{Reference Type}: Journal Article
{Title}: Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy.
{Author}: Assia Batzir N;Kishor Bhagwat P;Larson A;Coban Akdemir Z;Bagłaj M;Bofferding L;Bosanko KB;Bouassida S;Callewaert B;Cannon A;Enchautegui Colon Y;Garnica AD;Harr MH;Heck S;Hurst ACE;Jhangiani SN;Isidor B;Littlejohn RO;Liu P;Magoulas P;Mar Fan H;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;
{Journal}: Hum Mutat
{Volume}: 41
{Issue}: 3
{Year}: 03 2020
{Factor}: 4.7
{DOI}: 10.1002/humu.23960
{Abstract}: 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.