Clinical utility gene card for: Alagille Syndrome (ALGS)

Leonard, Laura D.; Chao, Grace F.; Baker, Alastair; Loomes, Kathleen M.; Spinner, Nancy B.

doi:10.1038/ejhg.2013.140

Cited by 36 publications

(38 citation statements)

References 20 publications

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“…The distribution of types of mutations in JAG1 in this study was similar to that reported in a previous study, except for gross deletions, including partial-exon deletions and whole-exon deletions (15). The gross deletions represented 18.5% of the patients in this study compared to the 10% reported previously.…”

Section: Discussionsupporting

confidence: 88%

“…The gross deletions represented 18.5% of the patients in this study compared to the 10% reported previously. Thus, gross deletions in JAG1 might be more frequent in Alagille syndrome subjects than previously recognised (12,15). The MLPA analysis is able to detect CNVs of specific genes, including small intragenic rearrangements (20).…”

Section: Discussionmentioning

confidence: 92%

“…To date, JAG1 mutations have been detected in 60-94% of subjects with clinically diagnosed Alagille syndrome using several genetic methods, such as Sanger sequencing, MLPA, single-strand conformation polymorphism, cap analysis of gene expression and denaturing high-performance liquid chromatography (6)(7)(8). NOTCH2 mutations were identified in about 1.5% of patients with Alagille syndrome in a previous study (15). In this study, our detection rate of mutations in JAG1 and NOTCH2 was lower than that in Western countries (8), but approximately compatible with those in East Asian countries, namely 87.3% in China (16) and 73.6% in Korea (6).…”

Section: Discussionmentioning

confidence: 99%

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Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome

et al. 2017

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome

et al. 2017

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“…(1)(2)(3)(4) Mutations in JAGGED1 (JAG1) are identified in more than 90% of clinically defined patients with ALGS, and NOTCH2 mutations have been reported in a small minority. (5)(6)(7)(8) Cholestasis is a key clinical defining feature, and ALGS is, in fact, the most common cause of inherited cholestasis in children. (9) Current knowledge of the characteristics and outcomes of cholestasis in ALGS Abbreviations: ALGS, Alagille syndrome; ALT, alanine aminotransferase; ChiLDReN, Childhood Liver Disease Research Network; CSS, clinician scratch scale; DXA, dual energy X-ray absorptiometry; GGT, gamma-glutamyl transferase; JAG1, JAGGED1; TB, total bilirubin.…”

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confidence: 99%

Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study

Kamath

Goodrich

et al. 2020

Hepatol Commun

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Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder with cholestasis as a defining clinical feature. We sought to characterize hepatic outcomes in a molecularly defined cohort of children with ALGS‐related cholestasis. Two hundred and ninety‐three participants with ALGS with native liver were enrolled. Participants entered the study at different ages and data were collected retrospectively prior to enrollment, and prospectively during the study course. Genetic analysis in 206 revealed JAGGED1 mutations in 91% and NOTCH2 mutations in 4%. Growth was impaired with mean height and weight z‐scores of <−1.0 at all ages. Regression analysis revealed that every 10 mg/dL increase in total bilirubin was associated with a decrease in height z‐score by 0.10 (P = 0.03) and weight z‐score by 0.15 (P = 0.007). Total bilirubin was higher for younger participants (P = 0.03) with a median of 6.9 mg/dL for those less than 1 year old compared with a median of 1.3 mg/dL for participants 13 years or older. The median gamma glutamyl transferase also dropped from 612 to 268 in the same age groups. After adjusting for age, there was substantial within‐individual variation of alanine aminotransferase. By 20 years of age, 40% of participants had developed definite portal hypertension. Estimated liver transplant–free survival at the age of 18.5 years was 24%. Conclusions: This is the largest multicenter natural history study of cholestasis in ALGS, demonstrating a previously underappreciated burden of liver disease with early profound cholestasis, a second wave of portal hypertension later in childhood, and less than 25% of patients reaching young adulthood with their native liver. These findings will promote optimization of ALGS management and development of clinically relevant endpoints for future therapeutic trials.

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“…A similar phenomenon related to gene-gene interactions, or epistasis, may account for the diversity of presentations in biliary atresia. Nonmendelian inheritance is also observed in Alagille syndrome, which is the result of a haploid insufficiency of JAG1 or its receptor NOTCH2, which has a varied clinical presentation within families as well as between patients [58,59]. Considerations for epigenetic modification (e.g.…”

Section: Proposed Genetic Etiologies Of Biliary Atresiamentioning

confidence: 99%

Genetic Contributors and Modifiers of Biliary Atresia

Mezina

Karpen²

2015

Dig Dis

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To date, the etiology and pathogenic underpinning of the progression of the most prevalent serious neonatal liver disease, biliary atresia, remains elusive. This disease presents as an aggressive form of neonatal cholestasis characterized by the destruction and obliteration of the extrahepatic bile ducts within the first few weeks of life and a rapid progression of biliary fibrosis, likely due to unremitting cholestasis and retention of biliary constituents including bile acids. In ∼5% of patients, biliary atresia is associated with laterality features, suggesting a genetic underpinning to a disease that begins soon after birth. However, biliary atresia does not occur within families and twins are discordant, indicating an absence of strict mendelian inheritance. Despite this, genes related to bile duct dysmorphogenesis/ciliopathies overlapping with features of biliary atresia in both humans and nonhuman model systems have been proposed. Taken together, strict genetic etiologies leading to a common pathway of a neonatal cholangiopathy resulting in biliary atresia remain elusive. Contributions from fibrogenesis- and inflammation-based studies suggest that early engagement of these pathways contributes to disease progression, but a recent double-blind study did not suggest any benefit from early use of corticosteroids. However, there are genetic contributions to the adaptation and response to cholangiopathies and cholestasis that may be present in certain populations that likely impact upon the response to hepatoportoenterostomy and subsequent biliary tract function. Studies utilizing next generation sequencing technologies (e.g., exome analysis) are ongoing in several laboratories around the world; they are expected to provide insights into genetic contributions to biliary atresia outcomes. Altogether, combinations of exome sequencing and large population studies are expected to reveal causative and modifying genes relevant to patients with biliary atresia as a means to provide therapeutic targets and potential opportunities for genetic screening.

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Clinical utility gene card for: Alagille Syndrome (ALGS)

Cited by 36 publications

References 20 publications

Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome

Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome

Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study

Genetic Contributors and Modifiers of Biliary Atresia

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