A number sign (#) is used with this entry because of evidence that recurrent hydatidiform mole-3 (HYDM3) is caused by homozygous or compound heterozygous mutation in the MEI1 gene (608797) on chromosome 22q13.

Hydatidiform mole is a human pregnancy with abnormal or no embryonic development and excessive trophoblastic proliferation. Partial hydatidiform moles have a triploid dispermic genome, with 2 sets of paternal chromosomes and 1 set of maternal chromosomes; complete hydatidiform moles have a diploid androgenetic genome with all chromosomes originating from 1 (monospermic) or 2 (dispermic) sperms, and no maternal chromosomes (summary by Nguyen et al., 2018).

For a discussion of genetic heterogeneity of recurrent hydatidiform mole, see HYDM1 (231090).

Nguyen et al. (2018) identified 2 unrelated women with complete hydatidiform mole and biallelic mutation in the MEI1 gene. The first woman (proband 1333) had a history of 4 miscarriages followed by 4 hydatidiform moles, all from spontaneous conception. In addition, she had 1 failed cycle of in vitro fertilization by intracytoplasmic sperm injection (ICSI). Two of her sisters had 1 and 3 miscarriages, respectively, and both underwent total abdominal hysterectomy because of several uterine fibroids. None of the 3 women had any live births. The second woman (proband 880) had 6 miscarriages and 1 complete hydatidiform mole. Her brother, who was infertile, had nonobstructive azoospermia and no Y chromosome deletions. Nguyen et al. (2018) retrieved all hydatidiform mole tissue from affected probands 1333 and 880. By morphologic evaluation, all tissues fulfilled pathologic criteria of complete hydatidiform mole, did not express p57(KIP2) (600856) in the nuclei of the cytotrophoblast and villous mesenchyme cells, were diploid by flow cytometry, androgenetic monospermic by microsatellite DNA marker genotyping, and did not have aneuploidies by SNP microarrays.

The transmission pattern of HYDM3 in the families reported by Nguyen et al. (2018) was consistent with autosomal recessive inheritance.

To identify mutations responsible for recurrent hydatidiform mole, Nguyen et al. (2018) performed whole-exome sequencing on 65 women with recurrent hydatidiform moles (including all histopathologic and genotypic types), miscarriages, and infertility, who were negative for mutations in NLRP7 (609661) and KHDC3L (611687). Nguyen et al. (2018) identified biallelic deleterious mutations in 3 genes involved in meiotic double-strand breaks in 5 unrelated women. Two women (probands 1333 and 880) and affected family members carried mutations in the MEI1 gene (608797). Proband 1333, who had 4 miscarriages followed by 4 hydatidiform moles, and her 2 sisters, who had 1 and 3 miscarriages, respectively, were homozygous for a nonsense mutation in exon 28 (W1151X; 608797.0001). Proband 880, with 6 miscarriages and 1 complete hydatidiform mole, and her brother, with nonobstructive azoospermia and no Y chromosome deletions, were compound heterozygous for an invariant splice site mutation (608797.0002) and a 1-bp deletion (608797.0003).