DHX37 – 46,XY Sex Reversal 11

46,XY sex reversal 11 (SRXY11) is a form of 46,XY disorders of sex development (DSD) characterized by ambiguous genitalia and partial to complete gonadal dysgenesis ([PMID:38769888]). DHX37 encodes a DEAH-box RNA helicase essential for ribosome biogenesis and has emerged as a key gene in testis determination and maintenance.

Initial genetic evidence arose from a cohort of 87 individuals with 46,XY DSD, in which four heterozygous missense DHX37 variants were identified in five unrelated families (n = 11 affected relatives), implicating autosomal dominant inheritance ([PMID:31287541]). A subsequent study of 145 individuals uncovered 13 heterozygous pathogenic DHX37 variants, including five de novo events (p = 1.5×10⁻⁵) and significant enrichment of rare missense changes versus controls (p = 5.8×10⁻¹⁰) ([PMID:31337883]).

Recurrent alleles p.Arg308Gln and p.Arg674Trp account for approximately half of index cases, underscoring mutational hotspots in conserved helicase domains. For example, c.923G>A (p.Arg308Gln) has been reported in multiple families and sporadic patients, reinforcing its pathogenic role.

Segregation analysis confirmed variant co-segregation with SRXY11 in five pedigrees encompassing 11 affected relatives, consistent with high penetrance autosomal dominant transmission ([PMID:31287541]).

Functional assays demonstrate that the novel p.Arg671Thr variant does not alter subcellular localization but leads to markedly reduced DHX37 protein levels by Western blotting, indicating impaired protein stability ([PMID:38769888]). Immunohistochemistry of human testis further localizes DHX37 to germ and Leydig cells during critical stages of testicular development.

Together, these data support a mechanism of haploinsufficiency or dominant-negative disruption of ribosome biogenesis in gonadal differentiation. No studies to date dispute this association.

Key Take-home: DHX37 heterozygous missense variants are a validated autosomal dominant cause of 46,XY sex reversal 11 and should be included in diagnostic DSD gene panels.

References

• The Journal of clinical endocrinology and metabolism • 2019 • Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum PMID:31287541
• Genetics in medicine • 2020 • Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome PMID:31337883
• Molecular genetics & genomic medicine • 2024 • Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development PMID:38769888

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