G Ravenscroft1, S Pannell1, G O'Grady2, R Ong1, H C Ee3, F Faiz4, L Marns4, H Goel5, P Kumarasinghe6, E Sollis1, P Sivadorai4, M Wilson7, A Magoffin8, S Nightingale9, M-L Freckmann10, E P Kirk11, R Sachdev11, D A Lemberg12, M B Delatycki13, M A Kamm14, C Basnayake14, P J Lamont1, D J Amor15, K Jones6, J Schilperoort6, M R Davis4, N G Laing1,4. 1. Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, WA, Australia. 2. Department of Surgery, University of Auckland, Auckland, New Zealand. 3. Department of Gastroenterology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia. 4. PathWest Diagnostic Genomics, QE II Medical Centre, Nedlands, WA, Australia. 5. Hunter Genetics, Waratah, NSW, Australia. 6. Faculty of Medicine and Health Sciences, University of Western Australia, Nedlands, WA, Australia. 7. Department of Clinical Genetics, Children's Hospital at Westmead, Sydney, NSW, Australia. 8. Department of Gastroenterology, The Children's Hospital at Westmead, Westmead, NSW, Australia. 9. Paediatric Gastroenterology, John Hunter Children's Hospital, Newcastle, NSW, Australia. 10. ACT Genetics, The Canberra Hospital, Woden, ACT, Australia. 11. Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia. 12. Department of Paediatric Gastroenterology, Sydney Children's Hospital, Women's and Children's Health, University of New South Wales, Randwick, NSW, Australia. 13. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Melbourne, Vic., Australia. 14. Department of Gastroenterology, St Vincent's Hospital and University of Melbourne, Melbourne, Vic., Australia. 15. Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Melbourne, Vic., Australia.
Abstract
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 ACTG2, LMOD1, MYH11, 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 (ACTG2) and smooth muscle leiomodin (LMOD1) was performed on DNA from patients, and their relatives, where available. MYH11 and MYLK were screened by next-generation sequencing. KEY RESULTS: We identified heterozygous missense variants in ACTG2 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 LMOD1, MYH11, or MYLK were identified within our cohort. CONCLUSIONS AND INFERENCES: ACTG2 mutations represent a significant underlying cause of primary CIPO with visceral myopathy and associated phenotypes in Australasian patients. Thus, ACTG2 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.
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 ACTG2, LMOD1, MYH11, 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 (ACTG2) and smooth muscle leiomodin (LMOD1) was performed on DNA from patients, and their relatives, where available. MYH11 and MYLK were screened by next-generation sequencing. KEY RESULTS: We identified heterozygous missense variants in ACTG2 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 LMOD1, MYH11, or MYLK were identified within our cohort. CONCLUSIONS AND INFERENCES: ACTG2 mutations represent a significant underlying cause of primary CIPO with visceral myopathy and associated phenotypes in Australasian patients. Thus, ACTG2 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.
Authors: Nurit Assia Batzir; Pranjali Kishor Bhagwat; Austin Larson; Zeynep Coban Akdemir; Maciej Bagłaj; Leon Bofferding; Katherine B Bosanko; Skander Bouassida; Bert Callewaert; Ashley Cannon; Yazmin Enchautegui Colon; Adolfo D Garnica; Margaret H Harr; Sandra Heck; Anna C E Hurst; Shalini N Jhangiani; Bertrand Isidor; Rebecca O Littlejohn; Pengfei Liu; Pilar Magoulas; Helen Mar Fan; Ronit Marom; Scott McLean; Marjan M Nezarati; Kimberly M Nugent; Michael B Petersen; Maria L Rocha; Elizabeth Roeder; Robert Smigiel; Ian Tully; James Weisfeld-Adams; Katerina O Wells; Jennifer E Posey; James R Lupski; Arthur L Beaudet; Michael F Wangler Journal: Hum Mutat Date: 2019-12-19 Impact factor: 4.878
Authors: Almira Zada; Laura E Kuil; Bianca M de Graaf; Naomi Kakiailatu; Jonathan D Windster; Alice S Brooks; Marjon van Slegtenhorst; Barbara de Koning; René M H Wijnen; Veerle Melotte; Robert M W Hofstra; Erwin Brosens; Maria M Alves Journal: Front Cell Dev Biol Date: 2022-07-08