Recurrent biparental hydatidiform mole: additional evidence for a 1.1-Mb locus in 19q13.4 and candidate gene analysis

A maternal autosomal recessive mutation causing recurrent biparentally inherited complete hydatidiform moles (BiCHM) in affected women was previously mapped to a 12.4-cM interval in 19q13.4, which was recently further narrowed to a smaller 1.1-Mb region at the centromeric end. It is believed that the mutant gene in this condition is a major contributor to the regulation of imprinting in the maternal germline. To confirm and possibly narrow the critical interval we studied additional rare familial and recurrent cases.

Using polymorphic marker analysis, we first confirmed biparental inheritance on the studied molar tissues. We then performed targeted homozygosity mapping with markers in 19q13.4 on DNA from affected women of a new large consanguineous pedigree, an additional potentially familial case, and three cases with sporadic recurrent CHM. Direct sequencing of coding exons and Southern analysis with a coding-region probe for one candidate gene (NALP5) was also performed.

Biparental inheritance was confirmed for those molar tissues available for analysis. All women, except for one of the isolated cases, were homozygous for markers in the identified 1.1-Mb region in 19q13.4. No mutations or large genomic rearrangements were found in NALP5 (MATER), a gene with oocyte-specific expression. Heterozygosity for a single-nucleotide polymorphism in exon 13 of NALP5 in one patient may refine the candidate region to 1.0 Mb.

The reported candidate region for BiCHM in 19q13.4 was confirmed in additional families, further establishing it as the major locus that harbors a gene mutated in this condition.