Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review

Background: In humans, Desert Hedgehog (DHH) gene mutations are a very rare cause of 46,XY gonadal dysgenesis (GD), eventually associated with peripheral neuropathy. Patients and Methods: Clinical records of 12 patients with 46,XY GD and unknown genetic background were reviewed and a 46,XY woman with peripheral neuropathy was individuated. Her 46,XX sister affected by similar neuropathy was also investigated. Genomic DNA was extracted and DHH exons sequenced and analyzed. A comparative genomic hybridization array was also performed. Results: In both the 46,XY and 46,XX sisters, a homozygous c.554C>A mutation in exon 2 of the DHH gene was found, determining a premature termination codon (p.Ser 185*). Heterozygous consanguineous carrier parents showed neither reproductive problems nor peripheral neuropathy. In the proband and her sister, a 499-kb duplication in 9p22.1 was also found. Conclusion: A 46,XY European woman with 46,XY GD and a novel homozygous DHH pathogenic variant is reported, confirming that this gene plays a key role in male gonadal development. Her 46,XX sister, harboring the same mutation, showed normal internal and external female phenotype. Thus, DHH seems not to be involved in the ovarian development pathway or its postpubertal function. Homozygous DHH mutations cause a specific peripheral neuropathy in humans with both 46,XY and 46,XX karyotypes.

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The Desert Hedgehog Signalling Pathway in Human Gonadal Development and Differences of Sex Development

Sexual Development ◽

10.1159/000518308 ◽

2021 ◽

pp. 1-14

Author(s):

Svenja Pachernegg ◽

Elizabeth Georges ◽

Katie Ayers

Keyword(s):

Peripheral Neuropathy ◽

Gonadal Dysgenesis ◽

Gonadal Development ◽

Signalling Pathway ◽

Hedgehog Signalling ◽

Sex Development ◽

Xy Gonadal Dysgenesis ◽

Desert Hedgehog ◽

Differences Of Sex Development ◽

Hedgehog Signalling Pathway

While the Hedgehog signalling pathway is implicated in numerous developmental processes and maladies, variants in the Desert Hedgehog (DHH) ligand underlie a condition characterised by 46,XY gonadal dysgenesis with or without peripheral neuropathy. We discuss here the role and regulation of DHH and its signalling pathway in the developing gonads and examine the current understanding of how disruption to this pathway causes this difference of sex development (DSD) in humans.

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46,XY Gonadal Dysgenesis due to a Homozygous Mutation in Desert Hedgehog (DHH) Identified by Exome Sequencing

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2015-1314 ◽

2015 ◽

Vol 100 (7) ◽

pp. E1022-E1029 ◽

Cited By ~ 37

Author(s):

Ralf Werner ◽

Hartmut Merz ◽

Wiebke Birnbaum ◽

Louise Marshall ◽

Tatjana Schröder ◽

...

Keyword(s):

Exome Sequencing ◽

Gonadal Dysgenesis ◽

Homozygous Mutation ◽

Xy Gonadal Dysgenesis ◽

Desert Hedgehog

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DEAH-box helicase 37 (DHX37) defects are a novel molecular etiology of 46,XY gonadal dysgenesis spectrum

10.1101/477992 ◽

2018 ◽

Author(s):

Thatiana E. da Silva ◽

Nathalia L. Gomes ◽

Antonio M. Lerario ◽

Catherine E. Keegan ◽

Mirian Y. Nishi ◽

...

Keyword(s):

Gonadal Dysgenesis ◽

Autosomal Dominant ◽

Genetic Diagnosis ◽

Gonadal Development ◽

Incomplete Penetrance ◽

Coding Region ◽

Xy Gonadal Dysgenesis ◽

Testicular Regression ◽

Molecular Etiology ◽

Testicular Regression Syndrome

ABSTRACT46,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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In Vitro and Molecular Modeling Analysis of Two Mutant Desert Hedgehog Proteins Associated with 46,XY Gonadal Dysgenesis

DNA and Cell Biology ◽

10.1089/dna.2013.2052 ◽

2013 ◽

Vol 32 (9) ◽

pp. 524-530 ◽

Cited By ~ 8

Author(s):

Josué Joram Castro ◽

Juan Pablo Méndez ◽

Ramón Mauricio Coral-Vázquez ◽

Marvin Antonio Soriano-Ursúa ◽

Pablo Damian-Matsumura ◽

...

Keyword(s):

Molecular Modeling ◽

Gonadal Dysgenesis ◽

Xy Gonadal Dysgenesis ◽

Modeling Analysis ◽

Desert Hedgehog ◽

Hedgehog Proteins

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Clinical and molecular characteristics of patients with 46,XY DSD due to NR5A1 gene mutations

Problems of Endocrinology ◽

10.14341/probl12445 ◽

2020 ◽

Vol 66 (3) ◽

pp. 62-69

Author(s):

Natalia Yu. Kalinchenko ◽

Anna A. Kolodkina ◽

Nadezda Y. Raygorodskaya ◽

Anatoly N. Tiulpakov

Keyword(s):

Gonadal Dysgenesis ◽

Case Reports ◽

Molecular Genetic ◽

Disorders Of Sex Development ◽

Gene Mutations ◽

Gonadal Development ◽

Molecular Genetic Analysis ◽

Molecular Characteristics ◽

Sex Development ◽

Reproductive Axis

Steroidogenic factor 1 (SF1, NR5A1) is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Human mutations in SF1 were initially found in patients with severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in SF1 may also be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function. We have analyzed the gene encoding SF1 (NR5A1) in a cohort of 310 Russian patients with 46,XY disorders of sex development (DSD). Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described. We have not found any phenotype-genotype correlations and any clinical and laboratory markers that would allow to suspect this type of before conducting molecular genetic analysis.

