Meconium Ileus due to GUCY2C gene mutations in three unrelated South Indian families

Varkki, Sneha; Benjamin, Antony Terance; Athiyarath, Rekha; Danda, Sumita; Sowmya, Ravikumar; Connett, Gary

doi:10.1016/j.jcf.2021.03.023

Cited by 1 publication

(2 citation statements)

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“…Conversely, the clinical manifestation of autosomal recessive GUCY2C ‐related congenital disorder presents with meconium ileus and constipation similar to the gastrointestinal complications of cystic fibrosis (Romi et al, 2012; Smith et al, 2015; Varkki et al, 2021). Considering the downstream effects of inactivating variants, CFTR has been a therapeutic target of interest as it is the primary chloride channel present at the apical membrane of intestinal cells (Moon et al, 2015; Thiagarajah & Verkman, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Variants in GUCY2C with an autosomal dominant inheritance with a gain of function have been identified in extended families with CSD. Conversely, loss of function variants with an autosomal recessive inheritance causing meconium ileus have been identified in Lebanese (Smith et al, 2015), Bedouins (Romi et al, 2012), and South Indian families (Varkki et al, 2021). Given the rarity of presentation, there are currently no treatments directed at the mechanism of activating variants across the spectrum of CSD outside of in vitro studies.…”

Section: Introductionmentioning

confidence: 99%

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Clinical course and therapeutic trial for a case of congenital secretory diarrhea due to novel GUCY2C variant

Scott,

Wong,

Cramer

et al. 2023

American J of Med Genetics Pt A

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Chronic diarrhea presents a significant challenge for managing nutritional and electrolyte deficiencies, especially in children, given the higher stakes of impacting growth and developmental consequence. Congenital secretory diarrhea (CSD) compounds this further, particularly in the case of the activating variants of the guanylate‐cyclase 2C (GUCY2C) gene. GUCY2C encodes for the guanylate‐cyclase 2C (GC‐C) receptor that activates the downstream cystic fibrosis transmembrane receptor (CFTR) that primarily drives the severity of diarrhea with an unclear extent of influence on other intestinal channels. Thus far, management for CSD primarily consists of mitigating nutritional, electrolyte, and volume deficiencies with no known pathophysiology‐driven treatments. For activating variants of GUCY2C, experimental compounds have shown efficacy in vitro for direct inhibition of GC‐C but are not currently available for clinical use. However, Crofelemer, a CFTR inhibitory modulator with negligible systemic absorption, can theoretically help to treat this type of CSD. Herein, we describe and characterize the clinical course of a premature male infant with a de novo missense variant of GUCY2C not previously reported and highly consistent with CSD. With multi‐disciplinary family‐directed decision‐making, a treatment for CSD was evaluated for the first time to our knowledge with Crofelemer.

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