Alagille syndrome: understanding the genotype-phenotype relationship and its potential therapeutic impact

ABSTRACTIntroduction Alagille syndrome (ALGS) is an autosomal dominant, multisystem genetic disorder with wide phenotypic variability caused by mutations in the Notch signaling pathway, specifically from mutations in either the Jagged1 (JAG1) or NOTCH2 gene. The range of clinical features in ALGS can involve various organ systems including the liver, heart, eyes, skeleton, kidney, and vasculature. Despite the genetic mutations being well-defined, there is variable expressivity and individuals with the same mutation may have different clinical phenotypes.Areas covered While no clear genotype-phenotype correlation has been identified in ALGS, this review will summarize what is currently known about the genotype-phenotype relationship and how this relationship influences the treatment of the multisystemic disorder. This review includes discussion of numerous studies which have focused on describing the genotype-phenotype relationship of different organ systems in ALGS as well as relevant basic science and population studies of ALGS. A thorough literature search was completed via the PubMed and National Library of Medicine GeneReviews databases including dates from 1969, when ALGS was first identified, to February 2023.Expert opinion The genetics of ALGS are well defined; however, ongoing investigation to identify genotype-phenotype relationships as well as genetic modifiers as potential therapeutic targets is needed. Clinicians and patients alike would benefit from identification of a correlation to aid in diagnostic evaluation and management.KEYWORDS: Alagille syndromegenotype phenotype correlationliver diseasepediatricsJAG1NOTCH2 Article highlights Alagille syndrome (ALGS) is a genetic disorder caused by mutations in the NOTCH signaling pathway with phenotypic presentation varying from asymptomatic to significant multisystemic involvement.The most common systems affected are the hepatic, cardiovascular, renal, vascular, skeletal, ophthalmic, and nutritional needs, with each system having a range of clinical manifestations.Over 90% of the genetic mutations which lead to ALGS have been identified; however, there is no known correlation between genetic mutation and phenotypic presentation.Identification of a genotype–phenotype correlation would impact treatment of ALGS by allowing physicians to provide anticipatory guidance and early identification of system involvement.Treatment of ALGS is supportive and should be guided by a multidisciplinary team to allow for expertise in managing each system and symptom.Future treatment of ALGS will depend on the development of clinical guidelines through collaborative, multicenter studies, and the development of genetic modifiers of disease.Declaration of interestH Lin is on the medical advisory board for Albireo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThis paper was not funded.