Explore the vast range of titles available.

Female Infertility and Genetic DiseaseIn this study, women with unexplained infertility were more likely than persons represented in biobanks to carry pathogenic or likely pathogenic variants in genes causing genetic diseases.

Background Little is known about the genetic contribution to Müllerian aplasia, better known to patients as Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Mutations in two genes ( WNT4 and HNF1B ) account for a small number of patients, but heterozygous copy number variants (CNVs) have been described. However, the significance of these CNVs in the pathogenesis of MRKH is unknown, but suggests possible autosomal dominant inheritance. We are not aware of CNV studies in consanguineous patients, which could pinpoint genes important in autosomal recessive MRKH. We therefore utilized SNP/CGH microarrays to identify CNVs and define regions of homozygosity (ROH) in Anatolian Turkish MRKH patients. Result(s) Five different CNVs were detected in 4/19 patients (21%), one of which is a previously reported 16p11.2 deletion containing 32 genes, while four involved smaller regions each containing only one gene. Fourteen of 19 (74%) of patients had parents that were third degree relatives or closer. There were 42 regions of homozygosity shared by at least two MRKH patients which was spread throughout most chromosomes. Of interest, eight candidate genes suggested by human or animal studies ( RBM8A, CMTM7, CCR4, TRIM71, CNOT10, TP63, EMX2, and CFTR ) reside within these ROH. Conclusion(s) CNVs were found in about 20% of Turkish MRKH patients, and as in other studies, proof of causation is lacking. The 16p11.2 deletion seen in mixed populations is also identified in Turkish MRKH patients. Turkish MRKH patients have a higher likelihood of being consanguineous than the general Anatolian Turkish population. Although identified single gene mutations and heterozygous CNVs suggest autosomal dominant inheritance for MRKH in much of the western world, regions of homozygosity, which could contain shared mutant alleles, make it more likely that autosomal recessively inherited causes will be manifested in Turkish women with MRKH.

This article describes a young woman with marked estrogen resistance owing to a homozygous loss-of-function mutation in ESR1, which encodes estrogen receptor α. This case shows that disruption of ESR1 causes profound estrogen resistance in women. Mutations in the androgen-receptor gene have been shown to cause androgen resistance in 46,XY humans 1 , 2 and in murine models, 3 but estrogen-receptor mutations are rare. The action of estrogen in peripheral tissues is mediated through a receptor 4 that is predominantly nuclear in location. 5 After the cloning of this receptor, termed estrogen receptor α, 6 , 7 in 1985, a second receptor (estrogen receptor β) was identified in 1996. 8 – 10 Nonnuclear estrogen signaling has also been suggested. The action of estradiol influences breast development, and feedback from estradiol on the hypothalamus and pituitary involves estrogen receptor α. 11 In mice, the ablation of both . . .

The molecular basis of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome remains largely unknown. Pathogenic variants in WNT4 and HNF1B have been confirmed in a small percent of individuals. A variety of copy number variants have been reported, but causal gene(s) remain to be identified. We hypothesized that rare structural variants (SVs) would be present in some individuals with MRKH, which could explain the genetic basis of the syndrome. Large molecular weight DNA was extracted from lymphoblastoid cells from 87 individuals with MRKH and available parents. Optical genome mapping (OGM) was performed to identify SVs, which were confirmed by another method (quantitative PCR, chromosomal microarray, karyotype, or fluorescent in situ hybridization) when possible. Thirty-four SVs that overlapped coding regions of genes with potential involvement in MRKH were identified, 14 of which were confirmed by a second method. These 14 SVs were present in 17/87 (19.5%) of probands with MRKH and included seven deletions, three duplications, one new translocation in 5/50 cells—t(7;14)(q32;q32), confirmation of a previously identified translocation—t(3;16)(p22.3;p13.3), and two aneuploidies. Of interest, three cases of mosaicism (3.4% of probands) were identified—25% mosaicism for trisomy 12, 45,X(75%)/46,XX (25%), and 10% mosaicism for a 7;14 translocation. Our study constitutes the first systematic investigation of SVs by OGM in individuals with MRKH. We propose that OGM is a promising method that enables a comprehensive investigation of a variety of SVs in a single assay including cryptic translocations and mosaic aneuploidies. These observations suggest that mosaicism could play a role in the genesis of MRKH.

