(Un)satisfactory effectiveness of whole-exome sequencing in detecting genetic causes of differential sexual development in 46,XY patients

Ewa Błaszczyk; Małgorzata Więcek; Aleksandra Jezela-Stanek; Grzegorz Kudela; Tomasz Koszutski; Karolina Kowalczyk; Jagoda Sikora; Agnieszka Bielska-Brodziak; Aneta Gawlik-Starzyk

doi:10.1530/endoabs.110.EP751

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Endocrine Abstracts (2025) 110 EP751 | DOI: 10.1530/endoabs.110.EP751

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

Author affiliations

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.

Table 1
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.