Parental insertional balanced translocations are an important cause of apparently de novo CNVs in patients with developmental anomalies

Abstract

In several laboratories, genome-wide array analysis has been implemented as the first tier diagnostic test for the identification of copy number changes in patients with mental retardation and/or congenital anomalies. The identification of a pathogenic copy number variant (CNV) is not only important to make a proper diagnosis but also to enable the accurate estimation of the recurrence risk to family members. Upon the identification of a de novo interstitial loss or gain, the risk recurrence is considered very low. However, this risk is 50% if one of the parents is carrier of a balanced insertional translocation (IT). The apparently de novo imbalance in a patient is then the consequence of the unbalanced transmission of a derivative chromosome involved in an IT. To determine the frequency with which insertional balanced translocations would be the origin of submicroscopic imbalances, we investigated the potential presence of an IT in a consecutive series of 477 interstitial CNVs, in which the parental origin has been tested by FISH, among 14,293 patients with developmental abnormalities referred for array. We demonstrate that ITs underlie ~2.1% of the apparently de novo, interstitial CNVs, indicating that submicroscopic ITs are at least sixfold more frequent than cytogenetically visible ITs. This risk estimate should be taken into account during counseling, and warrant parental and proband FISH testing wherever possible in patients with an apparently de novo, interstitial aberration.

Figure 1

Interchromosomal insertion. (a) Formation of the interchromosomal insertion. (b) Gamete production following independent pairing of the two sets of homolog.

Figure 2

Intrachromosomal insertion. (a) Formation of the interchromosomal insertion. (b) Gamete production following a recombination between the sites of rearrangement.

Figure 3

Balanced insertional translocations in nine balanced carriers. (a) FISH result with BAC clone RP11-809M12 showing translocation of 10q21.1. (b) FISH with RP11-98F19 probe showing translocation of 2q37.1. (c) FISH with RP11-679B20 showing intrachromosomal IT of region 19q13.12. (d) FISH with clone RP11-27N21 (red) showing translocated 8q21.13 and RP11-279K24 (green) indicating chromosome 5p15.2. (e) FISH with probe RP11-95M15 showing translocated region 6q23.3 (red), probe P308 (green) indicating centromere of chromosome 6. (f) FISH with RP11-13F20 (red) showing translocated region 4q22.3 and P63K5 (green) indicating chromosome 4qter. (g) FISH result with whole chromosome painting probes for chromosome 6 (green) and 11 (red). (h) FISH with FAT5 probe (red) showing translocated region 11p14.3 and centromere probe (green) indicating chromosome 11. (i) FISH with clone RP11-131P10 (red) showing translocated 13q13.3 region and probe indicating centromeres of chromosomes 13/21 (green).

Figure 4

Pedigree of the proband with a der(2)ins(1;2)(p13;q36.3q37.1) pat, who comes from a family of six individuals with severe unexplained learning disability and dysmorphisms in two generations, who had been repeatedly investigated over a 15-year period, with no abnormality found. A cryptic chromosomal rearrangement had always been highly suspected but not proven until genome-wide 32k BAC array CGH analysis was available. Affected family members showed similar facies of bitemporal narrowing, prominent jaw and abnormal palmar creases. In addition to the proband, array analysis revealed an interstitial, 2.1 Mb loss in 2q36.3q37.1 in each of the three affected family members. The unaffected parent of each person carried a cryptic balanced 1:2 insertional translocation (IT) of 2.1 Mb of 2q36.3q37.1 into 1p13. Carrier testing has been carried out in nine healthy family members, and in one an asymptomatic duplication of 2q36.3q37.1 was noted. One prenatal FISH analysis was performed and also revealed a duplication of 2q36.3q37.1, but because the aunt of this unborn child was an asymptomatic carrier of the same imbalance, the parents were reassured and continued the pregnancy. Apart from stressing the importance of being able to specifically test family members who are at risk of being a carrier of such a balanced IT, this family also exemplifies how large the difference can be between the clinical consequences of a loss versus a gain of the same chromosomal region.