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

Eleonora Di Gregorio,Alfredo Brusco,Gabriella Restagno,Alessandro Calcia,Elga Fabia Belligni,Giovanni Battista Ferrero,Elisa Giorgio,Flavia Talarico,Elisa Savin,Simona Cavalieri,Monica Grosso,Patrizia Pappi,Marina Gandione,Valeria Giorgia Naretto,Enrico Grosso,Giorgia Gai,Giorgia Mandrile,Giovanni Botta,Valentina Asnaghi,Cecilia Mancini,Elisa Biamino,Gaetana D′Alessandro,F Fiocchi ,Margherita Silengo

doi:10.1186/s13039-014-0082-7

Abstract

BackgroundConventional 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%.ResultsIn 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.ConclusionsLarge 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.

Highlights

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)
GTG-banding karyotype is a standard procedure in the diagnosis of patients with unexplained intellectual disability/developmental delay (ID/DD), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA) [1]
The detection of submicroscopic rearrangements by array-CGH has increased the diagnostic yield of patients with ID/DD and/or MCA of 15-20% [3,4,5], due to array-CGH higher resolution vs. karyotyping (50–100 kb on a 60 K Agilent platform) [3,6]

Summary

Introduction

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). The detection of submicroscopic rearrangements by array-CGH has increased the diagnostic yield of patients with ID/DD and/or MCA of 15-20% [3,4,5], due to array-CGH higher resolution vs karyotyping (50–100 kb on a 60 K Agilent platform) [3,6]. An estimate of the number of these overlooked rearrangements is still unknown These are likely to be mainly derivative chromosomes with deletions and duplications, involving chromosomal regions with a similar banding pattern and size. These anomalies can result from parental balanced translocations that malsegregate at meiosis. Whereas balanced translocation are associated with infertility and recurrent miscarriages [8], the clinical consequences of derivative chromosomes can be lethal or lead to complex severe phenotypes

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