Genetic Mapping of a Maternal Locus Responsible for Familial Hydatidiform Moles

Abstract

Hydatidiform mole (HM) is the product of an aberrant human pregnancy in which there is an abnormal embryonic development and proliferation of placental villi. The incidence of HM varies between ethnic groups, and occurs in 1 in every 1500 pregnancies in the USA. All HM cases are sporadic, except for extremely rare familial cases. The exact mechanisms leading to molar pregnancies are unknown. We previously postulated that women with recurrent hydatidiform moles are homozygous for an autosomal recessive defective gene. To map this gene genetically, we initiated a genome-wide scan with highly polymorphic short tandem repeats in individuals from two families with recurrent HM. Here, we demonstrate that a defective maternal gene is responsible for recurrent HM. This gene resides on chromosome 19q13.3-13.4 in a 15.2 cM interval flanked by D19S924 and D19S890. The identification of a gene for HM adds new insights into the molecular genetics of early embryogenesis and may be relevant to the large number of patients with sporadic HM.

Mole maker phenotype: possible narrowing of the candidate region

“…Sharing of both chromosome 19 haplotypes by the two sisters is in accordance with the localisation of the gene indicated by Moglabey et al 1 Interestingly, the two sisters were homozygous for the whole haplotype, excepted for the D19S418 locus. This extended homozygosity supports the hypothesis of a common ancestor for the parents, while the heterozygosity at the most centromeric marker suggests a narrowing of 2.8 cM of the candidate region proposed by Moglabey.…”

“…A careful revision of the families reported [6][7][8][9][10][11][12] suggests an autosomal recessive genotype of women experiencing recurrent familial molar pregnancies, as proposed by Helwani et al 12 Only one family has Candidate region for mole maker phenotype y been studied by molecular methods so far. 1 In this family the recurrent molar pregnancies demonstrated a biparental diploid chromosomal constitution.…”

“…1 Recurrence of molecular pregnancies is rare (1-5%), [2][3][4][5] but after two episodes the risk rises to 11-30%. [3][4][5] Familial HM (MIM 231090) is exceedingly rare, with only seven families having been reported so far.…”

Patients with familial biparental hydatidiform moles have normal methylation at imprinted genes

“…3,10 The aim of the present study was to follow up this investigation by analyzing the DNA methylation status at the same DMRs, but in somatic tissues (blood) from the two patients. Furthermore, using SNPs in informative samples and at informative DMRs, we analyzed the grandparental transmission of the abnormal epigenotype to examine its potential association with a particular grandparental inheritance.…”

Recurrent triploidy of maternal origin

“…Interestingly, recurrence of molar diandric pregnancies in a few families has proved to be inherited as an autosomal recessive trait and a susceptibility locus assigned to chromosome 19. 5,6 Here, we report on the recurrence of triploidy in three consecutive pregnancies. Molecular analysis in two of them has shown a maternal origin of the extra set of chromosomes.…”