Background: 46,XY gonadal dysgenesis (GD) is a spectrum disorder which lead to variable degrees of atypical external genitalia, ranging from female to micropenis and absent of gonadal tissue (known as Embryonic Testicular Regression Syndrome -ETRS). Most patients with 46,XY GD remains without a molecular diagnosis.
Objective: To report the DEAH-box helicase 37 gene (DHX37) as a novel candidate for the GD etiology.
Patients and methods: We studied 12 familial cases from 6 non-consanguineous families by whole exome sequencing, one familial case and 69 sporadic cases by target massively parallel sequencing, including 41 patients with GD, 16 patients with ETRS and 32 patients classified as 46,XY disorder of sex development of unknown etiology (UDSD) due to previous gonadectomy or an inconclusive hormone profile. An amplicon-based capture panel of 63 genes related to DSD for targeted sequencing was used. Sequencing was performed in the Illumina platforms. Paired-end reads were aligned to the hg19 assembly of the human genome with BWA-MEM. Variants were called and annotated with Platypus and ANNOVAR, respectively. Two sporadic cases and one family with ETRS had DHX37 studied by Sanger sequencing. Eighty-seven patients were Brazilian, including 6 families, one sporadic case was Chinese-American and two families were Argentinean and Chilean.
Results: Six different missense variants in DHX37 were identified in 8 sporadic cases and in 11 patients from 5 families. All variants are absent or in low frequency (<0.0002) in population (gnomAD) and Brazilian databases and are classified as deleterious by at least 8 prediction tools. The variant p.R308Q was recurrent in 2 non-related ETRS families and in three sporadic cases, including the Chinese-American patient. The p.R674W also recurred in the Argentinean and Chilean ETRS families and in one sporadic GD patient, who also bored a novel GATA4 p.P368R. Another three DHX37 variants were identified in three sporadic UDSD patients and one of them also harbored the novel NR5A1 p.G26V. All these variants are heterozygous and the segregated ones disclosed an autosomal dominant inheritance. One sporadic case of ETRS from a consanguineous family was homozygous for the DHX37 p.R151W. DHX37 is expressed in germ cells at different stages of maturation, as shown by immunohistochemical analysis.
Conclusion: The identification of several deleterious variants in DHX37, as monogenic or in digenic inheritance in familial and sporadic cases of 46,XY DSD patients from different parentage, reinforces it is a strong candidate gene for the spectrum of GD phenotypes.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology