitively associated with autosomal dominant Hajdu-Cheney syndrome and inform molecular diagnosis, family counseling, and potential targeted interventions.

References

• Human mutation • 2011 • Mutations in NOTCH2 in families with Hajdu-Cheney syndrome PMID:21681853
• Nature genetics • 2011 • Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis PMID:21378989
• American journal of medical genetics. Part A • 2013 • Clinical consequences in truncating mutations in exon 34 of NOTCH2: report of six patients with Hajdu-Cheney syndrome and a patient with serpentine fibula polycystic kidney syndrome PMID:23401378
• Orphanet journal of rare diseases • 2014 • Hajdu-Cheney syndrome: a review PMID:25491639
• The Journal of biological chemistry • 2019 • The Hajdu Cheney mutation sensitizes mice to the osteolytic actions of tumor necrosis factor α PMID:31371452

Evidence Based Scoring (AI generated)