Differences in sex development

Gene: DMRT1

Green List (high evidence)

Comment on list classification: There are now more than 3 cases reported in literature with heterozygous DMRT1 missense variants and gonadal dysgenesis. Based on available evidence, this gene can be promoted to Green on Differences in sex development at the next update, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.

Created: 25 Sep 2026, 3:07 p.m. | Last Modified: 25 Sep 2026, 3:08 p.m.

Panel Version: 4.26

PMID: 36110220 Zidoune H, et al., 2022
Large study of developmental disorders cohort from North Africa. See suppl material for case details.
P_73 - 29 days old male, het for de novo variant NM_021951.3(DMRT1):c.149G>C (p.Ser50Thr); phenotype: Genital bud, preputial orifice and perineal orifice, bifid labioscrotal folds, BC, NPG. Patient was also hemizygous for MAMLD1:NM_005491:c.C2075T:p.A692V - MAMLD1 is associated with Hypospadias 2, X-linked, OMIM:300758. Difficult to decouple the effect of each variant.

PMID: 31745530 Buonocore et al., 2019
Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25).
A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling.

PMID: 27711951 Chauhan et al., 2017
Study of 10 patients with 46,XY karyotype and variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln.

PMID: 28295047 Fan et al., 2017
P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4.

DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).

Created: 25 Sep 2026, 2:45 p.m. | Last Modified: 29 Sep 2026, 10:53 a.m.

Panel Version: 4.27

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
46 XY differences of sex development, MONDO:0020040

Publications

• 27711951
• 28295047
• 31745530
• 33057194
• 36110220

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

I don't know

Variants affecting DMRT1 have been reported in cases with 46,XY disorders/differences of sex development. PMID: 24934491 reports NM_021951.3(DMRT1):c.671A>G (p.Asn224Ser) in 2 unrelated azoospermic men with complete bilateral Sertoli cell-only syndrome and decreased testicular volume by ultrasound. PMID: 26139570 reports NM_021951.2 c.-223_-219CGAAA>T in the promoter of DMRT1, which is a region shown to be involved in the repression of Dmrt1 expression in rat and mouse Sertoli cells (PMID:11870074). Therefore this promoter variants could result in disruption of DMRT1 regulation. PMID: 39936125 reports four different deletions, which all encompass the DMRT1 region (9p24.3p23 - 9p24) in four unrelated cases with gonadal dysgenesis and .

Created: 17 Mar 2025, 11:24 a.m. | Last Modified: 17 Mar 2025, 11:24 a.m.

Panel Version: 4.11

Comment on publications: PMID: 39936125 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

Created: 17 Mar 2025, 11:14 a.m. | Last Modified: 17 Mar 2025, 11:14 a.m.

Panel Version: 4.11

Comment when marking as ready: Not associated with phenotype in OMIM or G2P. Probably involved in spermatogenesis, (from animal studies), but so far too few variants reported.

Created: 1 Nov 2016, 2:04 p.m.

Red List (low evidence)

Very rare cause of gonadal dysgenesis. More often due to monosomic deletion of Chr 9. Point mutants may have dominant negative effect.

Created: 4 Feb 2016, 4:10 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted