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


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.

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Figure 1: Identification of NOTCH2 mutations in individuals with Hajdu-Cheney syndrome.

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NCBI Reference Sequence


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We are grateful to the affected subjects and their families who participated in this study. We thank F. Gros, H. Eldjouzi, A. Briand, C. Beneteau and S. Lecointe for technical assistance, and R. Houlgatte and C. Chevalier from Biogenouest de Nantes. This research was funded by grants from Inserm, Fondation pour la Recherche Médicale, Fédération Française de Cardiologie and Région Pays-de-la-Loire. P.L. is supported by the Direction Hospitalière de l'Organisation des Soins (DHOS). S.J. is funded by the “bourse de relève acadèmique de la Facultè de Biologie et Mèdecine de l'Université de Lausanne.”

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C.L.C., B.I., S.B., V.C.-D., L.F. and A.D. conceived the project and planned the experiments. B.I., V.C.-D., L.F., M.L.M., S.J., D.M.-C., C.T.-R. and A.D. clinically characterized the HCS cases and collected blood samples. O.P. performed validation experiments. P.L., C.D., R.R., B.I., J.-L.M. and C.L.C. analyzed and interpreted the exome data. C.L.C., B.I., R.R., J.-L.M. and S.J. wrote the manuscript. All authors contributed to the final manuscript.

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Correspondence to Cédric Le Caignec.

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The authors declare no competing financial interests.

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Supplementary Tables 1–5, Supplementary Figures 1–3 and Supplementary Methods. (PDF 465 kb)

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Isidor, B., Lindenbaum, P., Pichon, O. et al. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet 43, 306–308 (2011).

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