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Variants in ACTG 2 underlie a substantial number of Australasian patients with primary chronic intestinal pseudo‐obstruction
Author(s) -
Ravenscroft G.,
Pannell S.,
O'Grady G.,
Ong R.,
Ee H. C.,
Faiz F.,
Marns L.,
Goel H.,
Kumarasinghe P.,
Sollis E.,
Sivadorai P.,
Wilson M.,
Magoffin A.,
Nightingale S.,
Freckmann M.L.,
Kirk E. P.,
Sachdev R.,
Lemberg D. A.,
Delatycki M. B.,
Kamm M. A.,
Basnayake C.,
Lamont P. J.,
Amor D. J.,
Jones K.,
Schilperoort J.,
Davis M. R.,
Laing N. G.
Publication year - 2018
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.13371
Subject(s) - missense mutation , intestinal pseudo obstruction , sanger sequencing , irritable bowel syndrome , myopathy , biology , genetics , phenotype , mutation , medicine , gene
Background Primary chronic intestinal pseudo‐obstruction (CIPO) is a rare, potentially life‐threatening disorder characterized by severely impaired gastrointestinal motility. The objective of this study was to examine the contribution of ACTG 2 , LMOD 1 , MYH 11, and MYLK mutations in an Australasian cohort of patients with a diagnosis of primary CIPO associated with visceral myopathy. Methods Pediatric and adult patients with primary CIPO and suspected visceral myopathy were recruited from across Australia and New Zealand. Sanger sequencing of the genes encoding enteric gamma‐actin ( ACTG 2 ) and smooth muscle leiomodin ( LMOD 1) was performed on DNA from patients, and their relatives, where available. MYH 11 and MYLK were screened by next‐generation sequencing. Key results We identified heterozygous missense variants in ACTG 2 in 7 of 17 families (~41%) diagnosed with CIPO and its associated conditions. We also identified a previously unpublished missense mutation (c.443C>T, p.Arg148Leu) in one family. One case presented with megacystis‐microcolon‐intestinal hypoperistalsis syndrome in utero with subsequent termination of pregnancy at 28 weeks' gestation. All of the substitutions identified occurred at arginine residues. No likely pathogenic variants in LMOD 1 , MYH 11, or MYLK were identified within our cohort. Conclusions and inferences ACTG 2 mutations represent a significant underlying cause of primary CIPO with visceral myopathy and associated phenotypes in Australasian patients. Thus, ACTG 2 sequencing should be considered in cases presenting with hypoperistalsis phenotypes with suspected visceral myopathy. It is likely that variants in other genes encoding enteric smooth muscle contractile proteins will contribute further to the genetic heterogeneity of hypoperistalsis phenotypes.