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1.
Stem Cell Res ; 79: 103494, 2024 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-39003885

RESUMEN

The transcription factor WT1 plays a critical role in several embryonic developmental processes such as gonadogenesis, nephrogenesis, and cardiac development. We generated a homozygous (MCRIi031-A-3) WT1 knockout induced pluripotent stem cell (iPSC) line from human fibroblasts using a one-step protocol for CRISPR/Cas9 gene-editing and episomal-based reprogramming. The cells exhibit a normal karyotype and morphology, express pluripotency markers, and have the capacity to differentiate into the three embryonic germ layers. These cell lines will allow us to further explore the role of WT1 in critical developmental processes.

2.
Clin Transl Sci ; 17(6): e13827, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38924306

RESUMEN

For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This study aims to: (i) review the genetic contributions to infertility, (ii) search for pharmacogenomic studies looking at interactions of cancer treatment, genetic predisposition and fertility-related outcomes. Systematic searches in MEDLINE Ovid, Embase Classic+Embase, and PubMed were conducted using the following selection criteria: (i) pediatric, adolescent, and young adult cancer survivors, below 25 years old at the time of diagnosis, (ii) fertility outcome measures after cancer therapy, (iii) genetic considerations. Studies were excluded if they were (i) conducted in animal models, (ii) were not published in English, (iii) editorial letters, (iv) theses. Articles were screened in Covidence by at least two independent reviewers, followed by data extraction and a risk of bias assessment using the Quality in Prognostic Studies tool. Eight articles were reviewed with a total of 29 genes. Outcome measures included sperm concentration, azoospermia, AMH levels, assessment of premature menopause, ever being pregnant or siring a pregnancy. Three studies included replication cohorts, which attempted replication of SNP findings for NPY2R, BRSK1, FANCI, CYP2C19, CYP3A4, and CYP2B6. Six studies were rated with a high risk of bias. Differing methods may explain a lack of replication, and small cohorts may have contributed to few significant findings. Larger, prospective longitudinal studies with an unbiased genome-wide focus will be important to replicate significant results, which can be applied clinically.


Asunto(s)
Supervivientes de Cáncer , Fertilidad , Neoplasias , Adolescente , Niño , Femenino , Humanos , Masculino , Adulto Joven , Antineoplásicos/efectos adversos , Supervivientes de Cáncer/estadística & datos numéricos , Fertilidad/genética , Fertilidad/efectos de los fármacos , Infertilidad/genética , Infertilidad/etiología , Infertilidad/terapia , Neoplasias/genética , Neoplasias/tratamiento farmacológico , Farmacogenética , Pruebas de Farmacogenómica
3.
Stem Cell Res ; 79: 103484, 2024 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-38924973

RESUMEN

The transcription factor SOX9 plays a critical role in several embryonic developmental processes such as gonadogenesis, chrondrogenesis, and cardiac development. We generated heterozygous (MCRIi031-A-1) and homozygous (MCRIi031-A-2) SOX9 knockout induced pluripotent stem cell (iPSC) lines from human fibroblasts using a one-step protocol for CRISPR/Cas9 gene-editing and episomal-based reprogramming. Both iPSC lines exhibit a normal karyotype and morphology, express pluripotency markers, and have the capacity to differentiate into the three embryonic germ layers. These cell lines will allow us to further explore the role of SOX9 in critical developmental processes.

4.
Clin Genet ; 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38779778

RESUMEN

Premature ovarian insufficiency is a common form of female infertility affecting up to 4% of women and characterised by amenorrhea with elevated gonadotropin before the age of 40. Oocytes require controlled DNA breakage and repair for homologous recombination and the maintenance of oocyte integrity. Biallelic disruption of the DNA damage repair gene, Fanconi anemia complementation group A (FANCA), is a common cause of Fanconi anaemia, a syndrome characterised by bone marrow failure, cancer predisposition, physical anomalies and POI. There is ongoing dispute about the role of heterozygous FANCA variants in POI pathogenesis, with insufficient evidence supporting causation. Here, we have identified biallelic FANCA variants in French sisters presenting with POI, including a novel missense variant of uncertain significance and a likely pathogenic deletion that initially evaded detection. Functional studies indicated no discernible effect on DNA damage sensitivity in patient lymphoblasts. These novel FANCA variants add evidence that heterozygous loss of one allele is insufficient to cause DNA damage sensitivity and POI. We propose that intragenic deletions, that are relatively common in FANCA, may be missed without careful analysis, and could explain the presumed causation of heterozygous variants. Accurate variant curation is critical to optimise patient care and outcomes.

