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. 2022 Oct 20;3(4):e258.
doi: 10.1097/PG9.0000000000000258. eCollection 2022 Nov.

Autosomal Recessive ACTG2-Related Visceral Myopathy in Brothers

Mari Mori  1   2 , Amanda R Clause  3 , Kristen Truxal  1   2 , R Tanner Hagelstrom  3 , Kandamurugu Manickam  1   2 , Stephen G Kaler  1   4 , Vinay Prasad  2   5 , Jonathan Windster  6   7 , Maria M Alves  6 , Carlo Di Lorenzo  2   8
Affiliations

Autosomal Recessive ACTG2-Related Visceral Myopathy in Brothers

Mari Mori et al. JPGN Rep. .

Abstract

Pediatric intestinal pseudo-obstruction (PIPO) is a heterogeneous condition characterized by impaired gastrointestinal propulsion, a broad clinical spectrum, and variable severity. Several molecular bases underlying primary PIPO have been identified, of which autosomal dominant ACTG2-related visceral myopathy is the most common in both familial or sporadic primary PIPO cases. We present a family with autosomal recessive ACTG2-related disease in which both parents have mild gastrointestinal symptoms and sons have severe PIPO and bladder dysfunction.

Methods: Clinical genome sequencing was performed on the patients and the mother. Immunohistochemistry was performed on intestinal tissue from the patients to show expression levels of the ACTG2.

Results: Genome sequencing identified a 6.8 kb 2p13.1 loss that includes the ACTG2 gene and a maternally inherited missense variant p.Val10Met in the ACTG2 gene.

Discussion: This case demonstrates that monoallelic hypomorphic ACTG2 variants may underly mild primary gastrointestinal symptoms, while biallelic mild variants can cause severe diseases. The Deletions of the noncoding ACTG2 exon can be an under-recognized cause of mild gastrointestinal symptoms unidentifiable by exome sequencing, explaining some instances of interfamilial variability with an apparent autosomal dominant inheritance. Genome sequencing is recommended as a genetic work-up for primary or idiopathic PIPO because of genetic heterogeneity.

Keywords: ACTG2-related disorder; chronic intestinal pseudo-obstruction; genome sequencing; megacystis microcolon intestinal hypoperistalsis syndrome; visceral myopathy.

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Conflict of interest statement

Dr Di Lorenzo receives consultant fees from Sucampo, Allergan, QOL Inc, Mahana, Innovative Health Solutions, and Mallinckrodt. Dr Kaler receives Consultant fees from Vivet Therapeutics, Inc. (Paris, France) as chair of a clinical trial Data Monitoring Committee. AC is an employee and shareholder of Illumina, Inc. The remaining authors report no conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.
2p13.1 deletion [chr2:g.74115998_74122821del(GRCh37)] detected in the family.
FIGURE 2.
FIGURE 2.
Immunohistochemistry performed in intestinal material obtained from the 2 PIPO patients and a neonatal control, shows distribution and expression of ACTG2 in the cytoplasm of smooth muscle cells of the muscularis mucosa, blood vessels and, the circular and longitudinal muscle of muscularis propria. No significant changes were detected in the composition of the intestine of patients and control, shown by HE staining and immunohistochemistry for NF and ACTA2. Scale bars: 800 μm. HE = hematoxylin and eosin; NF = neurofilament; PIPO = pediatric intestinal pseudo-obstruction.
See this image and copyright information in PMC

References

    1. Thapar N, Saliakellis E, Benninga MA, et al. . Paediatric intestinal pseudo-obstruction: evidence and consensus-based recommendations from an ESPGHAN-led expert group. J Pediatr Gastroenterol Nutr. 2018;66:991–1019. - PubMed
    1. Batzir NA, Bhagwat PK, Larson A, et al. . Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy. Hum Mutat. 2020;41:641–654. - PMC - PubMed
    1. Matera I, Rusmini M, Guo Y, et al. . Variants of the ACTG2 gene correlate with degree of severity and presence of megacystis in chronic intestinal pseudo-obstruction. Eur J Hum Genet. 2016;24:1211–1215. - PMC - PubMed
    1. Lehtonen HJ, Sipponen T, Tojkander S, et al. . Segregation of a missense variant in enteric smooth muscle actin γ-2 with autosomal dominant familial visceral myopathy. Gastroenterology. 2012;143:1482–1491.e3. - PubMed
    1. Monies D, Maddirevula S, Kurdi W, et al. . Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation. Genet Med. 2017;19:1144–1150. - PubMed