Relevance of Copy Number Variation at Chromosome X in Male Fetuses Inherited from the Mother May Be Ascertained by Including Male Relatives from the Maternal Lineage in Addition to Trio Analyses

Abstract

Chromosome microarray analysis has been used for prenatal detection of copy number variations (CNVs) and genetic counseling of CNVs has been greatly improved after the accumulation of knowledge from postnatal outcomes in terms of the genotype-phenotype correlation. However, a significant number of CNVs are still regarded as variants of unknown significance (VUS). CNVs at the chromosome X (X-CNVs) represent a unique group of genetic changes in genetic counseling; X-CNVs are similar to X-linked recessive monogenic disorders in that the prognosis in males is expected to be poor. Trio analysis is typically advised to patients with X-CNVs but such an approach may be inadequate in prenatal settings since the clinical relevance is sometimes uninformative, particularly for the maternally inherited X-CNVs in male fetuses. Here, we reported four healthy women whose male fetuses were found to have X-CNVs inherited from the mothers. The X-CNVs were initially recognized as VUS or likely pathogenic in males according to the publicly available information. After extending genetic analyses to male relatives of the maternal lineages, however, the relevance of the X-CNVs was reconsidered to be likely benign. The results highlight that an extended analysis to include more relatives, in addition to the parents, provides further information for genetic counseling when X-CNVs are encountered in prenatal settings.

Retrospective analysis of the sex chromosomal copy number variations in 186 fetuses using single nucleotide polymorphism arrays

“…Changes in STS ( Zhang et al, 2020 ; Crane and Paller, 2022 ) and SHOX ( Hirschfeldova et al, 2012 ; Ogushi et al, 2019 ) genes were associated with multiple genetic defects, and chromosomal alterations involved in those genes were defined as pathogenic CNVs. Determining the parent-of-origins of the deletions/duplications is critical for the prenatal diagnosis of sex chromosomal abnormalities ( Chen et al, 2020 ). In our study, we detected three cases of X or Y chromosomal deletions/duplications which were inherited from their parents with normal phenotypes and were defined as probably benign CNVs.…”

Difficulties of Prenatal Genetic Counseling for a Subsequent Child in a Family With Multiple Genetic Variations

“…Prenatal counseling of genome-wide tests is challenging due to the complexity of genomic data, in which large numbers of genetic variants are VOUS whose significance to the function or health of people is unknown ( Chen et al, 2020 ). The situation is further complicated by incidental (or secondary) findings not related to the indication or anticipation of the test.…”

“…Genome-wide tests, such as whole-exome sequencing (WES) and chromosomal microarray analysis (CMA), which includes a more detailed analysis of the human genome, have gradually become more popular in the setting of prenatal diagnosis ( Chang et al, 2020 ; Chen et al, 2020 ). WES provides comprehensive detection of variants in the exonic regions of genes of a genome compared with an analysis of a selective few genes.…”