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ey0015.6-13 | Disorders of Sex Development: New paradigm | ESPEYB15

6.13 A Novel Homozygous Missense Mutation in the FU-CRD2 Domain of the R-spondin1 Gene Associated with Familial 46,XX DSD

Y Naasse , A Bakhchane , H Charoute , F Jennane , J Bignon-Topalovic , A Malki , A Bashamboo , A Barakat , H Rouba , K McElreavey

To read the full abstract: Sex Dev. 2017;11(5-6):269-274[Comments on 6.11, 6.12 and 6.13] Evidence for factors necessary for female sexual development are presented in the above 3 publications. Studies of 46,XX DSD individuals show compiling evidence for factors necessary for female development and to counteract...

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ey0021.6-6 | Clinical and Molecular Insights into SF1 Deficiency | ESPEYB21

6.6. A conserved NR5A1-responsive enhancer regulates SRY in testis-determination

D Houzelstein , C Eozenou , CF Lagos , M Elzaiat , J Bignon-Topalovic , I Gonzalez , V Laville , L Schlick , S Wankanit , P Madon , J Kirtane , A Athalye , F Buonocore , S Bigou , GS Conway , D Bohl , JC Achermann , A Bashamboo , K McElreavey

Brief Summary: This study identified a conserved enhancer element located 5 of the mammalian SRY gene through comparative genomic analysis, which plays a crucial role in the regulation of sexual differentiation. NR5A1 binds to this element. The researchers discovered two distinct hemizygous base pair substitutions within this NR5A1 binding site, both of which involve highly conserved residues: one in a sporadic case of XY sex reversal and the other in a large fa...

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ey0021.7-6 | Clinical Guidance and Studies | ESPEYB21

7.6. Familial central precocious puberty due to DLK1 deficiency: novel genetic findings and relevance of serum DLK1 levels

L Montenegro , C Seraphim , F Tinano , M Piovesan , APM Canton , K McElreavey , S Brabant , NP Boris , M Magnuson , RS Carroll , UB Kaiser , J Argente , V Barrios , VN Brito , R Brauner , AC Latronico

Brief Summary: This cross-sectional study identifies two pathogenic variants in the Delta-like noncanonical notch ligand 1 ( DLK1 ) gene in a French cohort of 121 children with idiopathic central precocious puberty (CPP).DLK1 is a noncanonical ligand of the Delta Notch pathway known to be involved in adipocyte differentiation. Its hypothalamic expression suggests a potential role in coordinating reproductive and metabolic functions. Pathogenic v...

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ey0021.7-7 | Clinical Guidance and Studies | ESPEYB21

7.7. Contributions of common genetic variants to constitutional delay of puberty and idiopathic hypogonadotropic hypogonadism

MF Lippincott , EC Schafer , AA Hindman , W He , R Brauner , A Delaney , R Grinspon , JE Hall , JN Hirschhorn , K McElreavey , MR Palmert , R Rey , SB Seminara , RM Salem , YM Chan , Consortium Delayed Puberty Genetics

Brief Summary: this case-control study shows that the common genetic variants that influence pubertal timing in the general population also contribute to constitutional delay of puberty (CDP) and less significantly to normosmic idiopathic hypogonadotropic hypogonadism (IHH).CDP and IHH are two different conditions that are notoriously difficult to distinguish clinically on initial presentation. Because CDP has clear heritability traits1, and h...

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ey0019.6-6 | Basic and Genetic Research of DSD | ESPEYB19

6.6. Expanding DSD phenotypes associated with variants in the DEAH-box RNA helicase DHX37

H Zidoune , L Martinerie , DS Tan , M Askari , D Rezgoune , A Ladjouze , A Boukri , Y Benelmadani , K Sifi , N Abadi , D Satta , M Rastari , M Seresht-Ahmadi , J Bignon-Topalovic , I Mazen , J Leger , D Simon , R Brauner , M Totonchi , R Jauch , A Bashamboo , K McElreavey

Sex Dev. 2021;15(4):244-252. PMID: 34293745, doi: 10.1159/000515924.Brief Summary: This genetic study provides data of a large cohort of 140 patients with DSD who were screened for DHX37 variants.DHX37 emerges as a frequent cause of nonsyndromic 46,XY gonadal dysgenesis, and 46,XY testicular regression syndrome. Since the first description of the gene (1), <...

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ey0017.6-8 | Differences/Disorders of Sex Development: Genetics | ESPEYB17

6.8. Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome

K McElreavey , A Jorgensen , C Eozenou , T Merel , J Bignon-Topalovic , DS Tan , D Houzelstein , F Buonocore , N Warr , RGG Kay , M Peycelon , JP Siffroi , I Mazen , JC Achermann , Y Shcherbak , J Leger , A Sallai , JC Carel , L Martinerie , R Le Ru , GS Conway , B Mignot , L Van Maldergem , R Bertalan , E Globa , R Brauner , R Jauch , S Nef , A Greenfield , A Bashamboo

To read the full abstract: Genet Med. 2020, Jan; 22: 150-9. doi: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944638/pdf/41436_2019_Article_606.pdfMassive parallel sequencing of 145 46,XY DSD patients revealed 13 individuals with heterozygous missense pathogenic variants in the RNA helicase DHX37, explaining 11% of cases of 46,XY gonadal d...

