%0 Journal Article
%T Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy.
%A Assia Batzir N
%A Kishor Bhagwat P
%A Larson A
%A Coban Akdemir Z
%A Bagłaj M
%A Bofferding L
%A Bosanko KB
%A Bouassida S
%A Callewaert B
%A Cannon A
%A Enchautegui Colon Y
%A Garnica AD
%A Harr MH
%A Heck S
%A Hurst ACE
%A Jhangiani SN
%A Isidor B
%A Littlejohn RO
%A Liu P
%A Magoulas P
%A Mar Fan H
%A Marom R
%A McLean S
%A Nezarati MM
%A Nugent KM
%A Petersen MB
%A Rocha ML
%A Roeder E
%A Smigiel R
%A Tully I
%A Weisfeld-Adams J
%A Wells KO
%A  
%A Posey JE
%A Lupski JR
%A Beaudet AL
%A Wangler MF
%J Hum Mutat
%V 41
%N 3
%D 03 2020
%M 31769566
%F 4.7
%R 10.1002/humu.23960
%X 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.