Alagille syndrome in a Vietnamese cohort: Mutation analysis and assessment of facial features

Abstract

Alagille syndrome (ALGS, OMIM #118450) is an autosomal dominant disorder that affects multiple organ systems including the liver, heart, eyes, vertebrae, and face. ALGS is caused by mutations in one of two genes in the Notch Signaling Pathway, JAGGED1 or NOTCH2. In this study, analysis of 21 Vietnamese ALGS individuals led to the identification of 19 different mutations (18 JAGGED1 and 1 NOTCH2), 17 of which are novel, including the third reported NOTCH2 mutation in Alagille Syndrome. The spectrum of JAGGED1 mutations in the Vietnamese patients is similar to that previously reported, including nine frameshift, three missense, two splice site, one nonsense, two whole gene, and onw partial gene deletion. The missense mutations are all likely to be disease causing, as two are loss of cysteines (C22R and C78G) and the third creates a cryptic splice site in exon 9 (G386R). No correlation between genotype and phenotype was observed. Assessment of clinical phenotype revealed that skeletal manifestations occur with a higher frequency than in previously reported Alagille cohorts. Facial features were difficult to assess and a Vietnamese pediatric gastroenterologist was only able to identify the facial phenotype in 61% of the cohort. To assess the agreement among North American dysmorphologists at detecting the presence of ALGS facial features in the Vietnamese patients, 37 clinical dysmorphologists evaluated a photographic panel of 20 Vietnamese children with and without ALGS. The dysmorphologists were unable to identify the individuals with ALGS in the majority of cases, suggesting that evaluation of facial features should not be used in the diagnosis of ALGS in this population. This is the first report of mutations and phenotypic spectrum of ALGS in a Vietnamese population.

Repurposing Amlexanox as a Run the Red Light Cure-All with Readthrough a No-Nonsense Approach to Personalised Medicine

“…Notch mutations include substitution nonsense mutations that block appropriate signaling functions [146]. In terms of exercising a protective-type role, it has been found that disrupting mutations of Notch 3 lead to a hereditary adult onset condition of stroke and vascular dementia -CADASIL [143]. Although this study pinpoints mis-sense mutations as being disruptive it does indicate that the Notch signaling axis is crucial in maintaining central nervous system homeostasis.…”

“…Thus Hes3 forms a cancer therapy target since this marker relates to stem cells in, for example, GM. Hes3 is not only a relevant target for the elusive cancer stem cell population of GM but also for possibly other tumours as well [141][142][143].…”

Alagille syndrome mutation update: Comprehensive overview ofJAG1andNOTCH2mutation frequencies and insight into missense variant classification

“…Some of the patients in our cohort have been previously reported and are included here to provide a comprehensive summary of our clinical study, with prior reports referenced in all corresponding tables (Bauer et al, ; Colliton et al, ; Heritage et al, ; Izumi et al, ; Kamath et al, ; Kamath et al, ; Kamath et al, ; Krantz et al, ; Laufer‐Cahana et al, ; Li et al, ; Lin et al, ; McDaniell et al, ; Morrissette, Colliton, & Spinner, ; Oda et al, ; Warthen et al, ). Our cohort contains both probands and affected family members.…”

Novel JAG1 Deletion Variant in Patient with Atypical Alagille Syndrome

“…JAG1 mutations account for around 94% of cases, while NOTCH2 mutations are less common [1]. Both of these genes are involved in the Notch signaling pathway and play an important role in cell fate determination [8]. New mutations commonly occur (about 60%), and the rate of germline mosaicism may also be relatively high [7].…”