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ey0015.6-12 | Disorders of Sex Development: New paradigm | ESPEYB15

6.12 Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children

A Bashamboo , C Eozenou , A Jorgensen , J Bignon-Topalovic , JP Siffroi , C Hyon , A Tar , P Nagy , J Sólyom , Z Halász , A Paye-Jaouen , S Lambert , D Rodriguez-Buritica , R Bertalan , L Martinerie , E Rajpert-De Meyts , JC Achermann , K McElreavey

To read the full abstract: Am J Hum Genet. 2018 Mar 1;102(3):487-493See comment on 6.13...

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ey0021.7-8 | Clinical Guidance and Studies | ESPEYB21

7.8. Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty

K Duckett , A Williamson , JWR Kincaid , K Rainbow , LJ Corbin , HC Martin , RY Eberhardt , QQ Huang , ME Hurles , W He , R Brauner , A Delaney , L Dunkel , RP Grinspon , JE Hall , JN Hirschhorn , SR Howard , AC Latronico , AAL Jorge , K McElreavey , V Mericq , PM Merino , MR Palmert , L Plummer , RA Rey , RC Rezende , SB Seminara , K Salnikov , I Banerjee , BYH Lam , JRB Perry , NJ Timpson , P Clayton , YM Chan , KK Ong , S O'Rahilly

Brief Summary: this large patient cohort study identified an overrepresentation of functionally damaging variants in MC3R in individuals with constitutional delay of growth and puberty but not in patients with IHH.Melanocortin 3 receptor (MC3R) is a permissive signal expressed by hypothalamic kisspeptin-neurokinin B-dynorphin (KNDY) neurons. It activates puberty through the leptin-proopiomelanocortin pathway in response to nutritional signaling<...

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ey0015.6-15 | When should an extensive genetic investigation be performed? | ESPEYB15

6.15 Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies

MF Portnoi , MC Dumargne , S Rojo , SF Witchel , AJ Duncan , C Eozenou , J Bignon-Topalovic , SA Yatsenko , A Rajkovic , M Reyes-Mugica , K Almstrup , L Fusee , Y Srivastava , S Chantot-Bastaraud , C Hyon , C Louis-Sylvestre , P Validire , C de Malleray Pichard , C Ravel , S Christin-Maitre , R Brauner , R Rossetti , L Persani , EH Charreau , L Dain , VA Chiauzzi , I Mazen , H Rouba , C Schluth-Bolard , S MacGowan , WHI McLean , E Patin , E Rajpert-De Meyts , R Jauch , JC Achermann , JP Siffroi , K McElreavey , A Bashamboo

To read the full abstract: Hum Mol Genet. 2018 Apr 1;27(7):1228-1240See comment on 6.16...

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ey0021.6-2 | DSD - Novel Genes and Mechanisms involved in Gonadal Development | ESPEYB21

6.2. Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects

KL Ayers , S Eggers , BN Rollo , KR Smith , NM Davidson , NA Siddall , L Zhao , J Bowles , K Weiss , G Zanni , L Burglen , S Ben-Shachar , J Rosensaft , A Raas-Rothschild , A Jorgensen , RB Schittenhelm , C Huang , G Robevska , J van den Bergen , F Casagranda , J Cyza , S Pachernegg , DK Wright , M Bahlo , A Oshlack , TJ O'Brien , P Kwan , P Koopman , GR Hime , N Girard , C Hoffmann , Y Shilon , A Zung , E Bertini , M Milh , B Ben Rhouma , N Belguith , A Bashamboo , K McElreavey , E Banne , N Weintrob , B BenZeev , AH Sinclair

Brief Summary: This translational study reveals a novel mechanism underlying syndromic gonadal dysgenesis (GD). It introduces a condition termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY GONadal dysgenesis).46,XY gonadal dysgenesis (GD) is a rare disorder of sex development (DSD) affecting 1-9 per 100,000 live births. Gen...

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ESPE Yearbook of Paediatric Endocrinology

6.13 A Novel Homozygous Missense Mutation in the FU-CRD2 Domain of the R-spondin1 Gene Associated with Familial 46,XX DSD

6.6. A conserved NR5A1-responsive enhancer regulates SRY in testis-determination

7.6. Familial central precocious puberty due to DLK1 deficiency: novel genetic findings and relevance of serum DLK1 levels

7.7. Contributions of common genetic variants to constitutional delay of puberty and idiopathic hypogonadotropic hypogonadism

6.6. Expanding DSD phenotypes associated with variants in the DEAH-box RNA helicase DHX37

6.8. Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome

6.12 Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children

7.8. Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty

6.15 Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies

6.2. Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects

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