Germline variants in genes of the subcortical maternal complex and Multilocus Imprinting Disturbance are associated with miscarriage/infertility or Beckwith-Wiedemann progeny

Abstract

Beckwith-Wiedemann syndrome (BWS, OMIM # 130650) is an imprinting disorder, associated with overgrowth and increased risk of embryonal tumors. Patients carrying hypomethylation in the KCNQ1OT1:TSS DMR (11p15.5) show MLID (Multilocus Imprinting Disturbance) upon epimutations at other imprinted regions. Few cases of BWS MLID's mothers with biallelic pathogenetic variants in maternal effect genes, mainly components of the subcortical maternal complex, are reported. We describe two families, one with a history of conception difficulties with a novel homozygous nonsense NLRP2 variant and another experiencing 8 miscarriages with a compound heterozygous PADI6 variant.

Keywords: Beckwith–Wiedemann syndrome; Infertility; Maternal effect genes; Multiple loci imprinting disorders; Multiple miscarriages; Subcortical maternal complex genes.

Fig. 1

Pedigrees and schematic of PADI6 and NLRP2 proteins. a three generation pedigree of family 1 showing a BWS-MLID child and multiple miscarriages; b scheme of PADI6 protein: variants associated with BWS-MLID are indicated by hexagons. Same color hexagons point to compound heterozygous women. All the PADI6 variants in BWS-MLID families cluster in the PAD domain of the protein. c Pedigree of family 2; d Diagrammatic structure of the human NLRP2 protein showing Pyrin, NACHT, and leucine-rich repeat domains. Reported variants are associated with BWS-MLID progeny. Grey triangles indicate miscarriages with unknown phenotypes. The dot within the circle indicates a woman carrier of SCMC variants. Genotype is reported for each studied individual; variants described in this study are in red characters. Each hexagon represents a family. #Variants associated with recurrence of BWS children in the family