Prenatal diagnosis and genetic analysis: rare familial chromosomal duplications larger than 5 Mb without disease phenotypes.

Background: This study aimed to identify large duplications (>5 Mb) that are harmless through long-term clinical follow-ups of fetuses and phenotype analyses of carrier family members.

Methods: We retrospectively analyzed fetuses undergoing prenatal diagnosis and who had >5 Mb chromosomal duplications. Routine karyotyping and single-nucleotide polymorphism array analysis were performed to identify the source and location information of the duplicated segments. Genotype-phenotype analyses were conducted based on genetic information and phenotypes during postnatal follow-up.

Results: Eight eligible cases were included. All fetuses carried maternal or paternal duplications ranging in length from 5.3 to 12.2 Mb. The locations were as follows: 2q32.3q33.1 (Chr2:192322509-199548704), 4q22.1 (Chr4: 88347368-93602855), 4q34.2q35.2 (Chr4:176956406-189189971), 4q34.3q35.2 (Chr4:180613345-189353740), 5p14.3p14.1 (Chr5:19093749-28557664), 10q22.2q23.2 (Chr10:77448435-88786593), 12q21.31q21.32 (Chr12:81983257-87322734), and 13q14.11q14.2 (Chr13: 40825382-47633710). Karyotyping revealed that these duplications occurred within their respective chromosomal regions, except in pedigrees 6 and 7. In the eight pedigrees, the coordinates and lengths of duplicated segments in family members were matched with those in fetuses. Neither the fetuses nor other carriers were clinically symptomatic.

Conclusion: Our findings revealed that the eight pedigrees carrying duplications >5 Mb were asymptomatic, providing new data to inform genetic counseling for the observed segments.

Impact: We focused on unrelated fetuses among eight pedigrees who carried duplications of different chromosomal segments. These duplications had been stably transmitted through 2 or 3 generations of normal individuals. Importantly, phenotypic abnormalities were lacking, which was unexpected given that the maximum segment size was approximately 12.2 Mb. We found that duplications in these regions were benign in the context of prenatal genetic counseling. These results provide a foundation for addressing genotype-phenotype correlations. To our knowledge, this is the first description of normal phenotypes in individuals with duplications in these regions.