The Diverse Phenotype of Intestinal Dysmotility Secondary to ACTG2‐related Disorders

Abstract

Background and Aims:The initial description of a heterozygous dominant ACTG2 variant in familial visceral myopathy was followed by the identification of additional variants in other forms of intestinal dysmotility disorders. we aimed to describe the diverse phenotype of this newly reported and rare disease.Methods:Report of 4 new patients, and a systematic review of ACTG2-related disorders. we analyzed the population frequency and used in silico gene damaging predictions. Genotype-phenotype correlations were explored.Results:One hundred three patients (52% girls), from 14 publications, were included. Twenty-eight unique variants were analyzed, all exceedingly rare, and 27 predicted to be highly damaging. The median Combined Annotation Dependent Depletion (CADD) score was 29.2 (Interquartile range 26.3–29.4). Most patients underwent abdominal surgery (66%), about half required intermittent bladder catheterization (48.5%), and more than half were parenteral nutrition (PN)-dependent (53%). One-quarter of the patients died (25.7%), and 6 required transplant (5.8%). Girls had a higher rate of microcolon (P = 0.009), PN dependency (P = 0.003), and death/transplant (P = 0.029) compared with boys, and early disease onset (<2 years of age) was associated with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) features. There was no statistical association between disease characteristics and CADD scores.Conclusions:Damaging ACTG2 variants are rare, often associated with MMIHS phenotype, and overall have a wide phenotypic variation. Symptoms usually present in the perinatal period but can also appear at a later age. The course of the disease is marked by frequent need for surgical interventions, PN support, and mortality. Poor outcomes are more common among girls with ACTG2 variants.

Pediatric Intestinal Pseudo-Obstruction: An International Survey on Diagnostic and Management Strategies in the European Reference Network for Rare Inherited and Congenital Anomalies Intestinal Failure Teams

“…Although most cases of PIPO are sporadic with only few known genetic forms, a genetic counseling is recommended at least in all cases of PIPO associated with other congenital abnormalities and patients with syndromic forms (2). Primary PIPO, including sporadic or familial myopathy, neuropathy, mesenchymopathy, mitochondrial diseases, or neuropathy, has been linked to mutations such as ACTG2, SOX10, POLGI, FLNA, L1CAM, MYH11, MYLK, LMOD1, MYL9, RET, TYMP, RAD21, and SGOL1 (20)(21)(22). In ERNICA IF teams, genetic testing was in routine use in all except 1 center while routine genetic test panel was available in only 4 centers.…”

Maternal histone methyltransferases antagonistically regulate monoallelic expression inC. elegans

“…The variable onset of genetic diseases can also be explained by MAE. Genetic diseases like ACTG2 related visceral myopathy have variable onset, with some people remaining symptom-free until later in life 19 . This late onset is consistent with the idea that desilencing of pathological alleles could cause the later onset disease.…”

Multi-disciplinary Insights from the First European Forum on Visceral Myopathy 2022 Meeting

“…A CTG2 R40 variants have variable severity myopathy, whereas ACTG2 R38 variants are usually less severe. Second site modifiers (genetic or non-genetic) impact disease course and are responsible for the considerable variety in symptom onset and severity even within families [ 15 , 16 ]. An example is represented by a family of eleven people with a broad spectrum of visceral manifestations, where eight affected members showed severe complications due to biliary and/or urinary tracts dysfunction in addition to CIPO.…”