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Ken Mcelreavey - One of the best experts on this subject based on the ideXlab platform.
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pathogenic variants in the deah box rna helicase dhx37 are a frequent cause of 46 XY Gonadal Dysgenesis and 46 XY testicular regression syndrome
2020Co-Authors: Ken Mcelreavey, Joelle Bignontopalovic, Anne Jorgensen, Caroline Eozenou, Tiphanie Merel, Daisylyn Senna Tan, Denis Houzelstein, Federica Buonocore, Nick Warr, Raissa KayAbstract:XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by Gonadal Dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY Gonadal Dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including Gonadal Dysgenesis and TRS. Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10−10). Five variants are de novo (P value = 1.5 × 10−5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with Gonadal Dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including Gonadal Dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.
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Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY Gonadal Dysgenesis and 46,XY testicular regression syndrome
2019Co-Authors: Ken Mcelreavey, Anne Jorgensen, Caroline Eozenou, Tiphanie Merel, Daisylyn Senna Tan, Denis Houzelstein, Federica Buonocore, Nick Warr, Joelle Bignon-topalovic, Raissa KayAbstract:PURPOSE: XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by Gonadal Dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY Gonadal Dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. METHODS: We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including Gonadal Dysgenesis and TRS. RESULTS: Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10-10). Five variants are de novo (P value = 1.5 × 10-5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with Gonadal Dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. CONCLUSION: DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including Gonadal Dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.
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identification of nr5a1 mutations and possible digenic inheritance in 46 XY Gonadal Dysgenesis
2016Co-Authors: Inas Mazen, Mohamed S Abdelhamid, Mona K Mekkawy, Joelle Bignontopalovic, Radia Boudjenah, Mona El Gammal, Mona L Essawi, Anu Bashamboo, Ken McelreaveyAbstract:The phenotypic spectrum of patients carrying NR5A1 mutations ranges from 46,XY Gonadal Dysgenesis to male infertility. Phenotypic variability could be due to digenic or oligogenic inheritance of pathogenic variants in other testis-determining genes. Here, exome sequencing identified 2 pathogenic de novo NR5A1 mutations in 2 patients with 46,XY Gonadal Dysgenesis, p.Q206Tfs*20 and p.Arg313Cys. The latter patient also carried a missense mutation in MAP3K1. Our data extend the number of NR5A1 gene mutations associated with Gonadal Dysgenesis. The combination of an NR5A1 mutation with a MAP3K1 variant may explain the phenotypic variability associated with NR5A1 mutations.
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Genetic mutations and somatic anomalies in association with 46,XY Gonadal Dysgenesis.
2015Co-Authors: Claire Bastian, Ken Mcelreavey, Anu Bashamboo, Jean-baptiste Muller, Stephen Lortat-jacob, Claire Nihoul-fékété, Joelle Bignon-topalovic, Raja BraunerAbstract:Objective To assess genetic mutations and associated somatic anomalies in a series of patients with 46,XY Gonadal Dysgenesis (GD). Design Single center retrospective study. Setting University pediatric hospital. Patient(s) Fourteen patients with 46,XY GD. Intervention(s) None. Main Outcome Measure(s) Genotype-phenotype relationship. Result(s) The presenting symptom was disorders of sex development (6 patients), primary amenorrhea (2 patients), discordance between 46,XY karyotype and female external genitalia (3 patients), discovery of Mullerian structures at surgery (2 patients), or diagnosed in the evaluation of a Gonadal tumor (1 patient). Mullerian structures were shown by ultrasound evaluation in 7 of 13 patients, genitography in 3 of 6 patients and/or surgery in 8 of 10 patients (3 not seen at imaging), or only by histologic examination (1 patient). Three patients had gonadoblastoma and/or seminoma. A mutation was found in 7 patients of whom 2 had family history of reproductive problems and 5 had associated somatic anomalies. The mutations were FOG2/ZFPM2 (1 patient), SRY (2 patients), WT1 (1 patient), or deletions of distal chromosome 9p (3 patients). Among the three other patients with associated anomalies and no mutation, two had ectodermal dysplasia and one had leukemia. Conclusion(s) Mutations were observed in half of the patients with 46,XY GD with Mullerian structures. We also describe for the first time the association between GD and ectodermal dysplasia. Mullerian structures can be found in some cases only by histologic examination, which should be coupled to preventive gonadectomy because of the risk of tumor formation.
