Complex chromosome rearrangements related 15q14 microdeletion plays a relevant role in phenotype expression and delineates a novel recurrent syndrome

Abstract

Complex chromosome rearrangements are constitutional structural rearrangements involving three or more chromosomes or having more than two breakpoints. These are rarely seen in the general population but their frequency should be much higher due to balanced states with no phenotypic presentation. These abnormalities preferentially occur de novo during spermatogenesis and are transmitted in families through oogenesis.Here, we report a de novo complex chromosome rearrangement that interests eight chromosomes in eighteen-year-old boy with an abnormal phenotype consisting in moderate developmental delay, cleft palate, and facial dysmorphisms.Standard G-banding revealed four apparently balanced translocations [corrected] involving the chromosomes 1;13, 3;19, 9;15 and 14;18 that appeared to be reciprocal. Array-based comparative genomic hybridization analysis showed no imbalances at all the breakpoints observed except for an interstitial microdeletion on chromosome 15. This deletion is 1.6 Mb in size and is located at chromosome band 15q14, distal to the Prader-Willi/Angelman region. Comparing the features of our patient with published reports of patients with 15q14 deletion this finding corresponds to the smallest genomic region of overlap. The deleted segment at 15q14 was investigated for gene content.

Figure 1

Facial appearance of the patient. Front view (A) and side view (B).

Figure 2

Cytogenetic analysis. Karyotype from a peripheral blood metaphase of the patient: 46,XY,t(1;13)(p31.1;q13),t(3;19)(p23;p12),t(9;15)(p23;q14),t(14;18)(q22;p11.23). The arrows of the same color indicate the breakpoints of a reciprocal translocation.

Figure 3

FISH results. Two pictures for each reciprocal traslocation of the complex chromosome rearrangement are showed: t(1;13) (A) painting #1 and (B) co-hybridization between the BAC probe RP11-433N2 green (1p31.2) with the probe RB1 red (13q14.2) specific for the retinoblastoma gene; t(3;19) (C) painting #3 and (D) painting #19; t(9;15) (E) painting #9 and (F) probe PWS specific for the Prader-Willi critical region (SNRPN) red (15q11-13), centromeric probe for the chromosome 15 in green and PML in red (15q24.1) as controls; t(14;18) (G) painting #14 and (H) dual color FISH experiment with BACs RP11-151D11 red (18p11p.21) and RP11-138C24 green (18p11.31).

Figure 4

Molecular analysis. Array-CGH profile of the 1.6 Mb deleted region at 15q14 (A). Microsatellite analysis performed using informative STRs (D15S1042 and D15S118) included in the deleted region, showed allelic loss of heterozygosity and revealed the paternal origin of the rearrangement (B).

Figure 5

Zoom in 15q14. Map of the investigated region (red intervals starting from chromosome bands 15q13.3 and 15q14; from the UCSC database). Green solid bars represented the extent of the deletions observed in the cases reported in the literature. The genes included in the deleted region of our patient are surrounded by red frames.