ECEESPE2025 ePoster Presentations Growth Axis and Syndromes (132 abstracts)
(Un)satisfactory effectiveness of whole-exome sequencing in detecting genetic causes of differential sexual development in 46,XY patients
Ewa Błaszczyk 1,2 , Małgorzata Więcek 1 , Aleksandra Jezela-Stanek 3 , Grzegorz Kudela 4 , Tomasz Koszutski 4 , Karolina Kowalczyk 5 , Jagoda Sikora 1 , Agnieszka Bielska-Brodziak 6 & Aneta Gawlik-Starzyk 1
1Departments of Pediatrics and Pediatric Endocrinology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland; 2Medical University of Silesia, Katowice, Poland, Departments of Pediatrics and Pediatric Endocrinology, Faculty of Medical Sciences in Katowice, Katowice, Poland; 3Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland; 4Department of Pediatric Surgery and Urology, Medical University of Silesia, Katowice, Poland; 5Department of Endocrinological Gynecology, Medical University of Silesia, Katowice, Poland; 6Faculty of Law and Administration, University of Silesia, Katowice, Poland
JOINT1367
Introduction: Differential sexual development (DSD) with 46,XY is a group of rare congenital disorders of the structure and function of the urogenital system resulting from abnormal testicular development or disorders of androgens action. Published data shows that despite the increasingly frequent genetic diagnostics, the causes remain unclear in more than half of cases; with only 34-46% confirmed by molecular testing.
Aim of the study: An attempt to determine the genetic causes of DSD in patients with karyotype 46,XY using the whole-exome sequencing (WES) method.
Patients&Methods: In a consecutive group of 36 children diagnosed in our center as 46,XY DSD (aged 2.4 – 17.9, median age 5.13), 29 raised as boys and 7 raised as girls, with a detailed description of the clinical and biochemical profile, WES was performed.
Results: Pathogenic, potentially pathogenic and variants of uncertain clinical significance (VUS) are presented in the table. No variants that could be related to DSD symptoms were found in the remaining children.
| age [years] | assigned sex [F/M]] | fenotype | gene | variant | classification |
| 5.1 | M | scrotal hypospadias, scrotal transposition, gonads in the labio-scrotal folds | AR | c.2567G>A | |
| pathogenic | |||||
| 6.2 | F | inguinal hernia, absence of the uterus | AR | c.2301del | |
| 3.1 | M | micropenis, bilateral cryptorchidism, scrotal hypoplasia | DHX37 | c.2020C>T | |
| 4.7 | M | bilateral cryptorchidism, micropenis, opening of the urogenital sinus in the scrotum | AR | c.2134C>G | potentially pathogenic |
| 2.7 | M | bilateral testicular atrophy, micropenis | AR | c.1792A>G | |
| 13.7 | F | inguinal hernia, gonads in the inguinal canals | AR | c.2375C>T | |
| 2.7 | F | inguinal hernia | AR | c.2375C>T | |
| 8.0 | F | labioscrotal fold with gonad on the right side, phalanx | NR5A1 | c. 11_12del | VUS |
| 6.2 | M | bilateral cryptorchidism | DHX37 | c.2598_2600delGTAinsATG | |
| 7.4 | M | penile hypospadias, right-sided cryptorchidism | AR | c.721A>G | |
| 4.2 | M | hypoplasia of the right testicle, left-sided cryptorchidism | MAMLD1 | c.834C>A | |
| 3.9 | M | scrotal hypospadias, absent left testicle | SOS2 | c.586G>C | |
| 2.4 | M | bilateral cryptorchidism, micropenis, scrotal hypoplasia | FAM111 | c.1660G>C | |
| 14.1 | M | atrophic testicles bilaterally | DHX37 | c.1516G>A |
Conclusions: Currently WES is the state of the art method in terms of the quantity of covered genes, nevertheless genetic cause of DSD could still only be identified in less than half of 46,XY DSD patients, for whom the “glass is half full”. It is recommended to reexamine the WES results every 12 months and to verify the status of the identified VUS in the biological parents of the patients.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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