title: Ring chromosome 18 in combination with 18q12.1 (DTNA) interstitial microdeletion in a patient with multiple congenital defects.
abstract: BACKGROUND
  Ring chromosome 18 [r(18)] syndrome represents a relatively rare condition with a complex clinical picture including multiple congenital dysmorphia and varying degrees of mental retardation. The condition is cytogenetically characterized by a complete or mosaic form of ring chromosome 18, with ring formation being usually accompanied by the partial loss of both chromosomal arms. Here we observed a 20-year-old male patient who along with the features typical for r(18) carriers additionally manifested a severe congenital subaortic stenosis. To define the genetic basis of such a compound phenotype, standard cytogenetic and high-resolution molecular-cytogenetic analysis of the patient was performed.
  
  
  METHODS
  Standard chromosome analysis of cultured lymphocytes confirmed 46, XY, r(18) karyotype. Array-based comparative genomic hybridization (array-CGH) allowed to define precisely the breakpoints of 18p and 18q terminal deletions, thus identifying the hemizygosity extent, and to reveal an additional duplication adjoining the breakpoint of the 18p deletion. Apart from the terminal imbalances, we found an interstitial microdeletion of 442 kb in size (18q12.1) that encompassed DTNA gene encoding α-dystrobrevin, a member of dystrophin-associated glycoprotein complex. While limited data on the role of DTNA missense mutations in pathogenesis of human cardiac abnormalities exist, a microdeletion corresponding to whole DTNA sequence and not involving other genes has not been earlier described.
  
  
  CONCLUSIONS
  A detailed molecular-cytogenetic characterization of the patient with multiple congenital abnormalities enabled to unravel a combination of genetic defects, namely, a ring chromosome 18 with terminal imbalances and DTNA whole-gene deletion. We suggest that such combination could contribute to the complex phenotype. The findings obtained allow to extend the knowledge of the role of DTNA haploinsufficiency in congenital heart malformation, though further comprehensive functional studies are required.
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, 197341 Russia ; Institute of translational Medicine, ITMO University, Saint-Petersburg, 199034 Russia ; Cytology and Histology Department, Saint Petersburg State University, Saint-Petersburg, 199034 Russia.
authors.forename: Anna
authors.initials: A
authors.lastname: Zlotina
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, 197341 Russia.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Nikulina
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, 197341 Russia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Yany
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, 197341 Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Moiseeva
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, 197341 Russia.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Pervunina
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, 197341 Russia.
authors.forename: Eugeny
authors.initials: E
authors.lastname: Grekhov
authors.affiliation: Almazov Federal Medical Research Centre, Saint-Petersburg, 197341 Russia ; Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institute, Stockholm, 17176 Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Kostareva
keywords: Array-based CGH; DTNA deletion; Ring(18); Subaortic stenosis; α-dystrobrevin