Clinical significance of regions of homozygosity detection in prenatal chromosomal microarray analysis

TL;DR

This study examines the importance of detecting regions of homozygosity in prenatal genetic testing and how it helps in diagnosing genetic disorders.

Contribution

The study provides new insights into the diagnostic yield and clinical utility of follow-up tests for regions of homozygosity in prenatal chromosomal microarray analysis.

Findings

ROH detection in prenatal CMA has a 2.7% positive predictive value for autosomal-recessive disorders.

Follow-up testing identified UPD-related diseases in 9.6% of cases with ROH.

The overall additive diagnostic yield from ROH detection is 0.04%.

Abstract

Chromosomal microarray analysis (CMA) detects pathogenic copy-number variants (pCNVs) and regions of homozygosity (ROHs) in prenatal genetic analysis. This study evaluates the clinical significance of ROH detection in prenatal settings. We reviewed 178 fetuses with ROH detected by CMA among 20,546 fetuses from 2015 to 2023. Clinical and laboratory results, including ultrasound anomalies, cell-free DNA (cfDNA) screening, karyotyping, exome sequencing (ES), and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), were analyzed. These 178 fetuses with ROH accounted for 0.87% of prenatal cases. Among them, 24.2% had positive cfDNA screening results, and 52.8% underwent follow-up ES, trio CMA, and MS-MLPA. Follow-up studies detected pathogenic homozygous variants within ROH in two fetuses and uniparental disomy (UPD)-related diseases in five fetuses. Our results and findings from the other five large prenatal case series from literature indicated that ROH detection in prenatal CMA has a baseline positive predictive value of 2.7% for autosomal-recessive disorders, 9.6% for UPD-related diseases, and 0.04% overall additive diagnostic yield. These findings support the use of ES and MS-MLPA for follow-up testing and provide guidance for genetic counseling in fetuses with ROH.

This study evaluates the clinical significance of regions of homozygosity (ROH) detection in prenatal settings. Our results and findings from the other five large prenatal case series from the literature indicated that the use of exome sequencing and methylation-specific multiplex ligation-dependent probe amplification for follow-up testing and provide guidance for genetic counseling in fetuses with ROH.

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