Alternative titles; symbols
ORPHA: 254688, 99927; DO: 3393; MONDO: 0013671;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q13 | Hydatidiform mole, recurrent, 2 | 614293 | Autosomal recessive | 3 | KHDC3L | 611687 |
A number sign (#) is used with this entry because recurrent hydatidiform mole-2 (HYDM2) is caused by homozygous or compound heterozygous mutation in the C6ORF221 gene (KHDC3L; 611687) on chromosome 6q13.
A hydatidiform mole is an abnormal pregnancy characterized by hydropic placental villi, trophoblastic hyperplasia, and poor fetal development. Familial recurrent hydatidiform mole is an autosomal recessive condition in which women experience recurrent pregnancy losses, predominantly complete hydatidiform mole (CHM). However, unlike sporadic CHMs, which are androgenetic with 2 paternal chromosome complements, CHMs associated with familial recurrence are genetically biparental in origin with both a maternal and a paternal contribution to the genome. Other pregnancy losses in this condition include partial hydatidiform mole, stillbirths, ectopic pregnancies, early neonatal deaths, and miscarriages, some of which may be undiagnosed molar pregnancies. Normal pregnancies are extremely rare in families with this condition (summary by Fallahian et al., 2013).
For a discussion of genetic heterogeneity of recurrent hydatidiform mole, see HYDM1 (231090).
Judson et al. (2002) studied the sixth molar pregnancy of the index case in a biparental complete hydatidiform mole family with complex consanguinity, originating from the Mirpur region of Pakistan. The authors demonstrated biparental origin of the complete hydatidiform mole DNA using markers on 6 autosomes. They reported an inherited global imprinting defect, a recessive maternal-effect mutation disrupting the specification of imprint at multiple noncontiguous loci, with the result that genes normally carrying a maternal methylation imprint assume a paternal epigenetic pattern on the maternal allele. The resulting conception is phenotypically indistinguishable from an androgenetic complete hydatidiform mole, in which abnormal extraembryonic tissue proliferates while development of the embryo is absent or nearly so.
Reddy et al. (2013) reported an African American woman who had 7 hydatidiform molar pregnancies with 3 different partners. Another woman, of Turkish descent and born of consanguineous parents, had 5 HYDMs from natural conception and 2 failed cycles of in vitro fertilization followed by preimplantation genetic screening for aneuploidies; most of the embryos showed chromosomal abnormalities. In a third family, 2 sisters, born of consanguineous Indian parents, had recurrent hydatidiform moles.
The finding of a mutation in the C6ORF21 gene in the family studied by Judson et al. (2002) maps the disorder to chromosome 6q13 (Parry et al., 2011).
Exclusion Studies
In a Pakistani family with biparental complete hydatidiform mole, Judson et al. (2002) noted that lack of homozygosity for the DNMT3l gene (606588), which prevents specification of maternal imprints in the mouse germline, ruled out involvement of that locus. In addition, this family was not homozygous for the previously described 19q locus (HYDM1; 231090), making its involvement unlikely.
The transmission pattern of HYDM2 in the families reported by Parry et al. (2011) was consistent with autosomal recessive inheritance.
In the multiply consanguineous Pakistani family with biparental recurrent hydatidiform mole reported by Judson et al. (2002), Parry et al. (2011) performed a homozygosity scan and identified a mutation in the initiation codon of the C6ORF221 gene (611687.0001). The mutation segregated with disease in the family and was not found in 328 ethnically matched control chromosomes. By sequencing of C6ORF221 in 14 additional probands with recurrent hydatidiform mole who were known to be negative for mutation in the NLRP7 gene (609661) on chromosome 19q, Parry et al. (2011) found mutations in homozygous or compound heterozygous state (611687.0002-611687.0003) in 2 probands, both of whom had previously been studied, by Landolsi et al. (2011) and Wang et al. (2009), respectively. Parry et al. (2011) stated that the patients with mutations in C6ORF221 had 'typical' familial biparental hydatidiform mole that was indistinguishable clinically from that caused by mutation in NLRP7.
