title: New Insights into the Genetics of Fetal Megacystis: ACTG2 Mutations, Encoding γ-2 Smooth Muscle Actin in Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (Berdon Syndrome).
abstract: OBJECTIVE
  To identify the molecular basis for prenatally suspected cases of megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) (MIM 249210) in 3 independent families with clinical and radiographic evidence of MMIHS.
  
  
  METHODS
  Whole-exome sequencing (WES) and Sanger sequencing of the ACTG2 gene.
  
  
  RESULTS
  We identified a novel heterozygous de novo missense variant in ACTG2 c.770G>A (p.Arg257His) encoding x03B3;-2 smooth muscle actin (ACTG2) in 2 siblings with MMIHS, suggesting gonadal mosaicism of one of the parents. Two additional de novo missense variants (p.Arg257Cys and p.Arg178His) in ACTG2 were identified in 2 additional MMHIS patients. All of our patients had evidence of fetal megacystis and a normal or slightly increased amniotic fluid volume. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. ACTG2 immunostaining of the intestinal tissue showed an altered muscularis propria, a markedly thinned longitudinal muscle layer, and a reduced amount and abnormal distribution of ACTG2.
  
  
  CONCLUSIONS
  Our study demonstrates that de novo mutations in ACTG2 are a cause of fetal megacystis in MMIHS and that gonadal mosaicism may be present in a subset of cases. These findings have implications for the counseling of families with a diagnosis of fetal megacystis with a preserved amniotic fluid volume and associated gastrointestinal findings.
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, N.Y., USA.
authors.forename: Lea
authors.initials: L
authors.lastname: Tuzovic
authors.forename: Sha
authors.initials: S
authors.lastname: Tang
authors.forename: Russell S
authors.initials: RS
authors.lastname: Miller
authors.forename: Luis
authors.initials: L
authors.lastname: Rohena
authors.forename: Layla
authors.initials: L
authors.lastname: Shahmirzadi
authors.forename: Kelly
authors.initials: K
authors.lastname: Gonzalez
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Charles A
authors.initials: CA
authors.lastname: LeDuc
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Guo
authors.forename: Ashley
authors.initials: A
authors.lastname: Wilson
authors.forename: Ashley
authors.initials: A
authors.lastname: Mills
authors.forename: Kenneth
authors.initials: K
authors.lastname: Glassberg
authors.forename: Heidi
authors.initials: H
authors.lastname: Rotterdam
authors.forename: Antonia R
authors.initials: AR
authors.lastname: Sepulveda
authors.forename: Wenqi
authors.initials: W
authors.lastname: Zeng
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Kwame
authors.initials: K
authors.lastname: Anyane-Yeboa
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000199:Actins / Q000235:genetics*; D000328:Adult; D003106:Colon / Q000002:abnormalities*; D004252:DNA Mutational Analysis; D004386:Duodenum / Q000002:abnormalities* / Q000000981:diagnostic imaging; D005260:Female; D005315:Fetal Diseases / Q000000981:diagnostic imaging* / Q000235:genetics; D006801:Humans; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics*; D007421:Intestine, Small / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011247:Pregnancy; D011296:Prenatal Diagnosis; D016415:Sequence Alignment; D014463:Ultrasonography; D001743:Urinary Bladder / Q000002:abnormalities* / Q000000981:diagnostic imaging
chemical_list: C579475:ACTG2 protein, human; D000199:Actins