5.
Stem Cell Res ; 76: 103374, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38458031

RESUMEN

The NR2F2 gene encodes the transcription factor COUP-TFII, which is upregulated in embryonic mesoderm. Heterozygous variants in NR2F2 cause a spectrum of congenital anomalies including cardiac and gonadal phenotypes. We generated heterozygous (MCRIi030-A-1) and homozygous (MCRIi030-A-2) NR2F2-knockout induced pluripotent stem cell (iPSC) lines from human fibroblasts using a one-step protocol for CRISPR/Cas9 gene-editing and episomal-based reprogramming. Both iPSC lines exhibited a normal karyotype, typical pluripotent cell morphology, pluripotency marker expression, and the capacity to differentiate into the three embryonic germ layers. These lines will allow us to explore the role of NR2F2 during development and disease.


Asunto(s)
Células Madre Pluripotentes Inducidas , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Corazón , Heterocigoto , Homocigoto , Fenotipo , Sistemas CRISPR-Cas/genética , Factor de Transcripción COUP II/genética , Factor de Transcripción COUP II/metabolismo
6.
Genes (Basel) ; 15(3)2024 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-38540391

RESUMEN

Disruption of meiosis and DNA repair genes is associated with female fertility disorders like premature ovarian insufficiency (POI). In this study, we identified a homozygous missense variant in the HELQ gene (c.596 A>C; p.Gln199Pro) through whole exome sequencing in a POI patient, a condition associated with disrupted ovarian function and female infertility. HELQ, an enzyme involved in DNA repair, plays a crucial role in repairing DNA cross-links and has been linked to germ cell maintenance, fertility, and tumour suppression in mice. To explore the potential association of the HELQ variant with POI, we used CRISPR/Cas9 to create a knock-in mouse model harbouring the equivalent of the human HELQ variant identified in the POI patient. Surprisingly, Helq knock-in mice showed no discernible phenotype, with fertility levels, histological features, and follicle development similar to wild-type mice. Despite the lack of observable effects in mice, the potential role of HELQ in human fertility, especially in the context of POI, should not be dismissed. Larger studies encompassing diverse ethnic populations and alternative functional approaches will be necessary to further examine the role of HELQ in POI. Our results underscore the potential uncertainties associated with genomic variants and the limitations of in vivo animal modelling.


Asunto(s)
Infertilidad Femenina , Insuficiencia Ovárica Primaria , Animales , Femenino , Humanos , Ratones , ADN Helicasas/genética , Homocigoto , Infertilidad Femenina/genética , Mutación Missense , Insuficiencia Ovárica Primaria/genética
7.
Mol Cell Endocrinol ; 587: 112212, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38521400

RESUMEN

RESEARCH QUESTION: Premature ovarian insufficiency (POI) is characterised by amenorrhea associated with elevated follicle stimulating hormone (FSH) under the age of 40 years and affects 1-3.7% women. Genetic factors explain 20-30% of POI cases, but most causes remain unknown despite genomic advancements. DESIGN: We used whole exome sequencing (WES) in four Iranian families, validated variants via Sanger sequencing, and conducted the Acyl-cLIP assay to measure HHAT enzyme activity. RESULTS: Despite ethnic homogeneity, WES revealed diverse genetic causes, including a novel homozygous nonsense variant in SYCP2L, impacting synaptonemal complex (SC) assembly, in the first family. Interestingly, the second family had two independent causes for amenorrhea - the mother had POI due to a novel homozygous loss-of-function variant in FANCM (required for chromosomal stability) and her daughter had primary amenorrhea due to a novel homozygous GNRHR (required for gonadotropic signalling) frameshift variant. WES analysis also provided cytogenetic insights. WES revealed one individual was in fact 46, XY and had a novel homozygous missense variant of uncertain significance in HHAT, potentially responsible for complete sex reversal although functional assays did not support impaired HHAT activity. In the remaining individual, WES indicated likely mosaic Turners with the majority of X chromosome variants having an allelic balance of ∼85% or ∼15%. Microarray validated the individual had 90% 45,XO. CONCLUSIONS: This study demonstrates the diverse causes of amenorrhea in a small, isolated ethnic cohort highlighting how a genetic cause in one individual may not clarify familial cases. We propose that, in time, genomic sequencing may become a single universal test required for the diagnosis of infertility conditions such as POI.


