Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C

Abstract

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C.

Keywords: Beckwith-Wiedemann syndrome; CDKN1C; exomphalos; genomic imprinting; loss-of-function mutations.

Figure 1

CDKN1C pathogenic variants in the four families under study. (A) Domain structure of the human CDKN1C (isoform A, NP_000067.1) depicting the position of the identified variants (novel variants in red; known variant in gray). (B) On the left, pedigree and DNA sequences showing the segregation of the variant in family 1. The patients or fetuses with BWS features are represented with black-filled symbols; the unaffected carriers of CDKN1C mutations with a dot in the middle of the symbol. The sequence variants are highlighted by a blue-shaded stripe in the electropherograms and their cDNA (NM_000076.2) and genomic (chr11, GRCh38/hg38) positions are indicated. On the right, evolutionary conservation of the tryptophan 79 (dashed in red) in primates and other mammals (Jalview software, V.2.11.1.3). (C–E) Pedigrees and DNA sequences showing the segregation of the variants in families 2–4. Asterisks indicate individuals unavailable for molecular analysis. Abbreviations: gw—weeks of gestation; TA—therapeutic abortion; SA—spontaneous abortion.