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mutations in the fog2 zfpm2 gene are associated with anomalies of human testis determination
2014Co-Authors: Anu Bashamboo, R. Brauner, Joelle Bignontopalovic, Stephen Lortatjacob, Vasiliki Karageorgou, Diana Lourenco, Alessandro Guffanti, Ken McelreaveyAbstract:In recent years, considerable advances have been made in our understanding of genetics of mammalian gonad development; however, the underlying genetic aetiology in the majority of patients with 46,XY disorders of sex development (DSD) still remains unknown. Based on mouse models, it has been hypothesized that haploinsufficiency of the Friend of GATA 2 (FOG2) gene could lead to 46,XY Gonadal Dysgenesis on specific inbred genetic backgrounds. Using whole exome sequencing, we identified independent missense mutations in FOG2 in two patients with 46,XY Gonadal Dysgenesis. One patient carried a non-synonymous heterozygous mutation (p.S402R), while the other patient carried a heterozygous p.R260Q mutation and a homozygous p.M544I mutation. Functional studies indicated that the failure of testis development in these cases could be explained by the impaired ability of the mutant FOG2 proteins to interact with a known regulator of early testis development, GATA4. This is the first example of mutations in the coding sequence of FOG2 associated with 46,XY DSD in human and adds to the list of genes in the human known to be associated with DSD.
Raissa Kay - One of the best experts on this subject based on the ideXlab platform.
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pathogenic variants in the deah box rna helicase dhx37 are a frequent cause of 46 XY Gonadal Dysgenesis and 46 XY testicular regression syndrome
2020Co-Authors: Ken Mcelreavey, Joelle Bignontopalovic, Anne Jorgensen, Caroline Eozenou, Tiphanie Merel, Daisylyn Senna Tan, Denis Houzelstein, Federica Buonocore, Nick Warr, Raissa KayAbstract:XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by Gonadal Dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY Gonadal Dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including Gonadal Dysgenesis and TRS. Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10−10). Five variants are de novo (P value = 1.5 × 10−5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with Gonadal Dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including Gonadal Dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.
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Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY Gonadal Dysgenesis and 46,XY testicular regression syndrome
2019Co-Authors: Ken Mcelreavey, Anne Jorgensen, Caroline Eozenou, Tiphanie Merel, Daisylyn Senna Tan, Denis Houzelstein, Federica Buonocore, Nick Warr, Joelle Bignon-topalovic, Raissa KayAbstract:PURPOSE: XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by Gonadal Dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY Gonadal Dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. METHODS: We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including Gonadal Dysgenesis and TRS. RESULTS: Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10-10). Five variants are de novo (P value = 1.5 × 10-5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with Gonadal Dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. CONCLUSION: DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including Gonadal Dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.
Catherine E Keegan - One of the best experts on this subject based on the ideXlab platform.
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genetic evidence of the association of deah box helicase 37 defects with 46 XY Gonadal Dysgenesis spectrum
2019Co-Authors: Thatiana Evilen Da Silva, Catherine E Keegan, Hayk Barseghyan, Eric Vilain, Nathalia Lisboa Gomes, Antonio M Lerario, Filomena Marino Carvalho, Mirian Nishi, Alejandro MartinezaguayoAbstract:CONTEXT 46,XY Gonadal Dysgenesis (GD) is a heterogeneous group of disorders with a wide phenotypic spectrum, including embryonic testicular regression syndrome (ETRS). OBJECTIVE To report a gene for 46,XY GD etiology, especially for ETRS. DESIGN Screening of familial cases of 46,XY GD using whole-exome sequencing and sporadic cases by target gene-panel sequencing. SETTING Tertiary Referral Center for differences/disorders of sex development (DSD). PATIENTS AND INTERVENTIONS We selected 87 patients with 46,XY DSD (17 familial cases from 8 unrelated families and 70 sporadic cases); 55 patients had GD (among them, 10 patients from 5 families and 8 sporadic cases had ETRS), and 32 patients had 46,XY DSD of unknown etiology. RESULTS We identified four heterozygous missense rare variants, classified as pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase 37 (DHX37) gene in five families (n = 11 patients) and in six sporadic cases. Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases). The variants were specifically associated with ETRS (7/14 index cases; 50%). The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001). Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells. CONCLUSION This strong genetic evidence identifies DHX37 as a player in the complex cascade of male Gonadal differentiation and maintenance.
