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Genetic Counseling in Assisted Reproductive Technology
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Multiple single genes have been implicated in euploid pregnancy loss, including RYR1, CHRNA1, and DYNC2H1, among others (Colley et al., 2019). Others, including NLRP7 and KHDC3L, have been associated with recurrent diploid molar pregnancies (Carey et al., 2015). Loss of heterozygosity, including that caused by consanguineous unions, can increase the risk of recessive monogenic disease, potentially having an impact on fetal development. Expanded carrier screening should be performed to assess the risk of single gene disorders. The inclusion of any genes of interest should be investigated, and other targeted or recurrent pregnancy loss panel can be explored as appropriate.
Gestational Trophoblastic Neoplasia
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
CHMs nearly always only contain paternal DNA and are therefore androgenetic.4 This occurs mostly because a single sperm bearing a 23X set of chromosomes fertilizes an ovum lacking maternal genes and then duplicates to form the homozygote, 46XX4–10 (Figure 23.2a). However, in up to 25% of CHMs, fertilization can take place with two spermatozoa, resulting in the heterozygous 46XY or 46XX configuration11,12 (Figure 23.2b). A 46YY conceptus has not yet been described and is presumably non-viable. Interestingly, CHMs retain some maternal elements, including the mitochondrial DNA.13 Rarely, a CHM can arise from a fertilized ovum that has retained its maternal nuclear DNA and is therefore biparental in origin (BiCHM).14,15 Women with BiCHM suffer repetitive molar pregnancies and rarely achieve a normal pregnancy. The condition is autosomal recessive and is also known as familial recurrent HM syndrome (FRHM). Most are due to mutations in NLRP716 and much less frequently in KHD3CL (C6orf221)17 and other as yet un-identified genes. Recently, two triploid cases of FRHM have been described, which morphologically are also CHM.18
Gestational trophoblastic disease
Published in David M. Luesley, Mark D. Kilby, Obstetrics & Gynaecology, 2016
Fieke E M Froeling, Michael J Seckl
All forms of GTD arise from components of the placenta, either the villous trophoblast (hydatidiform moles and choriocarcinoma) or the interstitial trophoblast (PSTT). Most complete and partial moles have distinct morphological characteristics (Table 111.1) but suspected cases should be reviewed by specialist histopathologists. Complete hydatidiform moles are usually diploid and androgenic in origin, the most common type being 46XX from duplication of the haploid genome of a single sperm (~ 80%). In approximately 20 percent, a molar pregnancy develops from dispermic fertilisation. In either scenario, the maternal chromosomes are lost before or after fertilisation (Fig. 111.1A, B). Some patients with recurrent CHM can have a biparental karyotype due to familial recurrent hydatidiform mole (FRHM), an autosomal recessive disease (Fig. 111.1C). Mutations in two genes, NLRP7 and, more rarely, KHDC3L, have been associated with this condition.3 PHMs are generally triploid, most often from dispermic fertilisation of normal ova (Fig. 111.1D). When a fetus is present it often has the features of triploidy, including growth retardation and multiple congenital malformations, and is never viable.
Detection of Parental Contribution to Molar Genome Leads to Diagnosis of Recurrent Hydatidiform Mole in a Family with NLRP7 Variants
Published in Fetal and Pediatric Pathology, 2022
Rong-Yue Wang, Yu-Juan Li, Li Zhen, Fan Jiang, Cong-Min Gu, Dong-Zhi Li
So far, three maternal-effect genes, NLRP7, KHDC3L and recently PADI6, have been identified to be responsible for RHM [10–12]. Studies from various groups and populations concur that NLRP7 is a major gene for this condition and is mutated in 48–80% of patients with at least two HM pregnancies [11,13]. This form of RHM is inherited in an autosomal recessive fashion, indicating that patients usually carry two defective alleles. The underlying mechanisms for maternal-effect NLRP7 for correct imprint establishment during human oogenesis are unknown. Possibly, NLRP7 has a role in controlling the timing of oocyte growth, or in transducing signals required to initiate imprint establishment [14]. Interestingly, a male with NLRP7 compound heterozygous mutations in the present family has been found to have no reproductive problems, suggesting that NLRP7 is not required for normal spermatogenesis. Currently, there is no evidence that the risk of gestational trophoblastic disease in biparental moles is increased.
A case report on recurrent partial moles in three consecutive pregnancies
Published in Journal of Obstetrics and Gynaecology, 2022
Prashida Guha Sarkar, Saroj Dalmia, Pinky Khatri
A small subgroup of women with recurrent HM were found to have an autosomal recessive condition, familial recurrent HM (FRHM) and these molar pregnancies were diploid and biparental in origin. Subsequent analysis identified mutations in NLRP7 gene to be the major cause of biparental HM (Qian et al. 2007). Patients with personal history of molar pregnancies but no family history usually have androgenetic complete HM. Women with FHRM are predisposed to molar pregnancies with little chance of a successful pregnancy and might consider IVF with donor eggs to achieve a viable pregnancy (Eagles et al. 2015).
Recurrent hydatidiform mole in nine consecutive pregnancies: a rare case report from India
Published in Journal of Obstetrics and Gynaecology, 2022
HM is an abnormal conception with abundant trophoblastic proliferation and hydropic degeneration of chorionic villi, with recurrence rates between 1–2%. The exact aetiology remains unknown, but risk factors like extreme-age, Asian-ethnicity, previous h/o molar pregnancy, antioxidant and proteins deficient diet, AB blood group, genetic defect, smoking, and previous abortions are identified (Bagshawe et al. 1986; Sebire et al. 2002; Al-Ghamdi 2011; Daftary and Padubidri 2014). HM exists as a complete or partial mole. Complete moles occur sporadically (85%) resulting from fertilisation of an empty ovum by a haploid sperm (23X) which doubles its chromosomes after meiosis (46XX), known as androgenesis (Kalogiannidis et al. 2018). In the remaining (15%), there is di-spermic fertilisation of an empty ovum resulting in a 46XX or 46XY heterozygous chromosomal constitution (Kalogiannidis et al. 2018). Apart from androgenetic moles, diploid complete moles (having both maternal and paternal chromosomes) also exist occasionally but have been reported (Kalogiannidis et al. 2018). These occur due to maternal autosomal recessive gene defect namely NLRP7 or KHDC3L genes with normal paternal genotype (Williams et al. 2010). These invoke interest due to their association with recurrence and familial clustering. Ulker V et al, reported novel NLRP7 mutations in two families with recurrent biparental complete moles. In the first family, three affected sisters with past history of molar pregnancies were homozygous for a nonsense mutation, while in the second family, three affected sisters were heterozygous for a 60-kb deletion removing large portions of the NLRP2 and NLRP7 genes(Ulker et al. 2013). Similarly, another study reported NLRP7 mutation among two sisters in the same family. One of them had history of pregnancy wastage while another had previous 5 molar pregnancies in whom oocyte donation allowed successful pregnancy and child birth, thus explaining familial clustering(Fallahi et al. 2019). So, such patients presenting with recurrent molar pregnancy should be offered mandatory genetic testing to differentiate between these two types as the management varies. IVF with donor egg or adoption are the options in familial recurrent molar pregnancy. On the other hand, in patients with androgenetic recurrent moles, ICSI and PGD can be considered. ICSI ensures monospermic fertilisation and PGD identifies 46XX embryos resulting from duplication of haploid sperm and thus can be excluded (Agarwal et al. 2004; Kumari et al. 2020). Although our patient had no family history of recurrent molar pregnancy, she was advised genetic testing to rule out any possible association, but refused due to financial crunch.