Asunto(s)
Amenorrea , Insuficiencia Ovárica Primaria , Humanos , Femenino , Adulto , Masculino , Amenorrea/diagnóstico , Amenorrea/genética , Irán , Insuficiencia Ovárica Primaria/genética , Mutación Missense , Genómica , ADN Helicasas/genética
8.
Cell Biosci ; 14(1): 3, 2024 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-38178246

RESUMEN

BACKGROUND: The absence of expression of the Y-chromosome linked testis-determining gene SRY in early supporting gonadal cells (ESGC) leads bipotential gonads into ovarian development. However, genetic variants in NR2F2, encoding three isoforms of the transcription factor COUP-TFII, represent a novel cause of SRY-negative 46,XX testicular/ovotesticular differences of sex development (T/OT-DSD). Thus, we hypothesized that COUP-TFII is part of the ovarian developmental network. COUP-TFII is known to be expressed in interstitial/mesenchymal cells giving rise to steroidogenic cells in fetal gonads, however its expression and function in ESGCs have yet to be explored. RESULTS: By differentiating induced pluripotent stem cells into bipotential gonad-like cells in vitro and by analyzing single cell RNA-sequencing datasets of human fetal gonads, we identified that NR2F2 expression is highly upregulated during bipotential gonad development along with markers of bipotential state. NR2F2 expression was detected in early cell populations that precede the steroidogenic cell emergence and that retain a multipotent state in the undifferentiated gonad. The ESGCs differentiating into fetal Sertoli cells lost NR2F2 expression, whereas pre-granulosa cells remained NR2F2-positive. When examining the NR2F2 transcript variants individually, we demonstrated that the canonical isoform A, disrupted by frameshift variants previously reported in 46,XX T/OT-DSD patients, is nearly 1000-fold more highly expressed than other isoforms in bipotential gonad-like cells. To investigate the genetic network under COUP-TFII regulation in human gonadal cell context, we generated a NR2F2 knockout (KO) in the human granulosa-like cell line COV434 and studied NR2F2-KO COV434 cell transcriptome. NR2F2 ablation downregulated markers of ESGC and pre-granulosa cells. NR2F2-KO COV434 cells lost the enrichment for female-supporting gonadal progenitor and acquired gene signatures more similar to gonadal interstitial cells. CONCLUSIONS: Our findings suggest that COUP-TFII has a role in maintaining a multipotent state necessary for commitment to the ovarian development. We propose that COUP-TFII regulates cell fate during gonad development and impairment of its function may disrupt the transcriptional plasticity of ESGCs. During early gonad development, disruption of ESGC plasticity may drive them into commitment to the testicular pathway, as observed in 46,XX OT-DSD patients with NR2F2 haploinsufficiency.

10.
Nat Commun ; 14(1): 3403, 2023 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-37296101

RESUMEN

Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY GONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.


Asunto(s)
Disgenesia Gonadal , Células Madre Pluripotentes Inducidas , Discapacidad Intelectual , Masculino , Humanos , Testículo/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Antígenos de Neoplasias
11.
Hum Genet ; 142(7): 879-907, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37148394

RESUMEN

Premature ovarian insufficiency (POI) is a common cause of infertility in women, characterised by amenorrhea and elevated FSH under the age of 40 years. In some cases, POI is syndromic in association with other features such as sensorineural hearing loss in Perrault syndrome. POI is a heterogeneous disease with over 80 causative genes known so far; however, these explain only a minority of cases. Using whole-exome sequencing (WES), we identified a MRPL50 homozygous missense variant (c.335T > A; p.Val112Asp) shared by twin sisters presenting with POI, bilateral high-frequency sensorineural hearing loss, kidney and heart dysfunction. MRPL50 encodes a component of the large subunit of the mitochondrial ribosome. Using quantitative proteomics and western blot analysis on patient fibroblasts, we demonstrated a loss of MRPL50 protein and an associated destabilisation of the large subunit of the mitochondrial ribosome whilst the small subunit was preserved. The mitochondrial ribosome is responsible for the translation of subunits of the mitochondrial oxidative phosphorylation machinery, and we found patient fibroblasts have a mild but significant decrease in the abundance of mitochondrial complex I. These data support a biochemical phenotype associated with MRPL50 variants. We validated the association of MRPL50 with the clinical phenotype by knockdown/knockout of mRpL50 in Drosophila, which resulted abnormal ovarian development. In conclusion, we have shown that a MRPL50 missense variant destabilises the mitochondrial ribosome, leading to oxidative phosphorylation deficiency and syndromic POI, highlighting the importance of mitochondrial support in ovarian development and function.


