Table 1.

Molecular Genetics of Nonsyndromic Disorders of Testicular Development

Gene 1 / Pathogenic MechanismProportion of Nonsyndromic DSD Attributed to Variants in GeneMOI
DHH Rare 2Rare 2AR
DMRT1 3Rare 4Rare 4AD
DHX37 20% 510%-15% 5AD
MAP3K1 10%-18% 610%-18% 6AD
NR5A1 10%-15% 710% of NR5A1 variants 7AD
SOX8 Rare 8Rare 8AD
SOX9 regulatory regionsRare 9Rare 9AD
SRY Rare 1010%-15% 10YL
Hemizygous duplication at Xp21 11, 12Rare 13Rare 13XL

AD = autosomal dominant; AR = autosomal recessive; CGD = complete gonadal dysgenesis; DSD = differences/disorders of sex development; MOI = mode of inheritance; XL = X-linked; YL = Y-linked


Genes are listed in alphabetic order.


Biallelic pathogenic variants in DHH have been confirmed by functional studies to cause 46,XY DSD and 46,XY CGD. However, heterozygous pathogenic DHH variants are unlikely to cause DSD [Ayers et al 2019]. Some individuals with biallelic pathogenic DHH variants have 46,XY DSD and develop peripheral neuropathy presenting between ages 20 and 30 years (OMIM 607080) [Sato et al 2017, Baldinotti et al 2018].


Pathogenic variants may include heterozygous complete or partial deletions of DMRT1 or pathogenic DMRT1 sequence variants.


Deletions of 9p24 are a recurrent cause of 46,XY DSD and 46,XY CGD. While most reports are of individuals who have larger deletions of this chromosome region leading to syndromic features (see Table 3), rare individuals with a nonsyndromic 46,XY disorder of testicular development and a small complete or partial deletion encompassing DMRT1 or a pathogenic variant in DMRT1 have been reported [Zarkower & Murphy 2022].


DHX37 pathogenic variants may explain 20% of cases of testicular regression syndrome [Elzaiat et al 2022, Gomes et al 2022].


NR5A1 pathogenic variants have been associated with a wide range of phenotypes including isolated 46,XY partial and complete gonadal dysgenesis, 46,XY undervirilization, vanishing testes, and male infertility. 46,XX individuals can have premature ovarian insufficiency, and some have been reported to have testicular or ovotesticular DSD. Adrenal insufficiency is a rare finding [Fabbri-Scallet et al 2020].


Disruption of the SOX8 locus has been reported to cause 46,XY CGD and 46,XY DSD [Portnoi et al 2018].


Deletion of SOX9 upstream enhancers has been reported to cause 46,XY CGD [Croft et al 2018]. Pathogenic variants in SOX9 cause campomelic dysplasia (see Table 3).


Hemizygous pathogenic variants in SRY primarily cause a 46,XY CGD phenotype [Buonocore et al 2019]. Rare reports of milder 46,XY DSD phenotypes in the setting of mosaicism for an SRY pathogenic variant have been published [Isidor et al 2009, Roberts et al 2018].


Genes involved in the duplications include MAGEB, NR0B1, CXorf21, GK, and a portion of MAP3K7IP3. However, NR0B1 (DAX1) is presumed to be the gene responsible for the phenotype, although this has not been definitively proven [Barbaro et al 2012, García-Acero et al 2019].


Hemizygous deletions and pathogenic variants in NR0B1 are known to cause a different phenotype (X-linked adrenal hypoplasia congenita).


From: Nonsyndromic Disorders of Testicular Development Overview

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