Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann Syndrome)

Abstract

Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth and human imprinting disorder resulting from the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. Most cases are sporadic and result from epimutations at either of the two 11p15.5 imprinting centres (IC1 and IC2). However, rare familial cases may be associated with germline 11p15.5 deletions causing abnormal imprinting in cis. We report a family with BWS and an IC2 epimutation in which affected siblings had inherited different parental 11p15.5 alleles excluding an in cis mechanism. Using a positional-candidate gene approach, we found that the mother was homozygous for a frameshift mutation in exon 6 of NLRP2. While germline mutations in NLRP7 have previously been associated with familial hydatidiform mole, this is the first description of NLRP2 mutation in human disease and the first report of a trans mechanism for disordered imprinting in BWS. These observations are consistent with the hypothesis that NLRP2 has a previously unrecognised role in establishing or maintaining genomic imprinting in humans.

Figure 1. Family pedigree (partial) to demonstrate complex consanguinity.

Figure 2. Germline NLRP2 mutation.

The alignments of NLRP2 nucleotides c.1465–c.1492 are shown. (A) is wildtype sequence in a control, (B) is heterozygous NLRP2 mutation (c.1479delAG) in the father, and (C) is homozygous 2bp deletion (c.1479delAG) in the mother.

Figure 3. Loss of methylation at PEG1 DMR.

Electropherogram of amplification products of MS-PCR. U, unmethylated product; M, methylated product. The X-axis represents the calculated product size (in bp and also represented as the top number in the box). The Y axis represents the peak height (bottom number in the box). The methylated to unmethylated ratio was calculated as the area under the curve (middle number in the box) of methylated versus unmethylated amplified products. (A) Normal Control (ratio 0.81), (B) Child 2 with LOM at PEG1.