Diagnostic limitations of routine low-coverage CNV-seq in detecting mosaic paternal uniparental disomy in Beckwith-Wiedemann syndrome: a case report.

Background: Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder primarily caused by imprinting defects at 11p15.5. Mosaic paternal uniparental disomy (pUPD) accounts for approximately 20% of cases but is challenging to detect prenatally using routine low-coverage CNV-seq, as this approach has limited sensitivity for copy-number-neutral events such as uniparental disomy, particularly when present in a mosaic state. Case presentation: We report a newborn presenting with macroglossia, giant omphalocele, and a birth weight of 4,200 g (>97th percentile). Critically, routine prenatal CNV-seq on amniotic fluid revealed only variants of uncertain significance and was reported as normal for aneuploidies and pathogenic copy number variants. Postnatal whole-exome sequencing identified a 28.2 Mb region of absence of heterozygosity (AOH) on chromosome 11p15.5-p14.1, suggestive of mosaicism. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) subsequently confirmed the diagnosis of BWS due to mosaic pUPD, demonstrating hypermethylation of ICR1 and hypomethylation of ICR2. The giant omphalocele was successfully repaired via primary closure at birth. The patient underwent partial glossectomy at 23 months of age. No evidence of embryonal tumors was detected during 2-year follow-up. Conclusion: This case demonstrates that a normal prenatal CNV-seq result does not exclude BWS, particularly when classic clinical features are present. MS-MLPA remains the gold standard for diagnosing pUPD-related BWS. Early recognition, multidisciplinary surgical management, and regular tumor surveillance contributed to a favorable outcome.