Xp22.31 copy number variations in 87 fetuses: refined genotype-phenotype correlations by prenatal and postnatal follow-up

Background: Xp22.31 deletion and duplication have been described in various studies, but different laboratories interpret pathogenicity differently.

Objectives: Our study aimed to refine the genotype-phenotype associations between Xp22.31 copy number variants in fetuses, with the aim of providing data support to genetic counseling.

Methods: We retrospectively analyzed karyotyping and single nucleotide polymorphism array results from 87 fetuses and their family members. Phenotypic data were obtained through follow-up visits.

Results: The percentage of fetuses carrying the Xp22.31 deletions (9 females, 12 males) was 24.1% (n = 21), while duplications (38 females, 28 males) accounted for 75.9% (n = 66). Here, we noted that the typical region (from 6.4 to 8.1 Mb, hg19) was detected in the highest ratio, either in the fetuses with deletions (76.2%, 16 of 21) or duplications (69.7%, 46 of 66). In female deletion carriers, termination of pregnancy was chosen for two fetuses, and the remaining seven were born without distinct phenotypic abnormalities. In male deletion carriers, termination of pregnancy was chosen for four fetuses, and the remaining eight of them displayed ichthyosis without neurodevelopmental anomalies. In two of these cases, the chromosomal imbalance was inherited from the maternal grandfathers, who also only had ichthyosis phenotypes. Among the 66 duplication carriers, two cases were lost at follow-up, and pregnancy was terminated for eight cases. There were no other clinical findings in the rest of the 56 fetuses, including two with Xp22.31 tetrasomy, for either male or female carriers.

Conclusion: Our observations provide support for genetic counseling in male and female carriers of Xp22.31 copy number variants. Most of them are asymptomatic in male deletion carriers, except for skin findings. Our study is consistent with the view that the Xp22.31 duplication may be a benign variant in both sexes.