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5′ Region Large Genomic Rearrangements in the BRCA1 Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints

Cancers ◽

10.3390/cancers13133171 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3171

Author(s):

Sandrine M. Caputo ◽

Dominique Telly ◽

Adrien Briaux ◽

Julie Sesen ◽

Maurizio Ceppi ◽

...

Keyword(s):

Brca1 Gene ◽

Genomic Rearrangements ◽

Comparative Genomic ◽

Homologous Region ◽

Exon 2 ◽

Large Genomic Rearrangements ◽

Causality Score ◽

Frequent Site ◽

First Time ◽

Intron 2

Background: Large genomic rearrangements (LGR) in BRCA1 consisting of deletions/duplications of one or several exons have been found throughout the gene with a large proportion occurring in the 5′ region from the promoter to exon 2. The aim of this study was to better characterize those LGR in French high-risk breast/ovarian cancer families. Methods: DNA from 20 families with one apparent duplication and nine deletions was analyzed with a dedicated comparative genomic hybridization (CGH) array, high-resolution BRCA1 Genomic Morse Codes analysis and Sanger sequencing. Results: The apparent duplication was in fact a tandem triplication of exons 1 and 2 and part of intron 2 of BRCA1, fully characterized here for the first time. We calculated a causality score with the multifactorial model from data obtained from six families, classifying this variant as benign. Among the nine deletions detected in this region, eight have never been identified. The breakpoints fell in six recurrent regions and could confirm some specific conformation of the chromatin. Conclusions: Taken together, our results firmly establish that the BRCA1 5′ region is a frequent site of different LGRs and highlight the importance of the segmental duplication and Alu sequences, particularly the very high homologous region, in the mechanism of a recombination event. This also confirmed that those events are not systematically deleterious.

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Pathogenic Determinants of the Mycobacterium kansasii Complex: An Unsuspected Role for Distributive Conjugal Transfer

Microorganisms ◽

10.3390/microorganisms9020348 ◽

2021 ◽

Vol 9 (2) ◽

pp. 348

Author(s):

Florian Tagini ◽

Trestan Pillonel ◽

Claire Bertelli ◽

Katia Jaton ◽

Gilbert Greub

Keyword(s):

Genomic Analysis ◽

Comparative Genomic ◽

Mycobacterium Kansasii ◽

Type Vii Secretion ◽

A Genome ◽

Genes Encoding ◽

Associated Proteins ◽

Immunosuppressed Patients ◽

Type Vii Secretion System ◽

Clinical Records

The Mycobacterium kansasii species comprises six subtypes that were recently classified into six closely related species; Mycobacterium kansasii (formerly M. kansasii subtype 1), Mycobacterium persicum (subtype 2), Mycobacterium pseudokansasii (subtype 3), Mycobacterium ostraviense (subtype 4), Mycobacterium innocens (subtype 5) and Mycobacterium attenuatum (subtype 6). Together with Mycobacterium gastri, they form the M. kansasii complex. M. kansasii is the most frequent and most pathogenic species of the complex. M. persicum is classically associated with diseases in immunosuppressed patients, and the other species are mostly colonizers, and are only very rarely reported in ill patients. Comparative genomics was used to assess the genetic determinants leading to the pathogenicity of members of the M. kansasii complex. The genomes of 51 isolates collected from patients with and without disease were sequenced and compared with 24 publicly available genomes. The pathogenicity of each isolate was determined based on the clinical records or public metadata. A comparative genomic analysis showed that all M. persicum, M. ostraviense, M innocens and M. gastri isolates lacked the ESX-1-associated EspACD locus that is thought to play a crucial role in the pathogenicity of M. tuberculosis and other non-tuberculous mycobacteria. Furthermore, M. kansasii was the only species exhibiting a 25-Kb-large genomic island encoding for 17 type-VII secretion system-associated proteins. Finally, a genome-wide association analysis revealed that two consecutive genes encoding a hemerythrin-like protein and a nitroreductase-like protein were significantly associated with pathogenicity. These two genes may be involved in the resistance to reactive oxygen and nitrogen species, a required mechanism for the intracellular survival of bacteria. Three non-pathogenic M. kansasii lacked these genes likely due to two distinct distributive conjugal transfers (DCTs) between M. attenuatum and M. kansasii, and one DCT between M. persicum and M. kansasii. To our knowledge, this is the first study linking DCT to reduced pathogenicity.

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