Approximately 0.5–1.4% of natal males and 0.2–0.3% of natal females meet DSM-5 criteria for gender dysphoria, with many of these individuals self-describing as transgender men or women. Despite recent improvements both in social acceptance of transgender individuals as well as access to gender affirming therapy, progress in both areas has been hampered by poor understanding of the etiology of gender dysphoria. Prior studies have suggested a genetic contribution to gender dysphoria, but previously proposed candidate genes have not yet been verified in follow-up investigation. In this study, we expand on the topic of gender identity genomics by identifying rare variants in genes associated with sexually dimorphic brain development and exploring how they could contribute to gender dysphoria. To accomplish this, we performed whole exome sequencing on the genomic DNA of 13 transgender males and 17 transgender females. Whole exome sequencing revealed 120,582 genetic variants. After filtering, 441 variants in 421 genes remained for further consideration, including 21 nonsense, 28 frameshift, 13 splice-region, and 225 missense variants. Of these, 21 variants in 19 genes were found to have associations with previously described estrogen receptor activated pathways of sexually dimorphic brain development. These variants were confirmed by Sanger Sequencing. Our findings suggest a new avenue for investigation of genes involved in estrogen signaling pathways related to sexually dimorphic brain development and their relationship to gender dysphoria.

PurposeMayer–Rokitansky–Küster–Hauser (MRKH) syndrome consists of congenital absence of the uterus and vagina and is often associated with renal, skeletal, cardiac, and auditory defects. The genetic basis is largely unknown except for rare variants in several genes. Many candidate genes have been suggested by mouse models and human studies. The purpose of this study was to narrow down the number of candidate genes.MethodsWhole exome sequencing was performed on 111 unrelated individuals with MRKH; variant analysis focused on 72 genes suggested by mouse models, human studies of physiological candidates, or located near translocation breakpoints in t(3;16). Candidate variants (CV) predicted to be deleterious were confirmed by Sanger sequencing.ResultsSanger sequencing verified 54 heterozygous CV from genes identified through mouse (13 CV in 6 genes), human (22 CV in seven genes), and translocation breakpoint (19 CV in 11 genes) studies. Twelve patients had ≥ 2 CVs, including four patients with two variants in the same gene. One likely digenic combination of LAMC1 and MMP14 was identified.ConclusionWe narrowed 72 candidate genes to 10 genes that appear more likely implicated. These candidate genes will require further investigation to elucidate their role in the development of MRKH.

Abstract Context We previously reported the first female with a causative ESR1 gene variant, who exhibited absent puberty and high estrogens. At age 15 years, she presented with lower abdominal pain, absent breast development, primary amenorrhea, and multicystic ovaries. The natural history of complete estrogen insensitivity (CEI) in women is unknown. Objective The purpose of this report is to present the neuroendocrine phenotype of CEI, identify potential ligands, and determine the effect of targeted treatment. Design We have characterized gonadotropin pulsatility and followed this patient’s endocrine profile and bone density over 8 years. Seventy-five different compounds were tested for transactivation of the variant receptor. A personalized medicine approach was tailored to our patient. Setting Academic medical center. Patient or Other Participants A 24-year-old adopted white female with CEI. Intervention(s) The patient was treated with diethylstilbestrol (DES) for approximately 2.5 years. Main Outcome Measure(s) Induction of secondary sexual characteristics. Results Luteinizing hormone (LH) pulse studies demonstrated normal pulsatile LH secretion, elevated mean LH, and mildly elevated mean follicle-stimulating hormone (FSH) in the presence of markedly increased estrogens. DES transactivated the variant ESR1 in vitro. However, DES treatment did not induce secondary sexual characteristics in our patient. Conclusions Treatment with DES was not successful in our patient. She remains hypoestrogenic despite the presence of ovarian cysts with a hypoestrogenic vaginal smear, absent breast development, and low bone mineral mass. Findings suggest additional receptor mechanistic actions are required to elicit clinical hormone responses.

