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. 2014 Nov 19;7(1):82.
doi: 10.1186/s13039-014-0082-7. eCollection 2014.

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

Eleonora Di Gregorio  1 , Elisa Savin  2 , Elisa Biamino  3 , Elga Fabia Belligni  3 , Valeria Giorgia Naretto  2 , Gaetana D'Alessandro  2 , Giorgia Gai  2 , Franco Fiocchi  2 , Alessandro Calcia  4 , Cecilia Mancini  4 , Elisa Giorgio  4 , Simona Cavalieri  1 , Flavia Talarico  2 , Patrizia Pappi  2 , Marina Gandione  5 , Monica Grosso  6 , Valentina Asnaghi  6 , Gabriella Restagno  6 , Giorgia Mandrile  7 , Giovanni Botta  8 , Margherita Cirillo Silengo  3 , Enrico Grosso  2 , Giovanni Battista Ferrero  3 , Alfredo Brusco  1
Affiliations

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

Eleonora Di Gregorio et al. Mol Cytogenet. .

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.

Keywords: Array-CGH; CNV; GTG-banding; Genomic rearrangement; Intellectual disability; Unbalanced derivative chromosomes.

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Figures

Figure 1
Figure 1
Array-CGH and karyotyping in cases with inherited and de novo chromosomal rearrangements. Panel A. Array-CGH analysis resulting in telomeric rearrangements on two different chromosomes (left). On the X-axis, the log ratio is reported (log2 intensity of [Cy5 fluorochrome/Cy3 fluorochrome)]. Expected values are from −0.7 to −1 for a deletion (green dots), 0 for normal (black dots), and +0.5 to +1 for a duplication (red dots). On the right side, GTG-banding of the chromosomes involved in the structural rearrangements. In cases marked by an asterisk, the chromosomes on the right are from the parent carrying the cryptic translocation, because patient karyotype image was not available. Breakpoints are indicated by red bars on chromosomal ideograms. In panel B, array-CGH analysis displays telomeric rearrangements in probands with de novo rearrangements.
Figure 2
Figure 2
FISH analysis of the parents carrying balanced translocation. FISH probes hybridize on the normal homologues as well as on derivative chromosomes. Probes used in these analysis were the following: 3q SpectrumOrange (05 J04-003, Vysis TelVysion probe, Abbot, Illinois, USA), 4q SpectrumOrange (05 J04-004, Vysis TelVysion probe), 10p SpectrumGreen (05 J03-010, Vysis TelVysion probe), 10q SpectrumOrange (05 J04-010, Vysis TelVysion probe), 12p SpectrumGreen (05 J03-012, Vysis TelVysion probes), 12q SpectrumOrange (05 J04-012, Vysis TelVysion probe),15q SpectrumOrange (05 J04-015, Vysis TelVysion probe), painting 14 (LPP14R, CYTOCELL, Cambridge, UK), Prader-Willi/Angelman Region probe -LSI SNRP Spectrum orange/CEP15 (D15Z1) SpectrumAqua/LSI PML SpectrumGreen (05 J26-027, Vysis, Abbot).
Figure 3
Figure 3
Dysmorphological features of cases 1, 3 and 4. A. Subject 1 at 18 months, shows mild facial dysmorphisms (triangular face, epicanthus, thin upper lip). B. Subject 3 (proband) at 6 yrs., dolico-trigonocephaly, thick eyebrows, mild synophris, mid-face hypoplasia. C. Younger brother of subject 3 at 2 yrs. showing similar dysmorphisms. D. Subject 4 at 14 yrs., showing bristly hair, left palpebral ptosis, broad nasal root, small ears.
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