Asunto(s)
Disgenesia Gonadal 46 XX , Pérdida Auditiva Sensorineural , Insuficiencia Ovárica Primaria , Femenino , Humanos , Disgenesia Gonadal 46 XX/genética , Pérdida Auditiva Sensorineural/genética , Mitocondrias/genética , Mutación Missense , Insuficiencia Ovárica Primaria/genética , Animales , Drosophila melanogaster
12.
Clin Genet ; 103(3): 277-287, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36349847

RESUMEN

46,XY gonadal dysgenesis (GD) is a Disorder/Difference of Sex Development (DSD) that can present with phenotypes ranging from ambiguous genitalia to complete male-to-female sex reversal. Around 50% of 46,XY DSD cases receive a molecular diagnosis. In mice, Fibroblast growth factor 9 (FGF9) is an important component of the male sex-determining pathway. Two FGF9 variants reported to date disrupt testis development in mice, but not in humans. Here, we describe a female patient with 46,XY GD harbouring the rare FGF9 variant (missense mutation), NM_002010.2:c.583G > A;p.(Asp195Asn) (D195N). By biochemical and cell-based approaches, the D195N variant disrupts FGF9 protein homodimerisation and FGF9-heparin-binding, and reduces both Sertoli cell proliferation and Wnt4 repression. XY Fgf9D195N/D195N foetal mice show a transient disruption of testicular cord development, while XY Fgf9D195N/- foetal mice show partial male-to-female gonadal sex reversal. In the general population, the D195N variant occurs at an allele frequency of 2.4 × 10-5 , suggesting an oligogenic basis for the patient's DSD. Exome analysis of the patient reveals several known and novel variants in genes expressed in human foetal Sertoli cells at the time of sex determination. Taken together, our results indicate that disruption of FGF9 homodimerization impairs testis determination in mice and, potentially, also in humans in combination with other variants.


Asunto(s)
Factor 9 de Crecimiento de Fibroblastos , Disgenesia Gonadal 46 XY , Humanos , Masculino , Femenino , Ratones , Animales , Dimerización , Factor 9 de Crecimiento de Fibroblastos/genética , Testículo , Gónadas , Disgenesia Gonadal 46 XY/genética
13.
Eur J Hum Genet ; 31(4): 453-460, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36450801

RESUMEN

Premature ovarian insufficiency (POI) affects 1 in 100 women and is a leading cause of female infertility. There are over 80 genes in which variants can cause POI, with these explaining only a minority of cases. Whole exome sequencing (WES) can be a useful tool for POI patient management, allowing clinical care to be personalized to underlying cause. We performed WES to investigate two French sisters, whose only clinical complaint was POI. Surprisingly, they shared one known and one novel likely pathogenic variant in the Perrault syndrome gene, LARS2. Using amino-acylation studies, we established that the novel missense variant significantly impairs LARS2 function. Perrault syndrome is characterized by sensorineural hearing loss in addition to POI. This molecular diagnosis alerted the sisters to the significance of their difficulty in following conversation. Subsequent audiology assessment revealed a mild bilateral hearing loss. We describe the first cases presenting with perceived isolated POI and causative variants in a Perrault syndrome gene. Our study expands the phenotypic spectrum associated with LARS2 variants and highlights the clinical benefit of having a genetic diagnosis, with prediction of potential co-morbidity and prompt and appropriate medical care, in this case by an audiologist for early detection of hearing loss.


Asunto(s)
Aminoacil-ARNt Sintetasas , Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva , Insuficiencia Ovárica Primaria , Humanos , Femenino , Aminoacil-ARNt Sintetasas/genética , Mutación , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Pérdida Auditiva/diagnóstico , Pérdida Auditiva/genética , Insuficiencia Ovárica Primaria/diagnóstico , Insuficiencia Ovárica Primaria/genética
14.
Genes (Basel) ; 13(11)2022 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-36421788

