Abstract
Background: Chromosomal aberrations contribute to human phenotypic diversity and disease susceptibility, but it is difficult to assess their pathogenic effects in the clinic. Therefore, it is of great value to report new cases of chromosomal aberrations associated with normal phenotypes or clinical abnormalities. Methods: This was a retrospective analysis of seven pedigrees that carried 21q21.1–q21.2 aberrations. G-banding and single-nucleotide polymorphism array techniques were used to analyze chromosomal karyotypes and copy number variations in the fetuses and their family members. Results: All fetuses and their family members showed normal karyotypes in seven pedigrees. Here, it was revealed that six fetuses carried maternally inherited 21q21.1–q21.2 duplications, ranging from 1 to 2.7 Mb, but none of the mothers had an abnormal phenotype. In one fetus, an 8.7 Mb deletion of 21q21.1–q21.2 was found. An analysis of the pedigree showed that the deletion was also observed in the mother, brother, and maternal grandmother, but no abnormal phenotypes were found. Conclusion: This study identified 21q21.1–q21.2 aberrations in Chinese pedigrees. The carriers of 21q21.1–q21.2 duplications had no clinical consequences based on their phenotypes, and the 21q21.1–q21.2 deletion was transmitted through three generations of normal individuals. This provides benign clinical evidence for pathogenic assessment of 21q21.1–q21.2 duplication and deletion, which was considered a variant of uncertain significance and a likely pathogenic variant in previous reports.
Highlights
To date, the 21q21 duplication and deletion have not been included in the known pathogenicity syndromes
We further identified a rare 8.7 Mb deletion of 21q21.1–21.2 containing NCAM2, which had been transmitted through three generations of normal individuals
These findings provide benign evidence, which is important for accurate genetic counseling on 21q21.1–21.2 aberrations in prenatal diagnosis
Summary
The 21q21 duplication and deletion have not been included in the known pathogenicity syndromes. Three cases of neurodevelopmental disorders were reported, with clinical phenotypic abnormalities including global developmental delay, behavioral disorders, and impaired social interactions. All of them carried 21q21.1–21.2 deletions involving NCAM2 (Petit et al, 2015) Another case report revealed that a boy with autism spectrum disorder and macrocephaly carried a 1.6 Mb deletion of 21q21.1–21.2, containing the NCAM2 gene, but no other functional gene (Scholz et al, 2016). Duplications, deletions, and single-nucleotide polymorphisms of the NCAM2 gene have been found in individuals with intellectual disabilities or autism, and these studies suggest that NCAM2 might play a role in neurodevelopmental disorders. It is of great value to report new cases of chromosomal aberrations associated with normal phenotypes or clinical abnormalities
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