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Updated: May 14, 2026
06:41
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Mutations in NOTCH2 in patients with Hajdu-Cheney syndrome
1Endocrine Unit, Thier 10, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
Summary
Hajdu-Cheney syndrome (HCS) is caused by rare NOTCH2 gene mutations. This study identified new mutations, confirming NOTCH2
Area of Science:
- Genetics
- Rare Diseases
- Molecular Biology
Background:
- Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant disorder.
- Characterized by severe osteoporosis, acroosteolysis, and renal cysts.
- Heterozygous mutations in NOTCH2 are the identified cause of HCS.
Purpose of the Study:
- To describe clinical and genetic findings in nine patients with Hajdu-Cheney syndrome.
- To identify and characterize mutations in the NOTCH2 gene in HCS patients.
- To expand the known mutational spectrum of HCS.
Main Methods:
- Recruitment of nine patients with typical HCS presentations (familial and sporadic cases).
- DNA extraction from peripheral blood samples.
- Exome sequencing followed by Sanger sequencing to confirm NOTCH2 mutations.
Main Results:
- Deleterious heterozygous mutations in the last NOTCH2 exon were identified in all nine patients.
- Five of the six identified mutations were novel.
- Functional analysis in HEK293 cells suggested a gain-of-function mechanism for the mutations.
Conclusions:
- Confirms heterozygous NOTCH2 mutations as the cause of Hajdu-Cheney syndrome.
- Expands the spectrum of NOTCH2 mutations associated with HCS.
- Findings support a gain-of-function mechanism for HCS pathogenesis.
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