title: Large cryptic genomic rearrangements with apparently normal karyotypes detected by array-CGH.
abstract: BACKGROUND
  Conventional karyotyping (550 bands resolution) is able to identify chromosomal aberrations >5-10 Mb, which represent a known cause of intellectual disability/developmental delay (ID/DD) and/or multiple congenital anomalies (MCA). Array-Comparative Genomic Hybridization (array-CGH) has increased the diagnostic yield of 15-20%.
  
  
  RESULTS
  In a cohort of 700 ID/DD cases with or without MCA, including 15 prenatal diagnoses, we identified a subgroup of seven patients with a normal karyotype and a large complex rearrangement detected by array-CGH (at least 6, and up to 18 Mb). FISH analysis could be performed on six cases and showed that rearrangements were translocation derivatives, indistinguishable from a normal karyotype as they involved a similar band pattern and size. Five were inherited from a parent with a balanced translocation, whereas two were apparently de novo. Genes spanning the rearrangements could be associated with some phenotypic features in three cases (case 3: DOCK8; case 4: GATA3, AKR1C4; case 6: AS/PWS deletion, CHRNA7), and in two, likely disease genes were present (case 5: NR2F2, TP63, IGF1R; case 7: CDON). Three of our cases were prenatal diagnoses with an apparently normal karyotype.
  
  
  CONCLUSIONS
  Large complex rearrangements of up to 18 Mb, involving chromosomal regions with similar size and band appearance may be overlooked by conventional karyotyping. Array-CGH allows a precise chromosomal diagnosis and recurrence risk definition, further confirming this analysis as a first tier approach to clarify molecular bases of ID/DD and/or MCA. In prenatal tests, array-CGH is confirmed as an important tool to avoid false negative results due to karyotype intrinsic limit of detection.
authors.affiliation: Department of Medical Sciences, University of Torino, via Santena 19, 10126 Torino, Italy ; Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Di Gregorio
authors.affiliation: Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Savin
authors.affiliation: Department of Public Health and Pediatrics, University of Torino, Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Biamino
authors.affiliation: Department of Public Health and Pediatrics, University of Torino, Turin, Italy.
authors.forename: Elga Fabia
authors.initials: EF
authors.lastname: Belligni
authors.affiliation: Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.
authors.forename: Valeria Giorgia
authors.initials: VG
authors.lastname: Naretto
authors.affiliation: Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.
authors.forename: Gaetana
authors.initials: G
authors.lastname: D'Alessandro
authors.affiliation: Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Gai
authors.affiliation: Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Fiocchi
authors.affiliation: Department of Medical Sciences, University of Torino, via Santena 19, 10126 Torino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Calcia
authors.affiliation: Department of Medical Sciences, University of Torino, via Santena 19, 10126 Torino, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Mancini
authors.affiliation: Department of Medical Sciences, University of Torino, via Santena 19, 10126 Torino, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giorgio
authors.affiliation: Department of Medical Sciences, University of Torino, via Santena 19, 10126 Torino, Italy ; Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Cavalieri
authors.affiliation: Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Talarico
authors.affiliation: Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pappi
authors.affiliation: Department of Neuropsychiatry, University of Torino, Turin, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Gandione
authors.affiliation: Laboratory of Molecular Genetics, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Grosso
authors.affiliation: Laboratory of Molecular Genetics, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Asnaghi
authors.affiliation: Laboratory of Molecular Genetics, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Restagno
authors.affiliation: Medical Genetics unit, San Luigi University Hospital, Orbassano, Italy ; Department Clinical and Biological Sciences, University of Torino, Torino, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Mandrile
authors.affiliation: Department of Pathology, Città della Salute e della Scienza University Hospital, Turin, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Botta
authors.affiliation: Department of Public Health and Pediatrics, University of Torino, Turin, Italy.
authors.forename: Margherita Cirillo
authors.initials: MC
authors.lastname: Silengo
authors.affiliation: Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Grosso
authors.affiliation: Department of Public Health and Pediatrics, University of Torino, Turin, Italy.
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Ferrero
authors.affiliation: Department of Medical Sciences, University of Torino, via Santena 19, 10126 Torino, Italy ; Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Brusco
keywords: Array-CGH; CNV; GTG-banding; Genomic rearrangement; Intellectual disability; Unbalanced derivative chromosomes