2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Mosaicism for genome wide homozygosity identified as an incidental finding in two healthy pregnant women

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Researchers have identified cases of mosaicism for genome-wide homozygosity in two healthy pregnant women. In the first case, a woman underwent carrier testing and was found to have skewed variant allele frequency (VAF) suggestive of homozygosity. Testing confirmed mosaicism for homozygosity in both blood and buccal swab DNA, with an estimated mosaicism percentage of 85% and 70%, respectively. The woman delivered a healthy baby, and further testing of the placenta showed mosaicism in the maternal decidua but normal results in the fetal villi.<br /><br />In the second case, a woman underwent carrier testing at an outside laboratory, which was inconclusive due to suspected mosaicism. Testing at the lab further confirmed significant mosaicism for homozygosity, with an estimated mosaicism percentage of 85%. The woman had a history of hyperinsulinism and organ monitoring, and her mother had a suspected molar pregnancy while pregnant with her. However, she gave birth to a healthy child.<br /><br />The study suggests that individuals with mosaic genome-wide homozygosity may appear clinically normal but may be at an increased risk for certain conditions associated with uniparental disomy. The researchers recommend genetic counseling and pregnancy monitoring for individuals with mosaic genome-wide homozygosity. Laboratories performing carrier testing should be aware of the possibility of finding mosaic homozygosity and should follow up on pathogenic variants with skewed VAF, which may indicate mosaicism. Chromosomal microarray analysis can provide further clarification on the etiology of skewed VAFs found in sequencing-based carrier tests.<br /><br />The underlying mechanism for mosaic paternal genome-wide uniparental disomy (GWUPD) in these cases is proposed to involve abnormal replication resulting in the formation of both a diploid and haploid genome, followed by subsequent duplication of the haploid genome.<br /><br />In conclusion, mosaicism for genome-wide homozygosity can be detected as an incidental finding in apparently healthy pregnant women. Genetic counseling and follow-up for associated conditions are recommended for individuals with mosaic genome-wide homozygosity.

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Presenting Author - Gloria Haskell, PhD, FACMG; Co-Author - Hussain Askree, PhD; Co-Author - Laura Kline, MS, CGC; Co-Author - Quoc-Huong Cabral, MSc; Co-Author - Linda Hasadri, MD, PhD; Co-Author - Inder Gadi, PhD, FACMG; Co-Author - Stuart Schwartz, PhD, FACMG;

Meta Tag

array CGH

Chromosomal Abnormalities

Clinical Cytogenetics

Counseling

Cytogenetics

Genetic Testing

Genomic Methodologies

Imprinting

Maternal Genetic Disease

Microarray

Molecular Cytogenetics

Sequencing

Uniparental Disomy

Variant Detection

Co-Author Hussain Askree, PhD

Co-Author Laura Kline, MS, CGC

Co-Author Quoc-Huong Cabral, MSc

Co-Author Linda Hasadri, MD, PhD

Co-Author Inder Gadi, PhD, FACMG

Co-Author Stuart Schwartz, PhD, FACMG

Presenting Author Gloria Haskell, PhD, FACMG

Keywords

mosaicism

genome-wide homozygosity

variant allele frequency

carrier testing

maternal decidua

fetal villi

uniparental disomy

genetic counseling

skewed VAF

chromosomal microarray analysis