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

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.