Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort

Eggers, Stefanie; Sadedin, Simon; van den Bergen, Jocelyn A.; Robevska, Gorjana; Ohnesorg, Thomas; Hewitt, Jacqueline; Lambeth, Luke; Bouty, Aurore; Knarston, Ingrid M.; Tan, Tiong Yang; Cameron, Fergus; Werther, George; Hutson, John; O’Connell, Michele; Grover, Sonia R.; Heloury, Yves; Zacharin, Margaret; Bergman, Philip; Kimber, Chris; Brown, Justin; Webb, Nathalie; Hunter, Matthew F.; Srinivasan, Shubha; Titmuss, Angela; Verge, Charles F.; Mowat, David; Smith, Grahame; Smith, Janine; Ewans, Lisa; Shalhoub, Carolyn; Crock, Patricia; Cowell, Chris; Leong, Gary  M.; Ono, Makato; Lafferty, Antony R.; Huynh, Tony; Visser, Uma; Choong, Catherine S.; McKenzie, Fiona; Pachter, Nicholas; Thompson, Elizabeth M.; Couper, Jennifer; Baxendale, Anne; Gecz, Jozef; Wheeler, Benjamin J.; Jefferies, Craig; MacKenzie, Karen; Hofman, Paul; Carter, Philippa; King, Richard I.; Krausz, Csilla; van Ravenswaaij-Arts, Conny M. A.; Looijenga, Leendert; Drop, Sten; Riedl, Stefan; Cools, Martine; Dawson, Angelika; Juniarto, Achmad Zulfa; Khadilkar, Vaman; Khadilkar, Anuradha; Bhatia, Vijayalakshmi; Dũng, Vũ Chí; Atta, Irum; Raza, Jamal; thi Diem Chi, Nguyen; Hao, Tran Kiem; Harley, Vincent; Koopman, Peter; Warne, Garry; Faradz, Sultana; Oshlack, Alicia; Ayers, Katie L.; Sinclair, Andrew H.

