DHX37 Variant Is One of the Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome/Partial Gonadal Dysgenesis without Müllerian Derivatives

Abstract

<b><i>Introduction:</i></b> The testicular regression syndrome (TRS) is a form of differences of sex development (DSD) in which the testes differentiate and function during early embryonic development, but subsequently regress. The clinical phenotype of TRS often overlaps with that of partial gonadal dysgenesis (PGD). Previous studies have demonstrated a causal association between TRS/PGD and heterozygous missense variants of <i>DHX37</i>. <b><i>Methods:</i></b> We enrolled 11 Japanese 46,XY individuals (from 10 families) with TRS/PGD who exhibited undetected or hypoplastic testes, Müllerian duct regression, and low serum testosterone or anti-Müllerian hormone levels. The subjects underwent targeted sequencing of 36 known causative genes for DSD, PCR-based Sanger sequencing of <i>DHX37</i>, or whole-exome sequencing. <b><i>Results:</i></b> Previously described pathogenic variants or novel nonsense variants (<i>SRY</i>, <i>NR5A1</i>, and <i>DMRT1</i>) were observed in four out of 10 families. Additionally, we identified two heterozygous rare variants of <i>DHX37</i> in four families: a previously reported pathogenic variant (c.923G&gt;A, p.Arg308Gln) in three and a novel likely pathogenic variant (c.1882A&gt;C, p.Thr628Pro) in one. The external genitalia of patients with the <i>DHX37</i> variants varied from female-type to male-type without micropenis. Eighty percent of Japanese patients with TRS/PGD had monogenic disorders including <i>DHX37</i> variant being the most commonly identified (40%). The external or internal genital phenotype of TRS/PGD overlaps between <i>DHX37</i> variant carriers and others. <b><i>Conclusions:</i></b> <i>DHX37</i> variant is one of the common genetic causes in Japanese patients with TRS/PGD without Müllerian derivatives. Genetic test is helpful in detecting <i>DHX37</i>-related TRS/PGD because of the phenotypic diversity of the external genitalia in this disorder.