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deah box helicase 37 dhx37 defects are a novel molecular etiology of 46 XY Gonadal Dysgenesis spectrum
2018Co-Authors: Thatiana Evilen Da Silva, Catherine E Keegan, Hayk Barseghyan, Eric Vilain, Nathalia Lisboa Gomes, Antonio M Lerario, Mirian Yumie Nishi, Filomena Marino Carvalho, Alejandro MartinezaguayoAbstract:46, XY Gonadal Dysgenesis is a heterogeneous disorder of sex development (DSD) that features abnormal Gonadal development and varying degrees of undervirilization of the external genitalia, ranging from micropenis to female-like genitalia. Embryonic testicular regression syndrome (ETRS; MIM: 273250) is considered part of the clinical spectrum of 46,XY Gonadal Dysgenesis. Most ETRS patients present micropenis or atypical genitalia associated with a complete absence of Gonadal tissue in one or both sides. In most patients with Gonadal Dysgenesis, the genetic diagnosis is unclear. We performed whole exome sequencing in ETRS patients and identified a rare variant, the p.Arg308Gln, in DEAH (Asp-Glu-Ala-His) box polypeptide 37 (DHX37) in 5 affected individuals from three unrelated families. We expanded the analysis of DHX37 coding region to additional 71 patients with 46,XY Gonadal Dysgenesis and identified the p.Arg308Gln and three other DHX37 missense variants (p.Arg151Trp, p.Thr304Met and p.Arg674Trp) in 11 affected members from eight distinct families (8 patients with ETRS, two with partial Gonadal Dysgenesis and one 46,XY DSD female patient previously gonadectomized). The p.Arg308Gln and p.Arg674Trp recurrent variants were identified in six and three families, respectively. Segregation analysis revealed sex-limited autosomal dominant inheritance in 4 families, autosomal dominant with incomplete penetrance in one family and autosomal recessive in another family. Immunohistochemical analysis of normal testes revealed that DHX37 is expressed in germ cells at different stages of maturation. This study demonstrates an expressive frequency of rare predicted to be deleterious DHX37 variants in 46,XY Gonadal Dysgenesis group, particularly those individuals exhibiting the ETRS phenotype (25% and 50%, respectively). Our findings indicate that DHX37 is a new player in the complex cascade of male Gonadal differentiation and maintenance, thus establishing a novel and frequent molecular etiology for 46,XY Gonadal Dysgenesis spectrum, mainly for embryonic testicular regression syndrome.
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exome sequencing for the diagnosis of 46 XY disorders of sex development
2015Co-Authors: Ruth Baxter, Catherine E Keegan, Hayk Barseghyan, Patricia Y Fechner, Valerie A Arboleda, M P Adam, Renee Bargman, Sharon Travers, Susan Schelley, Louanne HudginsAbstract:Context: Disorders of sex development (DSD) are clinical conditions where there is a discrepancy between the chromosomal sex and the phenotypic (Gonadal or genital) sex of an individual. Such conditions can be stressful for patients and their families and have historically been difficult to diagnose, especially at the genetic level. In particular, for cases of 46,XY Gonadal Dysgenesis, once variants in SRY and NR5A1 have been ruled out, there are few other single gene tests available. Objective: We used exome sequencing followed by analysis with a list of all known human DSD-associated genes to investigate the underlying genetic etiology of 46,XY DSD patients who had not previously received a genetic diagnosis. Design: Samples were either submitted to the research laboratory or submitted as clinical samples to the UCLA Clinical Genomic Center. Sequencing data were filtered using a list of genes known to be involved in DSD. Results: We were able to identify a likely genetic diagnosis in more than a third o...
