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.

Keywords: chronic constipation; hypoperistalsis; ileus; intestinal pseudo-obstruction.

Figure 1.

(A) Abdominal radiograph shows severe diffuse gaseous distension of bowel throughout the abdomen (asterisks). Scattered bubbly lucencies (within dashed line) may represent stool contents. Enteric tube and peripherally inserted central catheter (PICC) tip are also visible. (B) Hematoxylin and eosin (H&E) staining of the patient's small bowel (ileostomy) specimen reveals no abnormalities in smooth muscle band thickness or organization. (L) Longitudinal layer, (C) circular layer.

Figure 2.

(A) Pedigree of the patient (III-2), indicated with the arrow. The dot (II-4) indicates heterozygous carrier status; horizontal hatching (II-5) indicates a recent history of intermittent constipation. (B) Gene schema of ACTG2 with deletion indicated (red bar). The deletion harbored by the patient corresponds to part of exon 6 of 9, and part of intron 6. (C) Representation of whole-genome sequencing reads overlapping the intragenic ACTG2 deletion (red bar) for the proband (P) and mother (M). Colored nucleotides indicate bases that are mismatched with respect to the reference genome, because of the deletion. (D) Schema of the deletion (red bar) at the single base level, with the 24 deleted base pairs of exon 6 shown.