DMRT1 – 46,XY disorder of sex development

Heterozygous loss of DMRT1 due to somatic mosaic ring chromosome 9 structures has been reported in a 12-year-old 46,XY individual presenting as female with normal external genitalia, undeveloped gonads, intellectual disability and short stature, mimicking Turner syndrome—cytogenetic and FISH analysis confirmed haploinsufficiency of DMRT1 in the majority of cells (PMID:29760778). Submicroscopic deletions encompassing DMRT1 have also been identified in array-CGH and MLPA screens of patients with 46,XY disorder of sex development (PMID:26542297), although targeted screening of 33 non-syndromic 46,XY gonadal dysgenesis patients found no DMRT1 coding mutations (PMID:22939835). These limited case series provide sparse genetic evidence with no documented familial segregation or recurrent point mutations.

Functional studies demonstrate multiple DMRT1 isoforms in human testis with distinct expression levels, and zebrafish Dmrt1 splicing patterns support a conserved role in gonadal differentiation (PMID:15809088). Collectively, these data suggest that DMRT1 haploinsufficiency can disrupt testis determination, but the rarity of reported cases and lack of penetrance data limit the strength of the association.

Key take-home: DMRT1 haploinsufficiency is a rare cause of 46,XY disorder of sex development; cytogenetic and CNV analysis should be considered in unexplained cases.

References

• Molecular cytogenetics • 2018 • Loss of DMRT1 gene in a Mos 45,XY,-9[8]/46,XY,r(9)[29]… female presenting with short stature PMID:29760778
• Molecular and cellular pediatrics • 2015 • Submicroscopic copy-number variations associated with 46,XY disorders of sex development PMID:26542297
• European journal of medical genetics • 2012 • Absence of inactivating mutations and deletions in the DMRT1 and FGF9 genes in a large cohort of 46,XY patients with gonadal dysgenesis PMID:22939835
• Biochemical and biophysical research communications • 2005 • Gene structure, multiple alternative splicing, and expression in gonads of zebrafish Dmrt1 PMID:15809088

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