Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy.

TitleRecurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy.
Publication TypeJournal Article
Year of Publication2020
AuthorsBatzir, NAssia, Bhagwat, PKishor, Larson, A, Akdemir, ZCoban, Bagłaj, M, Bofferding, L, Bosanko, KB, Bouassida, S, Callewaert, B, Cannon, A, Colon, YEnchautegu, Garnica, AD, Harr, MH, Heck, S, Hurst, ACE, Jhangiani, SN, Isidor, B, Littlejohn, RO, Liu, P, Magoulas, P, Fan, HMar, Marom, R, McLean, S, Nezarati, MM, Nugent, KM, Petersen, MB, Rocha, ML, Roeder, E, Smigiel, R, Tully, I, Weisfeld-Adams, J, Wells, KO, Posey, JE, Lupski, JR, Beaudet, AL, Wangler, MF
Corporate AuthorsBaylor-Hopkins Center for Mendelian Genomics
JournalHum Mutat
Date Published2020 Mar
KeywordsAbnormalities, Multiple, Actins, Adult, Amino Acid Substitution, Arginine, Colon, DNA Mutational Analysis, Exome Sequencing, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Intestinal Pseudo-Obstruction, Male, Molecular Diagnostic Techniques, Mutation, Phenotype, Urinary Bladder, Young Adult

Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.

Alternate JournalHum Mutat
PubMed ID31769566
PubMed Central IDPMC7720429
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
R35 NS105078-01 / / National Institute of Neurological Disorders and Stroke (NINDS) / International

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