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Background <p><i>Cyclin-dependent kinase inhibitor 1&#xa0;C</i> (<i>CDKN1C</i>), encoding the p57KIP2 protein, serves as a critical negative regulator of cellular proliferation. Loss-of-function mutations in <i>CDKN1C</i> 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 <i>CDKN1C</i> variant in a familial BWS case.</p> Case Summary <p>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 <i>CDKN1C</i> (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 ( &gt; + 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.</p> Conclusion <p>This case reinforces the critical link between <i>CDKN1C</i> loss-of-function variants and abdominal wall defects. Our findings underscore the necessity of <i>CDKN1C</i> 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.</p>

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

  • 期刊论文

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  • 发表日期：

    2026年3月26日

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  • Shanshan Wu,
  • Yanan Zhang,
  • Huifeng Zhang,
  • Xue Yan,
  • Yalei Pi

摘要

Background

Cyclin-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.

Case Summary

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.

Conclusion

This 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.