Journal of assisted reproduction and genetics · 2025
Whole-genome and whole-exome sequencing of Mayer-Rokitansky-Küster-Hauser syndrome-discordant monozygotic twins.
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Ma Wenqing, Fu Fangfang, Wang Wenwen, Ma Xiangyi, Wang Shixuan, Wang Man, Li Yan
Аннотация
PURPOSE: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS), characterized by congenital uterine and vaginal aplasia, lacks definitive etiology. Discordant monozygotic (MZ) twins provide a unique model to dissect postzygotic drivers of phenotypic divergence. This study aimed to identify postzygotic mutations (SNVs, Indels, CNVs, SVs) underlying MRKHS discordance and redefine its molecular etiology.
METHODS: Whole-genome and exome sequencing (WGS/WES) were performed on blood-derived DNA from MRKHS discordant MZ twins. Variant detection utilized VarScan2, GATK, BreakDancer, and CNVnator, with stringent filtering for somatic mutations. Putative discordant variants were validated via Sanger sequencing.
RESULTS: High-coverage sequencing (mean WGS: 66.2x-68.2x; WES: 94.5x-126.6x) revealed four low-quality discordant SNVs, none of which were validated by Sanger sequencing. No pathogenic CNVs/SVs were detected, including in genes critical to Müllerian development (e.g., WNT4, LHX1). Blood-derived DNA analysis failed to identify high-penetrance coding mutations or tissue-specific mosaicism.
CONCLUSIONS: The absence of validated postzygotic mutations challenges coding variants as primary MRKHS drivers. Findings implicate Müllerian-restricted somatic mosaicism or epigenetic dysregulation (e.g., WNT4/LHX1 methylation) during embryogenesis, undetectable in peripheral blood. This underscores limitations of blood-based genomics and highlights the need for non-invasive biomarkers (e.g., cfDNA methylation) and prenatal environmental risk mitigation (e.g., endocrine disruptor avoidance). The study advocates integrating tissue-specific multi-omics and patient derived organoids to resolve MRKHS mechanisms, guiding fertility preservation and personalized reproductive interventions.
METHODS: Whole-genome and exome sequencing (WGS/WES) were performed on blood-derived DNA from MRKHS discordant MZ twins. Variant detection utilized VarScan2, GATK, BreakDancer, and CNVnator, with stringent filtering for somatic mutations. Putative discordant variants were validated via Sanger sequencing.
RESULTS: High-coverage sequencing (mean WGS: 66.2x-68.2x; WES: 94.5x-126.6x) revealed four low-quality discordant SNVs, none of which were validated by Sanger sequencing. No pathogenic CNVs/SVs were detected, including in genes critical to Müllerian development (e.g., WNT4, LHX1). Blood-derived DNA analysis failed to identify high-penetrance coding mutations or tissue-specific mosaicism.
CONCLUSIONS: The absence of validated postzygotic mutations challenges coding variants as primary MRKHS drivers. Findings implicate Müllerian-restricted somatic mosaicism or epigenetic dysregulation (e.g., WNT4/LHX1 methylation) during embryogenesis, undetectable in peripheral blood. This underscores limitations of blood-based genomics and highlights the need for non-invasive biomarkers (e.g., cfDNA methylation) and prenatal environmental risk mitigation (e.g., endocrine disruptor avoidance). The study advocates integrating tissue-specific multi-omics and patient derived organoids to resolve MRKHS mechanisms, guiding fertility preservation and personalized reproductive interventions.