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.

FIGURE 1.

Schematic representation of human gamma enteric smooth muscle actin, a protein encoded by 8 coding exons of the ACTG2 gene. The solved protein structure of ACTG2 folds into 4 distinct subdomains (SD1, SD2, SD3, and SD4). The positions of heterozygous dominant mutations known to cause chronic intestinal pseudo-obstruction are shown using the NCBI Ref Seq ID NP_001606.1 amino acid numbering. A novel Proline to Leucine variant at amino acid position 323 within subdomain3 first reported in this article is highlighted in red.

FIGURE 2.

Manifestations of ACTG2-related disorders and possible treatments. The frequency of reported clinical characteristics and interventions found in the systematic review is reported in brackets.