doi:10.1186/s13059-016-1105-y

Table 1 Diagnostic DSD genes included in the panel

From: Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort

	Gene	Locus	OMIM	Associated DSD	Inheritance	Coverage (>20×)
Gonadal development
	BMP15	Xp11.22	300247	46,XX DSD—ovarian dysgenesis	AD	95%
	CBX2	17q25.3	602770	46,XY DSD CGD	AR	96%
	DHH	12q13.12	605423	46XY PGD or CGD	AR, AD	99%
	DMRT1	9p24.3	602424	46,XY DSD	AD: deletion	98%
	DMRT2	9p24.3	604935	46,XY DSD	AD: deletion	99%
	FOXL2	3q22.3	608996	POI alone or with blepharophimosis, ptosis, and epicanthus inversus syndrome	AD	94%
	GATA4	8p23.1	600576	46,XY DSD	AD	91%
	NR0B1	Xp21.2	300473	46,XY GD—gain of function	XL-dup	100%
				46,XX CAH with HH	XLR
	NR5A1	9q33.3	184757	46,XY DSD (various)	AD	100%
				46,XX POI	AD
	MAP3K1	5q11.2	600982	46,XY GD	AD	99%
	RSPO1	1p34.3	609595	46,XX OT DSD with palmoplantar hyperkeratosis	AR	94%
	SOX3	Xq27.1	313430	46,XX T or OT DSD—gain of function	XL: dup	92%
	SOX9	17q24.3	608106	46,XY GD and campomelic dysplasia	AD	95%
				46,XX T DSD—duplication	AD: dup
	SRY	Yp11.2	480000	46,XX T DSD—gain of function	Translocation	58%*
				46,XY ovarian DSD	AD
	TSPYL1	6q22.1	604714	46,XY DSD with sudden infant death syndrome	AR	99%
	WNT4	1p36.12	603490	46,XY ovo or OT DSD or 46,XY CGD—duplication	AD: dup	99%
				46,XX T DSD	AR
				46,XX MRKH	AD
	WT1	11p13	607102	Frasier syndrome and Denys-Drash	AD	99%
	ZFPM2	8q23.1	603693	46,XY GD	AD	99%
Gonadal differentiation (androgen synthesis and action)
	AKR1C2	10p15.1	600450	46,XY DSD	AR	82%
	AKR1C4	10p15.1	600451	46,XY DSD	AR	99%
	AMH	19p13.3	600957	PMDS	AR	94%
	AMHR2	12q13.13	600956	PMDS	AR	100%
	AR	Xq12	313700	46,XY DSD. Complete AIS/partial AIS, isolated hypospadia	XL	97%
	ARX	Xp21.3	300215	X-linked lissencephaly with ambiguous genitalia	XL	90%
	ATRX	Xq21.1	300032	46,XY DSD associated with alpha-thalassemia X-linked intellectual disability syndrome	XL	99%
	CDKN1C	11p15.4	600856	Genital anomalies in association with Beckwith-Wiedemann and IMAGE syndrome	AD	61%
	CYB5A	18q22.3	613218	46,XY DSD	AR	99%
	CYP11A1	15q24.1	118485	46,XY sex reversal (partial or complete) with adrenal insufficiency. CAH	AR	100%
				Hypospadias	AD
	CYP11B1	8q24.3	610613	46,XX DSD. CAH due to steroid 11-beta-hydroxylase deficiency	AR	86%
	CYP17A1	10q24.32	609300	46, XY DSD. 17,20-lyase deficiency CAH	AR	100%
	CYP19A1	15q21.2	107910	46, XY DSD. Aromatase deficiency	AR	100%
	CYP21A2	6p21.33	613815	46, XX DSD virilization—21-hydroxylase-deficient CAH	AR	6%
	FGFR2	10q26.13	176943	46,XY GD with craniosynotosis. Apert syndrome	AD	99%
	HSD17B3	9q22.32	605573	46,XY DSD—17-β-hydroxysteroid dehydrogenase III deficiency	AR	100%
	HSD17B4	5q23.1	233400	Perrault syndrome (with ovarian dygeneisis in 46,XX)	AR	98%
	HSD3B2	1p12	613890	46,XY DSD and 46,XX DSD—3-β-hydroxysteroid dehydrogenase-deficient CAH	AR	99%
				Hypospadias	AD
	LHCGR	2p16.3	152790	46,XY DSD—Leydig cell hypoplasia,	AR	100%
				Precocious puberty (male)	AD
	NR3C1	5q31.3	138040	46,XX hyperandrogenism	AD	96%
	POR	7q11.23	124015	Cytochrome P450 oxidoreductase deficiency	AR	95%
	SRD5A2	2p23.1	607306	46,XY DSD. Steroid 5-α-reductase deficiency	AR	100%
				Hypospadias	AD
	STAR	8p11.23	600617	46,XY DSD—cholesterol desmolase-defient CAH	AR	100%
Central causes of hypogonadism
	BBS9	7p14.3	615986	Bardet-Biedl syndrome	AR	96%
	CHD7	8q12.2	608892	CHH or KS. CHARGE syndrome	AD	99%
	FGF8	10q24.32	612702	CHH or KS	AD	88%
	FGFR1	8p11.23	147950	CHH or KS	AD	100%
	FSHB	11p14.1	136530	CHH	AD	98%
	FSHR	2p16.3	136435	46,XX ovarian dysgenesis	AR	100%
	GNRH1	8p21.2	152760	CHH	AR	100%
	GNRHR	4q13.2	138850	CHH	AR	100%
	HESX1	3p14.3	601802	KS or CPHD	AD	98%
	KAL1	Xp22.31	300836	CHH or KS	XL	97%
	KISS1R	19p13.3	604161	CHH or KS	AD	96%
	LEP	7q32.1	164160	CHH with obesity	AR	99%
	LHX3	9q34.3	600577	CPHD	AR	89%
	PROK2	3p13	607002	CHH or KS	AD	99%
	PROKR2	20p12.3	607123	CHH or KS	AD	100%
	PROP1	5q35.3	601538	CPHD	AR	98%
	TAC3	12q13.3	162330	CHH	AR	98%
	WDR11	10q26.12	606417	CHH or KS	AD	93%
Other (isolated hypospadia, cryptorchidism, MRKH):
	ATF3	1q32.3	603148	46,XY isolated hypospadias	AD	97%
	HOXA13	7p15.2	142959	Hand-foot uterus syndrome - MRKH in 46,XX	AD	93%
				Guttmacher syndrome in 46,XY including hypospadias	AD
	INSL3	19p13.11	146738	Cryptorchidism	AD	99%
	MAMLD1	Xq28	300120	Hypospadias	XL	100%
	RXFP2	13q13.1	606655	Cryptorchidism	AD	96%

DSD genes considered as diagnostic that were included in the targeted gene panel. These are grouped according to their main action during development (gonadal development, androgen or hormonal activity, central causes of hypogonadism or other). Gene locus is shown as well as reference number for OMIM (Online Mendelian Inheritance in Man). The associated DSD(s) are shown for each gene. CGD complete gonadal dysgenesis, PGD partial gonadal dysgenesis, POI premature ovarian insufficiency, GD gonadal dysgenesis, CAH congenital adrenal hyperplasia, HH hypogonadotrophic hypogonadism, OT ovo-testicular, T testicular, MRKH Mayer-Rokitansky-Küster-Hauser syndrome, PMDS persistent Müllerian duct syndrome, AIS androgen insensitivity syndrome, CHH congenital hypogonadotrophic hypogonadism, KS Kallmann syndrome, CPHD central pituitary hormone defect. Mode of inheritance is shown: AR autosomal recessive, AD autosomal dominant, XL X-linked, dup duplication (gain of function). The percentage coverage with greater than 20× depth is also shown

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