Genomic Complexity and Complex Chromosomal Rearrangements in Genetic Diagnosis: Two Illustrative Cases on Chromosome 7

Abstract

Complex chromosomal rearrangements are rare events compatible with survival, consisting of an imbalance and/or position effect of one or more genes, that contribute to a range of clinical presentations. The investigation and diagnosis of these cases are often difficult. The interpretation of the pattern of pairing and segregation of these chromosomes during meiosis is important for the assessment of the risk and the type of imbalance in the offspring. Here, we investigated two unrelated pediatric carriers of complex rearrangements of chromosome 7. The first case was a 2-year-old girl with a severe phenotype. Conventional cytogenetics evidenced a duplication of part of the short arm of chromosome 7. By array-CGH analysis, we found a complex rearrangement with three discontinuous trisomy regions (7p22.1p21.3, 7p21.3, and 7p21.3p15.3). The second case was a newborn investigated for hypodevelopment and dimorphisms. The karyotype analysis promptly revealed a structurally altered chromosome 7. The array-CGH analysis identified an even more complex rearrangement consisting of a trisomic region at 7q11.23q22 and a tetrasomic region of 4.5 Mb spanning 7q21.3 to q22.1. The mother's karyotype examination revealed a complex rearrangement of chromosome 7: the 7q11.23q22 region was inserted in the short arm at 7p15.3. Finally, array-CGH analysis showed a trisomic region that corresponds to the tetrasomic region of the son. Our work proved that the integration of several technical solutions is often required to appropriately analyze complex chromosomal rearrangements in order to understand their implications and offer appropriate genetic counseling.

Keywords: array-CGH; chromosome 7; complex chromosomal rearrangements; genomic complexity; segmental duplications.

Figure 1

Case 1. (A) (from left to right): GTG and QFQ banded homologous chromosomes 7 of the proband, with the chromosome 7 ideogram in the middle; the arrows indicate the point of insertion. In the square on the right: FISH with whole chromosome 7 painting (top) and subtelomeric-specific probes of chromosome 7 (bottom, green 7ptel and red 7qtel). (B) BAC probes and their mapping region (band) and FISH results on chromosome dup(7) (+ single signal, ++ double signal) (Table 1); in the square on the right: FISH with RP11-115D14 (7p21.2, red distal signal), and the ELN probe (7q11.23, red signal) with the 7q22 control probe (green signal). The arrow indicates chromosome 7 with a double BAC probe signal. (C) Array-CGH profile, with an enlargement of the duplicated region.

Figure 2

Case 2. Left: QFQ and GTG banded chromosomes 7 of the mother; the ins(7) chromosome is on the right. (A) FISH with D7Z1 (green signal) and EGFR (7p11.2, red signal) probes; (B) FISH with wcp7 (green chromosomes); (C) FISH with ELN (7q11.23, red signal) and the 7q22 control probes (green signal). The signal proximity on the ins(7) chromosome shows that the 7q21.3q22.2 region is excised. Arrows indicate ins(7) chromosomes. Right: QFQ and GTG banded chromosomes 7 of the child; the rec(7)dup(7q) chromosome is on the right. (D) FISH with ELN (7q11.23, red signal) and the 7q22 control probes (green signal) show a normal hybridization pattern; (E) FISH with CUTL1 (7q22, green signal) and 7q36 (red signal) probes shows an anomalous additive signal for the CUTL1 probe on the p arm of the rec(7) (arrowed).

Figure 3

Case 2. Array-CGH profiles of the proband (on the left) and of the mother (on the right). Trisomic regions (in blue or pink) and tetrasomic regions (in red) are indicated. The ideogram of chromosome 7 and the respective alterations in the child’s and the mother’s chromosomes are schematized in the box on the right. A benign copy number variant (CNV) was also reported at 7p22.2 in both samples (in yellow). Bottom: reciprocal mapping and dimensions of the alterations identified by array-CGH analysis.

Figure 4

Diagram showing the suggested mechanism of formation of the recombinant chromosome of the child in case 2. (A) the normal (left) and the ins(7) (right) in maternal prophase 1. An incomplete pairing is supposed to be due to the region inserted at 7q11.23q22, which causes a loop in both chromosomes. (B) Meiotic recombinant chromosomes 7 following a single crossing-over event in the region near the centromere, Rec1 with 7q11.23q22 deletion and Rec2 with 7q11.23q22 duplication found in the child. The figure shows only one chromatid for each chromosome.