The obese gene (ob) product, leptin, has recently been shown to be produced by adipocytes and to circulate in the plasma acting as a hormone to modulate appetite and metabolism. Intriguingly, the ob/ob mutant female mouse, which does not produce an active form of leptin due to a mutation of the ob gene, has been shown to be acyclic and sterile. This sterility can be reversed by treatment with recombinant leptin, but not by diet restriction – suggesting that leptin is required for normal reproductive function. The mechanism(s) whereby leptin modulates reproductive function are unknown; however, it is possible that leptin could directly regulate reproductive tissues. To determine whether endocrine and neuroendocrine tissues could be targets for leptin action, we examined whether these tissues express the leptin receptor mRNA by utilizing reverse-transcription polymerase chain reaction (RT-PCR) analysis in selected tissues from the male and female rat. The results revealed that the leptin receptor mRNA transcript is highly expressed in the ovary, uterus and testis, moderately expressed in the hypothalamus and anterior pituitary, with low to no expression in the adrenal. The RT-PCR results were confirmed by Northern analysis. Furthermore, immortalized GnRH (GT1-7 and NLT) neurons and ovarian granulosa cells were also demonstrated by RT-PCR analysis to express the leptin receptor, suggsting that GnRH neurons and steroid-producing cells of the ovary could be targets for leptin action. Immunohistochemical studies revealed dense immunolocalization of the leptin receptor in the choroid plexus, and interestingly, in the arcuate nucleus/median eminence of the female rat – a key sit in the control of feeding and reproduction. Finally, treatment of the ob/ob mouse with recombinant leptin (0.15 mg/kg/day × 2 weeks) was found to markedly upregulate side chain cleavage and 17α-hydroxylase mRNA levels in the ovary, demonstrating that leptin, acting either through a direct or indirect mechanism, can regulate gene expression in reproductive tissues.

Background Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, or the congenital absence of uterus and vagina, is the most severe anomaly of the female reproductive tract. It affects 1 in 5,000 females, and is the second most common cause of primary amenorrhea. The etiology remains unknown in most patients, although four single gene defects and some repetitive copy number variants (CNVs) have been identified. Translocations in MRKH patients are very rare, and reported only in three patients previously without breakpoint mapping. We have identified the fourth MRKH translocation patient and are the first to characterize the breakpoints mapped by molecular methods. Results The proband is a 17- year old white female with agenesis of the uterus and vagina who had a peripheral blood karyotype revealing a de novo balanced translocation 46,XX,t(3;16)(p22.3;p13.3)dn. There were no known related anomalies present in the proband or her family. No CNVs were found by chromosomal microarray analysis, and no genes were directly disrupted by the translocation. DNA sequencing of six nearby candidate genes— TRIM71, CNOT10, ZNF200, OR1F1 , ZNF205 , and ZNF213 —did not reveal any mutations. RT-qPCR of proband lymphoblast RNA for 20 genes near the breakpoints of 3p22.3 and 16p13.3 showed significantly altered expression levels for four genes in the proband compared to three white female controls, after correction for multiple comparisons. Reduced expression was seen for CMTM7 and CCR4 on 3p22.3, while increased expression was observed for IL32 and MEFV on 16p13.3. Conclusion We have mapped the breakpoints of our t(3;16)(p22.3;p13.3) translocation patient using molecular methods to within 13.6 kb at 3p22.3 and within 1.9 kb for 16p13.3 and have suggested 10 nearby genes that become plausible candidate genes for future study.

Background Females with Xp;Yq translocations manifest short stature and normal fertility, but rarely have follow-up. The study purpose was to define the phenotype of a family with t(X;Y)(p22.3;q11.2), determine long-term reproductive function, and compare to all reported female cases. Methods Comprehensive clinical and molecular analyses were performed on the female proband, who had regular menses, normal endocrine function, and three pregnancies spanning seven years--a normal liveborn male and two with unbalanced translocations (liveborn female and stillborn male). Results The translocation truncated KAL1 and deleted 44 genes on der(X). Our report constitutes the longest follow-up of an X;Y translocation female. She had no evidence of Kallmann syndrome, gonadoblastoma, or cardiovascular disease. Detailed analysis of 50 published female cases indicated a uniform lack of follow-up and significant morbidity—intellectual disability (10%), facial dysmorphism (28%), eye abnormalities (14%), and skeletal defects (28%). Conclusions Our findings indicate normal ovarian function to date in a woman with an t(X;Y)(p22.3;q11.2). However, additional published studies in the literature suggest careful follow-up is necessary and contradict the generalization that females with Xp;Yq translocations are usually normal except for short stature.