TY - JOUR
T1 - Recurrent Arginine Substitutions in the ACTG2 Gene are the Primary Driver of Disease Burden and Severity in Visceral Myopathy
AU - Assia Batzir, Nurit
AU - Kishor Bhagwat, Pranjali
AU - Larson, Austin
AU - Coban Akdemir, Zeynep
AU - Bagłaj, Maciej
AU - Bofferding, Leon
AU - Bosanko, Katherine B.
AU - Bouassida, Skander
AU - Callewaert, Bert
AU - Cannon, Ashley
AU - Enchautegui Colon, Yazmin
AU - Garnica, Adolfo D.
AU - Harr, Margaret H.
AU - Heck, Sandra
AU - Hurst, Anna C.
AU - Jhangiani, Shalini N.
AU - Isidor, Bertrand
AU - Littlejohn, Rebecca O.
AU - Liu, Pengfei
AU - Magoulas, Pilar
AU - Mar Fan, Helen
AU - Marom, Ronit
AU - McLean, Scott
AU - Nezarati, Marjan M.
AU - Nugent, Kimberly M.
AU - Petersen, Michael B.
AU - Linda Rocha, Maria
AU - Roeder, Elizabeth
AU - Smigiel, Robert
AU - Tully, Ian
AU - Weisfeld-Adams, James
AU - Wells, Katerina O.
AU - Genomics, Baylor-Hopkins Center for Mendelian
AU - Posey, Jennifer E.
AU - Lupski, James R.
AU - Beaudet, Arthur L.
AU - Wangler, Michael F.
N1 - © 2019 Wiley Periodicals, Inc.
PY - 2020/3
Y1 - 2020/3
N2 - 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.
AB - 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.
KW - ACTG2
KW - dysmotility
KW - megacystis-microcolon intestinal hypoperistalsis
KW - smooth muscle
KW - visceral myopathy
UR - http://www.scopus.com/inward/record.url?scp=85076797731&partnerID=8YFLogxK
U2 - 10.1002/humu.23960
DO - 10.1002/humu.23960
M3 - Journal article
C2 - 31769566
SN - 1059-7794
VL - 41
SP - 641
EP - 654
JO - Human Mutation
JF - Human Mutation
IS - 3
ER -