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9p partial monosomy and disorders of sex development review and postulation of a pathogenetic mechanism
2013Co-Authors: Shane C Quinonez, John M Park, Raja Rabah, Kailey M Owens, Beverly M Yashar, Thomas W Glover, Catherine E KeeganAbstract:Deletion of the distal segment of 9p causes a syndrome comprising trigonocephaly, minor anomalies, and intellectual disability. Patients with this condition also frequently present with genitourinary abnormalities including cryptorchidism, hypospadias, ambiguous genitalia, or 46,XY testicular Dysgenesis. The region responsible for the Gonadal Dysgenesis has been localized to 9p24.3 with the likely responsible gene identified as DMRT1. Similar to patients with other molecular causes of 46,XY Gonadal Dysgenesis, patients with partial del 9p have an increased risk of gonadoblastoma. We present two patients with 46,XY Gonadal Dysgenesis due to partial 9p monosomy. Both patients were also diagnosed with gonadoblastoma following gonadectomy at an early age. Chromosomal microarray analyses refined the cytogenetic abnormalities and allowed potential genotype-phenotype relationships to be determined. We also review the literature as it pertains to partial 9p monosomy, genital abnormalities and gonadoblastoma and note that a large percentage of affected patients present with two copy number variations. We propose that a two-hit mechanism may be involved in the incomplete penetrance and variable expressivity of partial 9p monosomy and an abnormal genital phenotype. The significant percentage of gonadoblastoma in patients with 46,XY complete Gonadal Dysgenesis due to partial 9p monosomy also continues to support the necessity of gonadectomy in this patient population.
Joelle Bignontopalovic - One of the best experts on this subject based on the ideXlab platform.
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pathogenic variants in the deah box rna helicase dhx37 are a frequent cause of 46 XY Gonadal Dysgenesis and 46 XY testicular regression syndrome
2020Co-Authors: Ken Mcelreavey, Joelle Bignontopalovic, Anne Jorgensen, Caroline Eozenou, Tiphanie Merel, Daisylyn Senna Tan, Denis Houzelstein, Federica Buonocore, Nick Warr, Raissa KayAbstract:XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by Gonadal Dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY Gonadal Dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including Gonadal Dysgenesis and TRS. Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10−10). Five variants are de novo (P value = 1.5 × 10−5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with Gonadal Dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including Gonadal Dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.
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identification of nr5a1 mutations and possible digenic inheritance in 46 XY Gonadal Dysgenesis
2016Co-Authors: Inas Mazen, Mohamed S Abdelhamid, Mona K Mekkawy, Joelle Bignontopalovic, Radia Boudjenah, Mona El Gammal, Mona L Essawi, Anu Bashamboo, Ken McelreaveyAbstract:The phenotypic spectrum of patients carrying NR5A1 mutations ranges from 46,XY Gonadal Dysgenesis to male infertility. Phenotypic variability could be due to digenic or oligogenic inheritance of pathogenic variants in other testis-determining genes. Here, exome sequencing identified 2 pathogenic de novo NR5A1 mutations in 2 patients with 46,XY Gonadal Dysgenesis, p.Q206Tfs*20 and p.Arg313Cys. The latter patient also carried a missense mutation in MAP3K1. Our data extend the number of NR5A1 gene mutations associated with Gonadal Dysgenesis. The combination of an NR5A1 mutation with a MAP3K1 variant may explain the phenotypic variability associated with NR5A1 mutations.
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mutations in the fog2 zfpm2 gene are associated with anomalies of human testis determination
2014Co-Authors: Anu Bashamboo, R. Brauner, Joelle Bignontopalovic, Stephen Lortatjacob, Vasiliki Karageorgou, Diana Lourenco, Alessandro Guffanti, Ken McelreaveyAbstract:In recent years, considerable advances have been made in our understanding of genetics of mammalian gonad development; however, the underlying genetic aetiology in the majority of patients with 46,XY disorders of sex development (DSD) still remains unknown. Based on mouse models, it has been hypothesized that haploinsufficiency of the Friend of GATA 2 (FOG2) gene could lead to 46,XY Gonadal Dysgenesis on specific inbred genetic backgrounds. Using whole exome sequencing, we identified independent missense mutations in FOG2 in two patients with 46,XY Gonadal Dysgenesis. One patient carried a non-synonymous heterozygous mutation (p.S402R), while the other patient carried a heterozygous p.R260Q mutation and a homozygous p.M544I mutation. Functional studies indicated that the failure of testis development in these cases could be explained by the impaired ability of the mutant FOG2 proteins to interact with a known regulator of early testis development, GATA4. This is the first example of mutations in the coding sequence of FOG2 associated with 46,XY DSD in human and adds to the list of genes in the human known to be associated with DSD.
