Prenatal Diagnosis of Prader-Willi Syndrome via Maternal UPD15 with Placental Mosaicism: Incidental Discovery of Fetal DMD Carrier Status
Description
Prader-Willi syndrome (PWS) represents a paradigm of genomic imprinting disorders. Given the severe lifelong complications of PWS, prenatal diagnosis is crucial for early intervention and genetic counseling. Noninvasive prenatal testing (NIPT) indicated a high risk for fetal trisomy 15 (T15), prompting confirmatory invasive testing. Amniocentesis was performed, and amniotic fluid was analyzed by karyotyping, chromosomal microarray analysis (CMA), trio-based whole-exome sequencing (trio-WES), and short tandem repeat (STR) linkage analysis to investigate the genetic etiology. Post-termination, placental tissue was analyzed by copy number variant sequencing (CNVseq) to evaluate potential mosaicism. NIPT indicated a suspected T15 (Z-score: 16.4). Subsequent invasive testing confirmed the following: a 13.16 Mb region of homozygosity on chromosome 15q25.1q26.1, and a 273 kb Duchenne muscular dystrophy (DMD) gene deletion on chromosome Xp21.1, both identified by CMA. Trio-WES and STR linkage analysis revealed maternal segmental uniparental disomy of chromosome 15 (UPD15), confirming the genetic basis of PWS. Post-termination, CNVseq further demonstrated confined placental mosaicism (CPM) for T15. When NIPT suggests a high risk of T15, clinicians should maintain a high suspicion for the "trisomy rescue" mechanism, where an initially trisomic zygote undergoes mitotic correction, ultimately forming UPD15 with CPM. The potential discordance between NIPT and the actual fetal genetic status necessitates definitive prenatal diagnosis, which has critical implications for subsequent pregnancy management. Therefore, the concomitant findings of PWS and DMD carrier status require comprehensive prognostic evaluation and recurrence risk assessment.
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Whole Exome Sequencing (WES) Trio-WES was performed on gDNA from the amniotic fluid pellet (which was shared with CMA) and on parental blood gDNA. Libraries were prepared, captured by hybridization (Roche NimbleGen), and sequenced as paired-end 100-bp reads on MGISEQ-2000. Reads were processed with SOAPnuke (9) and aligned to GRCh37/hg19 using BWA (10); GATK was used for SNV/indel calling (11), followed by annotation and filtering against population and disease databases. Variant interpretation followed ACMG/AMP guidelines (12) with trio-based segregation, and exome-derived SNP/ROH information was leveraged to assess segmental UPD. Trio-WES strongly suggests the presence of maternal UPD15, encompassing regions of both isodisomy and heterodisomy. The isodisomy region contained a ~10.29 Mb ROH spanning 15q25.2q26.1 (GRCH37: g.83328542_93616975). Two heterodisomy regions were identified at 15q11q25.1 and 15q26.1q26.3 . These findings were consistent with four breaks and two crossover events on chromosome 15 during maternal meiosis Ⅰ. Additionally, a heterozygous deletion encompassing exons 45-51 of DMD (NM_004006.2: g.31792078_31986631, 194.6 kb) was classified as pathogenic based on the criteria of the ACMG.
Institutions
- Sun Yat-Sen University