A novel maternally inherited CDKN1C variant in a familial beckwith-wiedemann syndrome case: expanding the genotype-phenotype spectrum.

backgroundCyclin-dependent kinase inhibitor 1 C (CDKN1C), encoding the p57KIP2 protein, serves as a critical negative regulator of cellular proliferation. Loss-of-function mutations in CDKN1C are responsible for 5–8% of sporadic and 40% of familial Beckwith-Wiedemann syndrome (BWS) cases, with 133 variants catalogued in the Human Gene Mutation Database (HGMD). We herein report a novel CDKN1C variant in a familial BWS case. A female neonate delivered preterm via cesarean section for severe preeclampsia manifested large for gestational age, macroglossia, omphalocele, and nevus flammeus. Immediate postnatal repair of the omphalocele was conducted. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) analysis of genomic DNA from peripheral blood demonstrated normal methylation at the 11p15.5 imprinting control region without copy number variations. Whole-exome sequencing (WES) showed no pathogenic variants, whereas whole-genome sequencing (WGS) detected a novel maternally inherited heterozygous frameshift variant in CDKN1C (NM_000076.2: c.617_635dup, p.Ala213GlyfsTer34). Longitudinal follow-up to age 4.5 years documented persistent postnatal overgrowth, with weight consistently tracking above the 97th percentile ( > + 2 SD). Motor, language, and cognitive development had gradually improved, progressing from mild delay to normal status. A transient leg length difference was initially noted but resolved on follow-up examination. The tumor marker alpha-fetoprotein (AFP) had normalized, and no tumors were detected during monitoring.

conclusionThis case reinforces the critical link between CDKN1C loss-of-function variants and abdominal wall defects. Our findings underscore the necessity of CDKN1C sequencing in Beckwith-Wiedemann spectrum (BWSp) diagnostics, particularly for fetuses presenting with omphalocele and negative 11p15 epigenetic testing. The identification of the novel NM_000076.2: c.617_635dup variant expands the genotype-phenotype landscape of BWS, facilitating more precise genetic counseling and subtype-specific management.