ESPEYB17 6. Differences/Disorders of Sex Development and Transgender Medicine Differences/Disorders of Sex Development: Genetics (3 abstracts)
6.8. Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome
McElreavey K , Jorgensen A , Eozenou C , Merel T , Bignon-Topalovic J , Tan DS , Houzelstein D , Buonocore F , Warr N , Kay RGG , Peycelon M , Siffroi JP , Mazen I , Achermann JC , Shcherbak Y , Leger J , Sallai A , Carel JC , Martinerie L , Le Ru R , Conway GS , Mignot B , Van Maldergem L , Bertalan R , Globa E , Brauner R , Jauch R , Nef S , Greenfield A & Bashamboo A
To read the full abstract: Genet Med. 2020, Jan; 22: 150-9. doi: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944638/pdf/41436_2019_Article_606.pdf
Massive parallel sequencing of 145 46,XY DSD patients revealed 13 individuals with heterozygous missense pathogenic variants in the RNA helicase DHX37, explaining 11% of cases of 46,XY gonadal dysgenesis, and 25% of 46,XY testicular regression syndrome (TRS). Likewise, the group of Domenice (1) found familial and sporadic DSD cases with DHX37 pathogenic variants in 17/87 (19%) 46,XY DSD subjects. Half of the individuals with a TRS had a heterozygous DHX37 variant.
The DSD category of 46,XY gonadal dysgenesis is clinically heterogeneous. Abnormal gonadal development leads to a broad phenotype manifesting with different degrees of undervirilization of the external genitalia. TRS belongs to this group of DSD and is characterized by the absence of gonadal tissue on one or both sides due to presumed involution in utero or soon after birth.
DHX37 is an RNA helicase protein, but its exact role especially in relation to sex development is unknown. RNA helicase proteins are involved in basic RNA-related cell processes, such as transcription, splicing, translation and degradation, as well as ribosome biogenesis. They are known to cause ribosomopathies that are yet poorly understood. Homozygous missense variants of DHX37 cause severe microcephaly syndromes without the mention of genital anomalies (2), but those microcephaly-associated DHX37 variants do not lie in the highly conserved helicase core region where all the heterozygous DSD-associated variants were found. In support of the current findings, chromosomal aberrations of 12q24 containing the DHX37 gene cause multiple dysmorphic features including atypical genitalia (3).
It is interesting to observe how an unbiased next generation sequencing approach reveals novel genes causing DSD in biological processes never considered before. DHX37 seems to be an important player in male gonadal differentiation and maintenance. It explains a considerable number of DSD cases classified as gonadal dysgenesis (and especially TRS) and may therefore deserve to be included in first line (routine) genetic analysis of this type of 46,XY DSD, together with SRY, NR5A1/SF1 and MAP3K1.
References:
1. Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum. Da Silva TE, Gomes NL, Lerario AM, Keegan CE, Nishi MY, Carvalho FM, Vilain E, Barseghyan H, Martinez-Aguayo A, Forclaz MV, Papazian R, Pedroso de Paula LC, Costa EC, Carvalho LR, Jorge AAL, Elias FM, Mitchell R, Costa EMF, Mendonca BB, Domenice S. J Clin Endocrinol Metab. 2019, Dec 1; 104: 5923–34; DOI 10.1210/jc.2019-00984, PMID 31287541.
2. Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Karaca E, Harel T, Pehlivan D, Jhangiani SN, Gambin T, Coban Akdemir Z, Gonzaga-Jauregui C, Erdin S, Bayram Y, Campbell IM, Hunter JV, Atik MM, Van Esch H, Yuan B, Wiszniewski W, Isikay S, Yesil G, Yuregir OO, Tug Bozdogan S, Aslan H, Aydin H, Tos T, Aksoy A, De Vivo DC, Jain P, Geckinli BB, Sezer O, Gul D, Durmaz B, Cogulu O, Ozkinay F, Topcu V, Candan S, Cebi AH, Ikbal M, Yilmaz Gulec E, Gezdirici A, Koparir E, Ekici F, Coskun S, Cicek S, Karaer K, Koparir A, Duz MB, Kirat E, Fenercioglu E, Ulucan H, Seven M, Guran T, Elcioglu N, Yildirim MS, Aktas D, Alika?ifo?lu M, Ture M, Yakut T, Overton JD, Yuksel A, Ozen M, Muzny DM, Adams DR, Boerwinkle E, Chung WK, Gibbs RA, Lupski JR. Neuron. 2015 Nov 4;88(3):499–513. doi: 10.1016/j.neuron.2015.09.048. PMID: 26539891.
3. Chromosome 12q24.31-q24.33 deletion causes multiple dysmorphic features and developmental delay: First mosaic patient and overview of the phenotype related to 12q24qter defects. Al-Zahrani J, Al-Dosari N, Abudheim N, Alshidi TA, Colak D, Al-Habit O, Al-Odaib A, Sakati N, Meyer B, Ozand PT, Kaya N. Mol Cytogenet. 2011 Apr 2;4:9. doi: 10.1186/1755-8166-4-9. PMID: 21457577.
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ESPE Yearbook of Paediatric Endocrinology
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