NGS Gene Panel Analysis Revealed Novel Mutations in Patients with Rare Congenital Diarrheal Disorders

Esposito, Maria Valeria; Comegna, Marika; Cernera, Gustavo; Gelzo, Monica; Paparo, Lorella; Canani, Roberto Berni; Castaldo, Giuseppe

doi:10.3390/diagnostics11020262

Cited by 3 publications

(1 citation statement)

References 31 publications

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“…Congenital diarrheas and enteropathies (CODEs) constitute a heterogeneous group of individually rare disorders manifesting with devastating chronic diarrhea in infancy. Next Generation Sequencing (NGS) technologies have improved our understanding of the genetic architecture underlying CODEs, and accurate and timely molecular diagnoses are within reach (Thiagarajah et al 2018 ; Ye et al 2019 ; Esposito et al 2021 ). An increasingly recognized subgroup of CODEs is caused by genetic defects affecting the enteroendocrine cells (EECs), collectively the largest endocrine organ in the body (Caralli et al 2021 ; Sanchez et al 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Nonsense mutation in the novel PERCC1 gene as a genetic cause of congenital diarrhea and enteropathy

et al. 2022

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Congenital diarrheas and enteropathies (CODEs) constitute a heterogeneous group of individually rare disorders manifesting with infantile-onset chronic diarrhea. Genomic deletions in chromosome 16, encompassing a sequence termed the ‘intestine-critical region (ICR)’, were recently identified as the cause of an autosomal recessive congenital enteropathy. The regulatory sequence within the ICR is flanked by an unannotated open reading frame termed PERCC1, which plays a role in enteroendocrine cell (EEC) function. We investigated two unrelated children with idiopathic congenital diarrhea requiring home parenteral nutrition attending the Irish Intestinal Failure Program. Currently 12 and 19-years old, these Irish male patients presented with watery diarrhea and hypernatremic dehydration in infancy. Probands were phenotyped by comprehensive clinical investigations, including endoscopic biopsies and serum gastrin level measurements. Following negative exome sequencing, PCR and Sanger sequencing of the entire coding region and intron boundaries of PERCC1 were performed for each proband and their parents. In both patients, serum gastrin levels were low and failed to increase following a meal challenge. While no deletions involving the ICR were detected, targeted sequencing of the PERCC1 gene revealed a shared homozygous c.390C > G stop gain variant. We report clinical and molecular findings in two unrelated patients harboring a shared homozygous variant in PERCC1, comprising the first description of a point mutation in this gene in association with CODE. That both parenteral nutrition dependent children with unexplained diarrhea at our institution harbored a PERCC1 mutation underscores the importance of its inclusion in exome sequencing interpretation.

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Section: Introductionmentioning

confidence: 99%

Nonsense mutation in the novel PERCC1 gene as a genetic cause of congenital diarrhea and enteropathy

et al. 2022

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Exploring congenital sucrase‐isomaltase deficiency in autism spectrum disorder patients with irritable bowel syndrome symptoms: A prospective SI gene sequencing study

Zubarioglu,

Ulgen,

Akca‐Yesil

et al. 2024

Autism Research

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Congenital sucrase‐isomaltase deficiency (CSID) is an inherited metabolic disorder causing chronic gastrointestinal symptoms and malnutrition when untreated. Most CSID patients are likely to remain under‐ or misdiagnosed. This study aimed to investigate prevalence of CSID among patients with autism spectrum disorder (ASD) presenting with irritable bowel syndrome (IBS) symptoms via prospective SI gene sequencing. A prospective cross‐sectional study was conducted on 98 ASD patients exhibiting gastrointestinal symptoms consistent with IBS. Participants were assessed according to Rome IV criteria and underwent SI gene sequencing. Demographic, clinical, and dietary data were collected and analyzed. Sucrose content in various fruits and vegetables was evaluated using three‐day food record, and gastrointestinal symptoms were rated on Likert scale. Seven patients (7%) were diagnosed with CSID based on SI gene analysis, revealing six different variants, including four novel mutations. One patient was homozygous for one variant, and six patients were heterozygous. Clinical presentations predominantly included diarrhea, abdominal pain, and bloating, with two patients showing growth retardation. One patient was diagnosed in adulthood. Food allergy and lactose intolerance were the misdiagnoses prior to CSID diagnosis in two patients. Real prevalence of CSID is likely underestimated. Clinical heterogeneity and non‐specific symptoms contribute to diagnostic challenges. Gastrointestinal symptoms consistent with IBS in ASD patients should include CSID in differential diagnosis. Early genetic screening for SI variants in ASD patients with IBS symptoms can facilitate timely diagnosis and management, improving outcomes. Heterozygous variants of the SI gene should also be considered, as heterozygous patients can exhibit typical CSID symptoms.

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UNC45A-related osteo-oto-hepato-enteric syndrome in a Chinese neonate

Kong

Shi

et al. 2023

European Journal of Medical Genetics

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NGS Gene Panel Analysis Revealed Novel Mutations in Patients with Rare Congenital Diarrheal Disorders

Cited by 3 publications

References 31 publications

Nonsense mutation in the novel PERCC1 gene as a genetic cause of congenital diarrhea and enteropathy

Nonsense mutation in the novel PERCC1 gene as a genetic cause of congenital diarrhea and enteropathy

Exploring congenital sucrase‐isomaltase deficiency in autism spectrum disorder patients with irritable bowel syndrome symptoms: A prospective SI gene sequencing study

UNC45A-related osteo-oto-hepato-enteric syndrome in a Chinese neonate

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