RESUMEN

The mitochondrial ribosome is critical to mitochondrial protein synthesis. Defects in both the large and small subunits of the mitochondrial ribosome can cause human disease, including, but not limited to, cardiomyopathy, hypoglycaemia, neurological dysfunction, sensorineural hearing loss and premature ovarian insufficiency (POI). POI is a common cause of infertility, characterised by elevated follicle-stimulating hormone and amenorrhea in women under the age of 40. Here we describe a patient with POI, sensorineural hearing loss and Hashimoto's disease. The co-occurrence of POI with sensorineural hearing loss indicates Perrault syndrome. Whole exome sequencing identified two compound heterozygous variants in mitochondrial ribosomal protein 7 (MRPS7), c.373A>T/p.(Lys125*) and c.536G>A/p.(Arg179His). Both novel variants are predicted to be pathogenic via in-silico algorithms. Variants in MRPS7 have been described only once in the literature and were identified in sisters, one of whom presented with congenital sensorineural hearing loss and POI, consistent with our patient phenotype. The other affected sister had a more severe disease course and died in early adolescence due to liver and renal failure before the reproductive phenotype was known. This second independent report validates that variants in MRPS7 are a cause of syndromic POI/Perrault syndrome. We present this case and review the current evidence supporting the integral role of the mitochondrial ribosome in supporting ovarian function.


Asunto(s)
Disgenesia Gonadal 46 XX , Pérdida Auditiva Sensorineural , Insuficiencia Ovárica Primaria , Adolescente , Femenino , Humanos , Ribosomas Mitocondriales/patología , Disgenesia Gonadal 46 XX/genética , Disgenesia Gonadal 46 XX/patología , Insuficiencia Ovárica Primaria/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Proteínas Ribosómicas/genética , Proteínas Mitocondriales/genética
15.
J Clin Endocrinol Metab ; 107(12): 3328-3340, 2022 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-36074910

RESUMEN

CONTEXT: Premature ovarian insufficiency (POI) is a common form of female infertility that usually presents as an isolated condition but can be part of various genetic syndromes. Early diagnosis and treatment of POI can minimize comorbidity and improve health outcomes. OBJECTIVE: We aimed to determine the genetic cause of syndromic POI, intellectual disability, neutropenia, and cataracts. METHODS: We performed whole-exome sequencing (WES) followed by functional validation via RT-PCR, RNAseq, and quantitative proteomics, as well as clinical update of previously reported patients with variants in the caseinolytic peptidase B (CLPB) gene. RESULTS: We identified causative variants in CLPB, encoding a mitochondrial disaggregase. Variants in this gene are known to cause an autosomal recessive syndrome involving 3-methylglutaconic aciduria, neurological dysfunction, cataracts, and neutropenia that is often fatal in childhood; however, there is likely a reporting bias toward severe cases. Using RNAseq and quantitative proteomics we validated causation and gained insight into genotype:phenotype correlation. Clinical follow-up of patients with CLPB deficiency who survived to adulthood identified POI and infertility as a common postpubertal ailment. CONCLUSION: A novel splicing variant is associated with CLPB deficiency in an individual who survived to adulthood. POI is a common feature of postpubertal female individuals with CLPB deficiency. Patients with CLPB deficiency should be referred to pediatric gynecologists/endocrinologists for prompt POI diagnosis and hormone replacement therapy to minimize associated comorbidities.


Asunto(s)
Catarata , Menopausia Prematura , Neutropenia , Insuficiencia Ovárica Primaria , Femenino , Humanos , Endopeptidasa Clp/genética , Endopeptidasa Clp/metabolismo , Transcriptoma , Proteómica , Insuficiencia Ovárica Primaria/genética , Fenotipo , Catarata/genética
16.
Hum Mutat ; 43(10): 1443-1453, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35801529

RESUMEN

Premature ovarian insufficiency (POI) is a leading form of female infertility, characterised by menstrual disturbance and elevated follicle-stimulating hormone before age 40. It is highly heterogeneous with variants in over 80 genes potentially causative, but the majority of cases having no known cause. One gene implicated in POI pathology is TP63. TP63 encodes multiple p63 isoforms, one of which has been shown to have a role in the surveillance of genetic quality in oocytes. TP63 C-terminal truncation variants and N-terminal duplication have been described in association with POI, however, functional validation has been lacking. Here we identify three novel TP63 missense variants in women with nonsyndromic POI, including one in the N-terminal activation domain, one in the C-terminal inhibition domain, and one affecting a unique and poorly understood p63 isoform, TA*p63. Via blue-native page and luciferase reporter assays we demonstrate that two of these variants disrupt p63 dimerization, leading to constitutively active p63 tetramer that significantly increases the transcription of downstream targets. This is the first evidence that TP63 missense variants can cause isolated POI and provides mechanistic insight that TP63 variants cause POI due to constitutive p63 activation and accelerated oocyte loss in the absence of DNA damage.


