Expanding the genotypic spectrum of ACTG2-related visceral myopathy

Abstract

Visceral myopathies (VMs) encompass a spectrum of disorders characterized by chronic disruption of gastrointestinal function, with or without urinary system involvement. Pathogenic missense variation in smooth muscle γ-actin gene ( ACTG2 ) is associated with autosomal dominant VM. Whole-genome sequencing of an infant presenting with chronic intestinal pseudo-obstruction revealed a homozygous 187 bp (c.589_613 + 163del188) deletion spanning the exon 6–intron 6 boundary within ACTG2 . The patient's clinical course was marked by prolonged hospitalizations, multiple surgeries, and intermittent total parenteral nutrition dependence. This case supports the emerging understanding of allelic heterogeneity in ACTG2 -related VM, in which both biallelic and monoallelic variants in ACTG2 are associated with gastrointestinal dysfunction of similar severity and overlapped clinical presentation. Moreover, it illustrates the clinical utility of rapid whole-genome sequencing, which can comprehensively and precisely detect different types of genomic variants including small deletions, leading to guidance of clinical care decisions.

Intestinal Pathology in Patients With Pathogenic ACTG2-Variant Visceral Myopathy: 16 Patients From 12 Families and Review of the Literature

“…Some investigators specifically noted an absence of histological abnormalities. [3][4][5][6][7] Others reported a variety of other putative alterations in the muscularis propria including thinning of one or both muscle layers, [8][9][10] "vacuolar change", 7,9,11 intestinal neuronal dysplasia type B, 12 aplastic desmosis, 12 "disorderly arranged intramyenteric neural tissue", 13 nuclear palisading, 9 haphazard arrangement of smooth muscle cells, 13,14 muscle degeneration and fibrosis, 15 intracellular inclusion bodies, 16,17 and cytoplasmic aggregates or clumps of ACTG2-immunoreactive material. 10,16 These divergent findings prompted us to conduct a light and electron microscopic and immunohistochemical study of intestinal specimens from a series of 16 patients with pathogenic ACTG2 variants, in an effort to identify potentially distinctive features for patients with this form of visceral myopathy.…”

Autosomal Recessive ACTG2-Related Visceral Myopathy in Brothers

“…The noncoding ACTG2 exon 1 is typically not captured in standard ES. This is also illustrated by James et al (7), in which GS detected a homozygous exonic variant that was missed by 2 copy number and indel variant callers.…”

“…This patient was dependent on parenteral nutrition, presenting with infantile periodic abdominal pain, vomiting and growth deficiency. Most recently, James et al ( 7 ) reported a homozygous exon 6 deletion c.589_613 + 163del188 in a 13-month-old boy with severe visceral myopathy. We speculate that the exon 1 deletion of ACTG2 leads to loss-of-function, supported by their father’s chronic diarrhea and a small decrease of intestinal ACTG2 expression in the brothers, although the immunohistochemistry results need to be interpreted with care.…”

“…ACTG2-related visceral myopathy was initially reported as an autosomal dominant condition with variable severity and frequent de novo occurrences ( 3 , 4 ). More recently, PIPO cases due to a homozygous truncating ACTG2 variant p. Arg168* ( 5 ), a homozygous arginine substitution ACTG2 variant p.Arg336Trp ( 6 ), and a homozygous ACTG2 exon 6 deletion c.589_613 + 163del188 ( 7 ) have been reported, suggesting that some mild variants are associated with an autosomal recessive inheritance. Here, we describe a unique familial quartet illustrating carriers of mild ACTG2 variants with mild gastrointestinal symptoms and their children with severe PIPO.…”

Game-theoretic link relevance indexing on genome-wide expression dataset identifies putative salient genes with potential etiological and diapeutics role in colorectal cancer

“…The actin gamma smooth muscle 2 (ACTG2) gene ((LRI = 0.015873), belonging to the actin protein family, is imperative for maintaining the cytoskeleton through the regulation of cell movement and muscle contraction 86 . Genome sequencing studies have revealed that a homozygous and a heterozygous variant of ACTG2 is associated with gastrointestinal dysfunction 87 . Studies have demonstrated that the over-expression of ACTG2 has been found to play a critical role in the progression of hepatocellular carcinoma 88 and bladder cancer 89 .…”