Case Report: A rare chromosomal imbalance with dup 7q36.3-qter and del 7pter-p22.3 arising from parental pericentric inversion

Abstract

Chromosomal abnormality is a significant cause of neurodevelopmental delay and congenital malformation. Only a few cases of chromosome 7 imbalances with both duplication of the distal long arm (7q) and deletion of the distal short arm (7p) have been reported without a systematic analysis of the genotype-phenotype relationship. We identify a new case of chromosome 7 imbalance with dup 7q36.3-qter and del 7pter-p22.3 and thoroughly characterize the chromosomal abnormality in the patient and related family members using a variety of genetic tests. More importantly, similar cases of 7q duplication and 7p deletion arising from parental pericentric inversion are reviewed to clarify the genotype-phenotype correlation of the disease. In summary, in cases of normal prenatal and early postnatal growth, progressive neurodevelopmental delay, intellectual disability, limited speech, and mild facial dysmorphism, the rare combination of duplication and deletion of distal ends of chromosome 7 may be suspected. Parental pericentric chromosomal inversion is likely a genetic contributor to the duplication-deletion imbalance in the offspring despite normal phenotypes in the inversion carrier, so genetic testing and counseling are recommended for better disease management and prevention.

Keywords: chromosome 7 imbalance; del 7pter-p22.3; dup 7q36.3-qter; facial dysmorphism; genetic counseling; genotype-phenotype correlation; neurodevelopmental delay; parental pericentric inversion.

FIGURE 1

Clinical phenotypes of the proband with 7p22.3 deletion and 7q36.3 duplication at 10 months of age. (A,B) Dysmorphic facial features of the proband. (C) X-ray of the face. (D) Brain MRI showed a middle cranial fossa meningioma. The dashed red circle marks the approximate boundaries of the region associated with a middle cranial fossa meningioma. (E,F) normal trunk and limbs.

FIGURE 2

The heterozygous 7p22.3 deletion and 7q36.3 duplication were identified via CNV analysis utilizing next-generation sequencing (NGS) and SNP array in a male patient. (A) Scatter diagram of the CNV analysis with NGS data. This diagram shows the log2 ratio of sample/batch median (upper) and BAF value (lower) for chromosome 7, where deleted 7p22.3 and duplicated 7q36.3 are marked with chromosome coordinates (GRCh37). (B) The CNV variants from the proband are absent in both of his parents. This diagram shows the copy numbers for genes within deleted 7p22.3 (upper) and duplicated 7q36.3 (lower). Individual genes within each diagram are arranged according to their sequential locations on the chromosome. Red bars indicate genes affected by the CNV deletion/duplication in the patient, whereas black bars indicate genes unaffected. (C) CNVs were confirmed by SNP array. This diagram shows the log2 ratio of sample/batch median for chromosome 7, where deleted 7p22.3 (red) and duplicated 7q36.3 (blue) are marked with chromosome coordinates (GRCh37).

FIGURE 3

Genomic rearrangements disclosed by OGM and verified by Sanger sequencing. (A) OGM detects an intrachromosomal fusion of two distal chromosome 7 fragments (Sample map, blue ribbon), which matches a region next to the deleted 7p22.3 (left) and the duplicated 7q36.3 (right). The upper reference OGM map of normal Chromosome 7 (green ribbons) shows the deleted 7p22.3 (marked with a dashed line) and the neighboring region, and the lower reference map (green ribbons) shows the duplicated 7q36.3 (marked with a dashed line) and the neighboring region. Bands within the blue and green ribbons indicate specific labeling patterns of different chromosome regions via OGM. The matching of bands (gray connecting lines) suggests identical sequence compositions between compared regions. OGM does not specify the exact translocation breakpoints within the purple region. PCR primers designed to span the assumed translocation breakpoints are shown as red and blue arrows at corresponding chromosome regions. (B) Schematic representation of a proposed mechanism for how deletion/duplication imbalances of Chromosome 7 in the proband result from a balanced chromosome inversion carried by a parent. Normal chromosome (a-a’) may undergo pericentric inversion to form a balanced product (b-b’). In a heterozygous carrier, a-a’ and b-b’ can pair up in a loop configuration during meiosis, when a single crossover may lead to the production of four gametes, including a-a’ and b-b’, as well as recombinant c-c’ and d-d’ with deletion/duplication imbalances. The distal ends of the short and long arms of chromosome 7 are marked as yellow and purple, respectively. d-d’ with deleted 7p22.3 and duplicated 7q36.3 is present in the proband. Red and blue arrows indicate PCR primers for breakpoint verification and sequencing. (C) PCR results verify chromosome 7 translocation in the proband and inversion in his mother. PCR amplification was carried out using primers indicated above and DNA isolated from the proband’s and his parents’ blood samples. The results were analyzed by 2% agarose gel electrophoresis, and the size of the expected amplification product is 291 bp. (D) The exact breakpoints are identified by Sanger sequencing. DNA was gel purified from the bands shown above and then subjected to Sanger sequencing. The breakpoints in hg19 are chr7: (G)1705548 (p22.3) and chr7: (G)155251014 (q36.3), as indicated by arrows.