Asunto(s)
Insuficiencia Ovárica Primaria , Factores de Transcripción , Proteínas Supresoras de Tumor , Femenino , Humanos , Mutación Missense , Insuficiencia Ovárica Primaria/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética
17.
Biol Reprod ; 107(5): 1155-1158, 2022 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-35908231

RESUMEN

Genomic testing has the potential to transform outcomes for women with infertility conditions, such as premature ovarian insufficiency (POI), with growing calls for widespread diagnostic use. The current research literature, however, often uses poor variant curation leading to inflated diagnostic claims and fails to address the complexities of genomic testing for this condition. Without careful execution of the transition from research to the clinic, there is danger of inaccurate diagnoses and poor appreciation of broader implications of testing. This Forum outlines the benefits of genomic testing for POI and raises often overlooked concerns.


Asunto(s)
Infertilidad , Insuficiencia Ovárica Primaria , Humanos , Femenino , Insuficiencia Ovárica Primaria/diagnóstico , Insuficiencia Ovárica Primaria/genética , Infertilidad/genética , Pruebas Genéticas
19.
Eur J Hum Genet ; 30(2): 219-228, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34707299

RESUMEN

Premature ovarian insufficiency (POI), affecting 1 in 100 women, is characterised by loss of ovarian function associated with elevated gonadotropin, before the age of 40. In addition to infertility, patients face increased risk of comorbidities such as heart disease, osteoporosis, cancer and/or early mortality. We used whole exome sequencing to identify the genetic cause of POI in seven women. Each had biallelic candidate variants in genes with a primary role in DNA damage repair and/or meiosis. This includes two genes, REC8 and HROB, not previously associated with autosomal recessive POI. REC8 encodes a component of the cohesin complex and HROB encodes a factor that recruits MCM8/9 for DNA damage repair. In silico analyses, combined with concordant mouse model phenotypes support these as new genetic causes of POI. We also identified novel variants in MCM8, NUP107, STAG3 and HFM1 and a known variant in POF1B. Our study highlights the pivotal role of meiosis in ovarian function. We identify novel variants, consolidate the pathogenicity of variants previously considered of unknown significance, and propose HROB and REC8 variants as new genetic causes while exploring their link to pathogenesis.


Asunto(s)
Insuficiencia Ovárica Primaria , Animales , Proteínas de Ciclo Celular/genética , Cromosomas , ADN Helicasas/genética , Proteínas de Unión al ADN , Femenino , Humanos , Meiosis/genética , Ratones , Fenotipo , Insuficiencia Ovárica Primaria/genética , Insuficiencia Ovárica Primaria/patología , Secuenciación del Exoma
20.
J Invest Surg ; 34(2): 227-233, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31012339

RESUMEN

Background: Complete androgen insensitivity syndrome (CAIS) is a congenital condition caused by genetic defects in the androgen receptor (AR) gene located on the X chromosome, which lead to a phenotypical female individual with a 46, XY karyotype. Early diagnosis of CAIS is essential for proper clinical management, allows assessment of familial risk and contributes to healthcare decisions. However, diagnosis of CAIS can be overlooked in girls with inguinal hernia, resulting in inappropriate management. Methods: Five female patients from three unrelated families presented to our genetic clinic with primary amenorrhea. Each patient had been diagnosed with inguinal hernia in childhood and had undergone hernia repair without further investigation into what was contained in the hernial sac. We carried out physical examination, cytogenetic studies, hormonal evaluation, and molecular analysis to establish a comprehensive diagnosis. Family history and pedigree were collated to identify at-risk family members. Results: All patients presented with female external genitalia. Cytogenetic studies revealed a 46, XY karyotype and hormonal analysis suggested a diagnosis of CAIS. Sequencing of the AR gene in all patients and suspected family members revealed pathogenic variants in the AR gene and confirmed the molecular diagnosis of CAIS. Conclusions: We report the delayed diagnosis of CAIS in female Indonesian patients with a history of inguinal hernia in childhood. An early diagnosis of CAIS is essential for appropriate clinical management, as well as assessing familial risk. Increasing awareness among clinicians is paramount, and we encourage a CAIS diagnosis to be considered in any patient presenting with female appearance and inguinal hernia.


Asunto(s)
Síndrome de Resistencia Androgénica , Hernia Inguinal , Síndrome de Resistencia Androgénica/diagnóstico , Síndrome de Resistencia Androgénica/genética , Niño , Femenino , Hernia Inguinal/genética , Hernia Inguinal/cirugía , Herniorrafia , Humanos , Indonesia , Cariotipificación , Masculino
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