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• Commentary on clinical utility of NOTCH2 sequencing analysis in Alagille syndrome
  Daniela Marchetti
  Published on: 27 April 2016

• Published on: 27 April 2016

  Commentary on clinical utility of NOTCH2 sequencing analysis in Alagille syndrome

  • Daniela Marchetti, Geneticist
  • Other Contributors:
    • Maria Iascone

  It was with great interest that we have read the recent article published by Kamath et al. [1] dealing with NOTCH2 mutations in patients affected by Alagille syndrome (ALGS) negative for JAG1 gene mutations and rearrangements. This original article brings relevant information about the mutation frequencies and genotype-phenotype data regarding NOTCH2 gene. Previously only two mutations, one missense and one splicing, have been rep...

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  It was with great interest that we have read the recent article published by Kamath et al. [1] dealing with NOTCH2 mutations in patients affected by Alagille syndrome (ALGS) negative for JAG1 gene mutations and rearrangements. This original article brings relevant information about the mutation frequencies and genotype-phenotype data regarding NOTCH2 gene. Previously only two mutations, one missense and one splicing, have been reported in two families with ALGS and renal disease [2]. Here we report a family with two siblings affected by a severe cholestasis carrying a maternal inherited frameshift mutation in exon 18 (NM_024408.2:c.2765del;p.Asn922MetfsX9) of NOTCH2 gene. The novel unreported variant was predicted to activate the nonsense mediated mRNA decay and is localized on EGF-like 24 domain of the protein. Moreover, it was absent in the unaffected father and in the third unaffected sibling such as in a cohort of 566 healthy control alleles. Subsequent analysis of genomic DNA from maternal healthy grandparents indicated that the mutation had occurred de novo in the mother. After a deep clinical and instrumental re-evaluation, our patients did not show any cardiac disease, skeletal, ocular abnormalities or facies typical of ALGS. NOTCH2 sequencing analysis has been performed in other 9 cases negatives for JAG1 mutations. No other patient with NOTCH2 mutations has been identified. The two siblings underwent liver transplantation due to the severe liver dysfunction, while the mother presented only a mild hypercholesterolemia, suggesting a wide variable expressivity of the disease in the family. Also the patient described by Kamath et al. [1], carrying a frameshift mutation in exon 16 (p.Ser856fs16X), had only liver involvement further confirming the phenotypic variability associated with this inherited disease. The variable expressivity is typical of patients affected by ALGS carrying mutations in JAG1 gene. Classic diagnostic criteria for ALGS combine the presence of bile duct paucity on liver biopsy with three of five systems affected: liver, heart, skeleton, eye and dysmorphic facies. Recently, it has been shown that JAG1 mutations are present also in patients having only one or two ALGS criteria [3]. This finding is not surprising, considering that even family members sharing the same mutation can have a wide spectrum of phenotypic manifestations ranging from life-threatening cardiac or liver disease to subtle or null clinical features. In our experience, JAG1 mutations are identified in 93% of patients with three or more diagnostic criteria, while they are rarely identified (4 mutated out of 55 indexes analyzed) in patients having cholestasis alone or associated to another ALGS diagnostic feature. The low mutational detection rate in JAG1 and NOTCH2 genes leads to question the real utility to perform the sequencing analysis of such large genes in a clinical context in this cohort of patients. The "cascade" screening of these genes is expensive and time consuming in isolated cholestasis associated or not with others minor clinical features creating anxiety and false expectations in families. For this reasons, we believe that a new strategy of analysis, based on targeted next-generation sequencing (NGS) of all genes causative of liver diseases, may be more appropriate for characterizing atypical ALGS patients. A comprehensive NGS analysis of liver genes may be more useful for clinicians, patients and families decreasing time and costs by ending the diagnostic odyssey as already demonstrated for other genetic conditions. References: 1. Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, Hardikar W, Hirschfield G, Jara P, Krantz ID, Lapunzina P, Leonard L, Ling S, Ng VL, Hoang PL, Piccoli DA, Spinner NB. NOTCH2 mutations in Alagille syndrome. J Med Genet 2012;49:138-44. 2. McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006;79:169-73. 3. Guegan K, Stals K, Day M, Turnpenny P, Ellard S. JAG1 mutations are found in approximately one third of patients presenting with only one or two clinical features of Alagille syndrome. Clin Genet 2011. doi: 10.1111/j.1399-0004.2011.01749.x. [Epub ahead of print].

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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