Large cryptic genomic rearrangements with apparently normal karyotypes detected by array-CGH

Molecular Cytogenetics

Alfredo Brusco⁴  Giovanni Battista Ferrero⁷  Enrico Grosso⁴  Margherita Cirillo Silengo⁷  Giovanni Botta²  Giorgia Mandrile³  Gabriella Restagno⁵  Valentina Asnaghi⁵  Monica Grosso⁵  Marina Gandione⁶  Patrizia Pappi⁴  Flavia Talarico⁴  Simona Cavalieri⁴  Elisa Giorgio¹  Cecilia Mancini¹  Alessandro Calcia¹  Franco Fiocchi⁴  Giorgia Gai⁴  Gaetana D¿Alessandro⁴  Valeria Giorgia Naretto⁴  Elga Fabia Belligni⁷  Elisa Biamino⁷  Elisa Savin⁴  Eleonora Di Gregorio⁴ 

[1] Department of Medical Sciences, University of Torino, via Santena 19, Torino, 10126, Italy;Department of Pathology, Città della Salute e della Scienza University Hospital, Turin, Italy;Department Clinical and Biological Sciences, University of Torino, Torino, Italy;Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy;Laboratory of Molecular Genetics, Città della Salute e della Scienza University Hospital, Turin, Italy;Department of Neuropsychiatry, University of Torino, Turin, Italy;Department of Public Health and Pediatrics, University of Torino, Turin, Italy

关键词: Intellectual disability;    Genomic rearrangement;    CNV;    Unbalanced derivative chromosomes;    Array-CGH;    GTG-banding;   

Others  :  1163002
DOI  :  10.1186/s13039-014-0082-7

 received in 2014-08-19, accepted in 2014-10-29,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Di Gregorio et al.; licensee BioMed Central Ltd.

【 图 表 】

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