Alagille syndrome caused by NOTCH2 mutation presented atypical pathological changes

ShenTu, Yiling; Mi, Xiaoxiao; Tang, Dongfang; Jiang, Yanming; Gao, Ling; Ma, Xiaojie; Zhou, Bing; Yang, Wenjun; Shi, Junping; Lan, Dixiang; Chen, Gongying; Gong, Ling

doi:10.1016/j.cca.2021.07.026

Cited by 6 publications

(3 citation statements)

References 14 publications

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“…Variants in the Notch signaling pathway, including in NOTCH2 , underlie Alagille syndrome, which can mimic BA in early infancy with presentations of cholestasis and bile duct paucity (Gilbert et al, 2019; Kamath et al, 2012; ShenTu et al, 2021). Hence, it is possible that the infant identified with a variant in NOTCH2 was misdiagnosed with BA.…”

Section: Discussionmentioning

confidence: 99%

Exome‐wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child–parent trios and a case–control design to identify novel rare variants

Sok

Sabo

Almli

et al. 2023

American J of Med Genetics Pt A

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The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein‐altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child–parent trios, one child–mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio‐based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case–control analysis using a sequence kernel‐based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex.

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Section: Discussionmentioning

confidence: 99%

Exome‐wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child–parent trios and a case–control design to identify novel rare variants

Sok

Sabo

Almli

et al. 2023

American J of Med Genetics Pt A

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“…However, compared with the JAG1 (+) cohort, NOTCH2 (+) probands possessed a significantly lower frequency of vertebral abnormalities and facial features and less cardiac involvement. Recently, several larger studies have also shown that ALGS patients are prone to renal and vascular abnormalities ( 6 , 12 , 13 ). Based on these findings, the current diagnostic criteria for ALGS were adjusted as follows: if three of the seven characteristic clinical criteria are met, then there is a sufficient case for clinical diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…In the absence of a molecular diagnosis or family history, a diagnosis can be made only if at least three organs are involved ( 7 ). Liver biopsy is no longer considered a mandatory means of diagnosing ALGS as the presence of cholestasis can already meet this diagnostic criterion ( 12 ). Hence, considering the young age of our patient, we did not perform a liver biopsy.…”

Section: Discussionmentioning

confidence: 99%

Alagille syndrome due to a de novo NOTCH2 mutation presenting as prenatal oligohydramnios and congenital bilateral renal hypodysplasia: A case report

Pan

et al. 2022

Front. Pediatr.

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IntroductionHere, we report the case of an infant suffering from Alagille syndrome (ALGS), manifesting with the atypical clinical manifestations of prenatal oligohydramnios and renal lesions. To the best of our knowledge, this is the first case of ALGS presenting as prenatal oligohydramnios and renal lesions caused by a de novo variant of the NOTCH2 gene.Case presentationA 3-month-old male infant was hospitalized for severe malnutrition. He presented with prenatal oligohydramnios from 28+4 weeks of gestation. After birth, he failed to thrive and suffered from impaired motor development, thermoregulation disorders, congenital bilateral renal hypodysplasia, which initially manifested as stage 5 before improving to stage 3 chronic renal impairment, slightly elevated levels of transaminases, cholestasis, and dysmorphic facial features. We used a diagnostic screening panel of 4,047 pathogenic genes and whole exome sequencing (WES) to analyze the proband and his parents (who had normal kidneys). We found that the proband carried a de novo heterozygous splicing variant (c.5930-2A > G) in intron 33 of the NOTCH2 gene. Transcriptome sequencing confirmed that the mutation of this gene site would affect the splicing of NOTCH2 mRNA and lead to exon 33 skipping.ConclusionsOur case expands the spectrum of pathogenic variants of the NOTCH2 gene that are known to be associated with ALGS and characterized by prenatal oligohydramnios and renal lesions. It also reminds us of the necessity to monitor the liver and kidney function of the infant if a mother has oligohydramnios during pregnancy and we recommend ALGS as an additional differential diagnosis in prenatal renal abnormalities.

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Evolution of cerebrovascular imaging and associated clinical findings in children with Alagille syndrome

Cerron-Vela,

Tierradentro-García,

Rimba

et al. 2024

Neuroradiology

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Alagille syndrome caused by NOTCH2 mutation presented atypical pathological changes

Cited by 6 publications

References 14 publications

Exome‐wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child–parent trios and a case–control design to identify novel rare variants

Exome‐wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child–parent trios and a case–control design to identify novel rare variants

Alagille syndrome due to a de novo NOTCH2 mutation presenting as prenatal oligohydramnios and congenital bilateral renal hypodysplasia: A case report

Evolution of cerebrovascular imaging and associated clinical findings in children with Alagille syndrome

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