Discordant clinical phenotype in monozygotic twins with Alagille syndrome: Possible influence of non‐genetic factors

Abstract

Alagille syndrome is a multisystem developmental disorder characterized by bile duct paucity, congenital heart disease, vertebral anomalies, posterior embryotoxon, and characteristic facial features. Alagille syndrome is typically the result of germline mutations in JAG1 or NOTCH2 and is one of several human diseases caused by Notch signaling abnormalities. A wide phenotypic spectrum has been well documented in Alagille syndrome. Therefore, monozygotic twins with Alagille syndrome provide a unique opportunity to evaluate potential phenotypic modifiers such as environmental factors or stochastic effects of gene expression. In this report, we describe an Alagille syndrome monozygotic twin pair with discordant placental and clinical findings. We propose that environmental factors such as prenatal hypoxia may have played a role in determining the phenotypic severity.

The Roles of Notch Signaling in Liver Development and Disease

“…This observation suggests that when considering potential genetic modifiers of Notch signaling in Alagille syndrome and perhaps in other diseases of haploinsufficiency, one cannot limit the search to those genes which already have a significant phenotype in a wild-type context. Finally, given the reports on discordant phenotypes in monozygotic twins with ALGS [57,58], environmental factors are likely to contribute to the phenotypic variability in this disease, as was shown in an elegant study of gene-environment interaction in another Notch-related disease, namely congenital scoliosis [119].…”

“…However, there is no known genotype-phenotype correlation in ALGS [53,54,55,56]. Importantly, several studies have reported discordant phenotypes in monozygotic twins with ALGS [57,58,59], strongly suggesting a key role for the environment in determining the severity of the ALGS phenotypes. In addition, Jag1 heterozygous phenotypes in mice are highly sensitive to genetic background and to the gene dosage of other Notch pathway components [9,10,60,61,62], suggesting that genetic modifiers are also likely to contribute to the ALGS phenotypic variability.…”

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.…”

“…Early studies aimed to determine whether the location of pathogenic variants is able to predict the clinical manifestation of the disease do not support a genotype‐phenotype correlation (Crosnier et al, ; Spinner et al, ). Conversely, a high degree of variable expressivity has been observed, and often significant phenotypic variability is reported in families harboring the same pathogenic variant (Dhorne‐Pollet, Deleuze, Hadchouel, & Bonaiti‐Pellie, ; Elmslie et al, ; Emerick et al, ; Izumi et al, ; Kamath, Bason, Piccoli, Krantz, & Spinner, ; Kamath, Krantz, Spinner, Heubi, & Piccoli, ; Krantz et al, ; Shulman, Hyams, Gunta, Greenstein, & Cassidy, ). These observations have led to the hypothesis that a second gene could act as a modifier, and studies have been carried out to test this theory.…”

Genetic Basis of Human Congenital Heart Disease

“…Alagille syndrome is a condition consisting of CHD, hepatic complications including bile duct paucity and cholestasis, and skeletal and ophthalmologic anomalies. There is significant variability in the expression even within the same family, with some individuals displaying very mild features and others with severe CHD or liver disease leading to transplant or death (Quiros-Tejeira et al 1999;Kamath et al 2003;Izumi et al 2016;Ziesenitz et al 2016). More than 90% of patients with Alagille syndrome have cardiovascular involvement.…”