NOTCH2 gene


Gene (OMIM No.)
Function of gene/protein
  • Transmembrane protein receptor for membrane-bound ligands (Jagged and Delta proteins)
  • Expressed ubiquitously
  • Involved in the Notch signaling pathway that regulates cell-fate determination
  • Essential for the normal embryonic development of various organs (heart, liver, kidneys, teeth, bones etc.)
Clinical phenotype
(OMIM phenotype no.)
  • Alagille Syndrome (#610205)
  • Hajdu-Cheney Syndrome (#102500)
  • Splenic marginal zone lymphoma
  • De novo sporadic
  • Autosomal dominant
Ocular features
  • Alagille Syndrome: posterior embryotoxon is the most prevalent ocular feature (95% of patients)
  • Hajdu-Cheney Syndrome: severe myopia, nystagmus, cataracts, hypertensive retinopathy, optic nerve anomalies and one case of congenital glaucoma
Systemic featuresAlagille syndrome
  • Intra- and interfamilial variability in clinical presentation and severity
  • Cardiac defects
  • Jaundice due to bile duct paucity
  • Vertebral anomalies (a characteristic “butterfly” vertebrae may be seen)
  • Dysmorphic facial features (prominent forehead, moderate hypertelorism with deep set eyes, prominent ears, triangular face with a pointed chin and broad nasal bridge)
  • Various other systemic features (see Alagille syndrome)
Hajdu-Cheney syndrome
  • Intra- and interfamilial variability in clinical presentation and severity
  • Skeletal abnormalities (acro-osteolysis of hands and feet, osteoporosis, short and broad digits, vertebral anomalies)
  • Short stature
  • Craniofacial dysmorphism (bathrocephaly, mild hypertelorism with telecanthus, downslanted eyes with synorphrys, low-set ears, long philtrum micrognathia with high-arched/cleft palate); coarser over time
  • Dental abnormalities
  • Renal cysts
  • Cardiac abnormalities (patent ductus arteriosus, atrial/ventricular septal defects, mitral/aortic valve abnormalities)
  • Developmental delays
  • Neurological symptoms (basilar invagination, hydrocephalus, sensorineural hearing loss, central respiratory arrest, sudden death)
Key investigations
  • Refraction
  • Blood tests (particularly liver function studies for Alagille syndrome)
  • Liver ultrasound +/- biopsy (histological finding of bile duct paucity is diagnostic of Alagille syndrome)
  • Cardiac assessment (echocardiogram)
  • Renal assessment
  • Skeletal studies demonstrating acro-osteolysis of the distal phalanges of the hands and feet, and other skeletal abnormalities in Hajdu-Cheney syndrome
  • DEXA scan to assess bone health
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (ASD)
  • Whole exome sequencing
  • Whole genome sequencing
  • Multidisciplinary approach in managing associated symptoms
  • Ocular features in Alagille rarely require intervention or monitoring
  • Management of Alagille syndrome
Therapies under research
Further information

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Additional information

There is no specific genotype-phenotype relationship in Alagille syndrome but mutations causing Hajdu-Cheney syndrome are all localised to exon 34 on the NOTCH2 gene in germline cells.[5-9] NOTCH2 mutations in somatic cells can cause splenic marginal zone lymphoma.[12]

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  1.  Hajdu n, kauntze r. Cranio-skeletal dysplasia. Br J Radiol. 1948;21(241):42-48. doi:10.1259/0007-1285-21-241-42
  2.  Alagille D, Odièvre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. 1975;86(1):63-71. doi:10.1016/s0022-3476(75)80706-2
  3.  Larsson C, Lardelli M, White I, Lendahl U. The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation. Genomics. 1994;24(2):253-258. doi:10.1006/geno.1994.1613
  4.  McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006;79(1):169-173. doi:10.1086/505332
  5.  Spinner NB, Gilbert MA, Loomes KM, Krantz ID. Alagille Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; May 19, 2000
  6.  Simpson MA, Irving MD, Asilmaz E, et al. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet. 2011;43(4):303-305. Published 2011 Mar 6. doi:10.1038/ng.779
  7.  Majewski J, Schwartzentruber JA, Caqueret A, et al. Mutations in NOTCH2 in families with Hajdu-Cheney syndrome. Hum Mutat. 2011;32(10):1114-1117
  8.  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. 2011;43(4):306-308
  9.  Gray MJ, Kim CA, Bertola DR, et al. Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome. Eur J Hum Genet. 2012;20(1):122-124
  10.  Canalis E, Zanotti S. Hajdu-Cheney syndrome: a review. Orphanet J Rare Dis. 2014;9:200
  11.  Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137(2):216-233. doi:10.1016/j.cell.2009.03.045
  12.  Kiel MJ, Velusamy T, Betz BL, et al. Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma. J Exp Med. 2012;209(9):1553-1565
  13.  Swan L, Gole G, Sabesan V, Cardinal J, Coman D. Congenital Glaucoma: a Novel Ocular Manifestation of Hajdu-Cheney Syndrome. Case Rep Genet. 2018;2018:2508345. Published 2018 Oct 21. doi:10.1155/2018/2508345
  14.  Rennie CA, Chowdhury S, Khan J, et al. The prevalence and associated features of posterior embryotoxon in the general ophthalmic clinic. Eye (Lond). 2005;19(4):396-399. doi:10.1038/sj.eye.6701508
  15.  Gasch AT, Janjani A, Weber M, Garland DL, Chan CC. Ocular pathology and lens analysis in Hajdu-Cheney syndrome. Ann Ophthalmol. 2001;33(2):141-144. doi:10.1007/s12009-001-0011-3

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Updated on November 30, 2020
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