Alejandro Martinezaguayo - One of the best experts on this subject based on the ideXlab platform.
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genetic evidence of the association of deah box helicase 37 defects with 46 XY Gonadal Dysgenesis spectrum
2019Co-Authors: Thatiana Evilen Da Silva, Catherine E Keegan, Hayk Barseghyan, Eric Vilain, Nathalia Lisboa Gomes, Antonio M Lerario, Filomena Marino Carvalho, Mirian Nishi, Alejandro MartinezaguayoAbstract:CONTEXT 46,XY Gonadal Dysgenesis (GD) is a heterogeneous group of disorders with a wide phenotypic spectrum, including embryonic testicular regression syndrome (ETRS). OBJECTIVE To report a gene for 46,XY GD etiology, especially for ETRS. DESIGN Screening of familial cases of 46,XY GD using whole-exome sequencing and sporadic cases by target gene-panel sequencing. SETTING Tertiary Referral Center for differences/disorders of sex development (DSD). PATIENTS AND INTERVENTIONS We selected 87 patients with 46,XY DSD (17 familial cases from 8 unrelated families and 70 sporadic cases); 55 patients had GD (among them, 10 patients from 5 families and 8 sporadic cases had ETRS), and 32 patients had 46,XY DSD of unknown etiology. RESULTS We identified four heterozygous missense rare variants, classified as pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase 37 (DHX37) gene in five families (n = 11 patients) and in six sporadic cases. Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases). The variants were specifically associated with ETRS (7/14 index cases; 50%). The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001). Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells. CONCLUSION This strong genetic evidence identifies DHX37 as a player in the complex cascade of male Gonadal differentiation and maintenance.
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deah box helicase 37 dhx37 defects are a novel molecular etiology of 46 XY Gonadal Dysgenesis spectrum
2018Co-Authors: Thatiana Evilen Da Silva, Catherine E Keegan, Hayk Barseghyan, Eric Vilain, Nathalia Lisboa Gomes, Antonio M Lerario, Mirian Yumie Nishi, Filomena Marino Carvalho, Alejandro MartinezaguayoAbstract:46, XY Gonadal Dysgenesis is a heterogeneous disorder of sex development (DSD) that features abnormal Gonadal development and varying degrees of undervirilization of the external genitalia, ranging from micropenis to female-like genitalia. Embryonic testicular regression syndrome (ETRS; MIM: 273250) is considered part of the clinical spectrum of 46,XY Gonadal Dysgenesis. Most ETRS patients present micropenis or atypical genitalia associated with a complete absence of Gonadal tissue in one or both sides. In most patients with Gonadal Dysgenesis, the genetic diagnosis is unclear. We performed whole exome sequencing in ETRS patients and identified a rare variant, the p.Arg308Gln, in DEAH (Asp-Glu-Ala-His) box polypeptide 37 (DHX37) in 5 affected individuals from three unrelated families. We expanded the analysis of DHX37 coding region to additional 71 patients with 46,XY Gonadal Dysgenesis and identified the p.Arg308Gln and three other DHX37 missense variants (p.Arg151Trp, p.Thr304Met and p.Arg674Trp) in 11 affected members from eight distinct families (8 patients with ETRS, two with partial Gonadal Dysgenesis and one 46,XY DSD female patient previously gonadectomized). The p.Arg308Gln and p.Arg674Trp recurrent variants were identified in six and three families, respectively. Segregation analysis revealed sex-limited autosomal dominant inheritance in 4 families, autosomal dominant with incomplete penetrance in one family and autosomal recessive in another family. Immunohistochemical analysis of normal testes revealed that DHX37 is expressed in germ cells at different stages of maturation. This study demonstrates an expressive frequency of rare predicted to be deleterious DHX37 variants in 46,XY Gonadal Dysgenesis group, particularly those individuals exhibiting the ETRS phenotype (25% and 50%, respectively). Our findings indicate that DHX37 is a new player in the complex cascade of male Gonadal differentiation and maintenance, thus establishing a novel and frequent molecular etiology for 46,XY Gonadal Dysgenesis spectrum, mainly for embryonic testicular regression syndrome.