In a 28-year-old Iranian woman with 4 complete hydatidiform mole pregnancies, previously studied by Wang et al. (2009) and found to be compound heterozygous for mutations in the C6ORF221 gene (611687.0002-611687.0003) by Parry et al. (2011), Fallahian et al. (2013) performed genetic analysis of tissue from the fourth CHM. Although DNA was unavailable from her partner, 2 alleles were maternal in origin and a third allele was nonmaternal, consistent with a digynic triploid conceptus. The proband had 1 sister with 3 normal pregnancies, but another sister, who was also compound heterozygous for the KHDC3L mutations, had undergone 2 CHM pregnancies; genotyping of the second CHM showed that it was a biparental CHM, with both a maternal and paternal contribution to the genome. Fallahian et al. (2013) stated that these findings were consistent with a role for KHDC3L in setting and/or maintaining the maternal imprint.
In 4 women from 3 unrelated families with HYDM2, Reddy et al. (2013) identified 2 different homozygous truncating mutations in the KHDC3L gene (611687.0002 and 611687.0004). Flow cytometric analysis of 5 different conceptuses from 1 patient showed that all were diploid biparental. Immunologic studies of hematopoietic cells from 2 patients showed that both C-terminal truncated mutant proteins had normal subcellular localization, and that KHDC3L colocalized with NLRP7 (609661).
By haplotype analysis, Reddy et al. (2013) demonstrated a founder effect for a 4-bp deletion in the KHDC3L gene (c.322delGACT; 611687.0002) in HYDM2 families of Indian, Turkish, and Tunisian descent.
Fallahian, M., Sebire, N. J., Savage, P. M., Seckl, M. J., Fisher, R. A. Mutations in NLRP7 and KHDC3L confer a complete hydatidiform mole phenotype on digynic triploid conceptions. Hum. Mutat. 34: 301-308, 2013. [PubMed: 23125094] [Full Text: https://doi.org/10.1002/humu.22228]
Judson, H., Hayward, B. E., Sheridan, E., Bonthron, D. T. A global disorder of imprinting in the human female germ line. Nature 416: 539-542, 2002. [PubMed: 11932746] [Full Text: https://doi.org/10.1038/416539a]
Landolsi, H., Rittore, C., Philibert, L., Missaoui, N., Hmissa, S., Touitou, I., Gribaa, M., Yacoubi, M. T. Screening for NLRP7 mutations in familial and sporadic recurrent hydatidiform moles: report of 2 Tunisian families. Int. J. Gynecol. Pathol. 30: 348-353, 2011. [PubMed: 21623199] [Full Text: https://doi.org/10.1097/PGP.0b013e31820dc3b0]
Parry, D. A., Logan, C. V., Hayward, B. E., Shires, M., Landolsi, H., Diggle, C., Carr, I., Rittore, C., Touitou, I., Philibert, L., Fisher, R. A., Fallahian, M., Huntriss, J. D., Picton, H. M., Malik, S., Taylor, G. R., Johnson, C. A., Bonthron, D. T., Sheridan, E. G. Mutations causing familial biparental hydatidiform mole implicate C6orf221 as a possible regulator of genomic imprinting in the human oocyte. Am. J. Hum. Genet. 89: 451-458, 2011. [PubMed: 21885028] [Full Text: https://doi.org/10.1016/j.ajhg.2011.08.002]
Reddy, R., Akoury, E., Nguyen, N. M. P., Abdul-Rahman, O. A., Dery, C., Gupta, N., Daley, W. P., Ao, A., Landolsi, H., Fisher, R. A., Touitou, I., Slim, R. Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7. Europ. J. Hum. Genet. 21: 957-964, 2013. [PubMed: 23232697] [Full Text: https://doi.org/10.1038/ejhg.2012.274]
Wang, C. M., Dixon, P. H., Decordova, S., Hodges, M. D., Sebire, N. J., Ozalp, S., Fallahian, M., Sensi, A., Ashrafi, F., Repiska, V., Zhao, J., Xiang, Y., Savage, P. M., Seckl, M. J., Fisher, R. A. Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich region. J. Med. Genet. 46: 569-575, 2009. [PubMed: 19246479] [Full Text: https://doi.org/10.1136/jmg.2008.064196]