Table 1.
Primary gene list for whole-exome variant analysis of disorders of sex development (DSDs)
| Gene name | Alternative gene name(s) | Exome coverage | Associated condition(s) |
|---|---|---|---|
| Genes associated with sex determination (e.g., gonadal dysgenesis, testicular DSD, and ovotesticular DSD) | |||
| RSPO1 | RSPONDIN | 100% | 46,XX DSD and palmoplantar hyperkeratosis |
| SOX9 | SRA1 | 100% | 46,XX DSD and campomelic dysplasia |
| SRY | TDF | 100% | 46,XX testicular DSD and 46,XY ovarian DSD |
| CBX2 | CDCA6 | 99% | 46,XY DSD |
| NR0B1 | DAX1/AHCH | 98% | 46,XY DSD |
| NR5A1 | SF1 | 97% | 46,XY DSD and 46,XX premature ovarian failure |
| WWOX | 95% | 46,XY DSD | |
| DMRT1 | DMT1 | 93% | 46,XY gonadal dysgenesis |
| WNT4 | 92% | 46,XX DSD | |
| MAP3K1 | MEKK | 89% | 46,XY gonadal dysgenesis |
| DHH | HHG | 85% | 46,XY partial or complete gonadal dysgenesis |
| LHX1 | 85% | Mayer-Rokitansky-Küster-Hauser syndrome | |
| SOX3 | PHP | 78% | 46,XX and 46,XY DSD |
| WT1 | AWT1/WAGR | 77% | WAGR (Wilms’s tumor, aniridia, genital anomalies, and mental retardation) |
| DMRT2 | 76% | 46,XY gonadal dysgenesis | |
| GATA4 | 64% | 46,XY ambiguous genitalia or gonadal dysgenesis | |
| AMH | MIS | 59% | Persistent Müllerian duct syndrome |
| Genes associated with differentiation (e.g., steroid synthesis/receptors) | |||
| AKR1C4 | 3-alpha-HSD/C11/CDR/DD4/HAKRA | 100% | 46,XY DSD |
| AMHR2 | MISR2 | 100% | Persistent Müllerian duct syndrome |
| ATRX | RAD54 | 100% | Alpha-thalassemia X-linked intellectual disability syndrome |
| CYP11A1 | P450SCC | 100% | Congenital adrenal hyperplasia |
| CYP17A1 | 100% | 17-Alpha-hydroxylase-deficient congenital adrenal hyperplasia | |
| FGFR2 | 100% | Apert syndrome | |
| HSD17B3 | SDR12C2 | 100% | 17-Beta-hydroxysteroid dehydrogenase III deficiency |
| HSD3B2 | SDR11E2 | 100% | 3-Beta-hydroxysteroid dehydrogenase–deficient congenital adrenal hyperplasia |
| POR | 100% | Cytochrome P450 oxidoreductase deficiency | |
| SRD5A2 | 100% | Steroid 5-alpha-reductase deficiency | |
| STAR | StAR/STARD1 | 100% | Cholesterol desmolase–deficient congenital adrenal hyperplasia |
| AR | AIS | 95% | Complete or partial androgen insensitivity syndrome |
| LHCGR | LCGR/LGR2/LHR/ULG5 | 92% | Leydig cell hypoplasia |
| AKR1C2 | BABP/DD/DD2/HAKRD/MCDR2 | 91% | 46,XY DSD |
| CYP21A2 | CA21H/CAH1/CPS1 | 79% | 21-Hydroxylase-deficient congenital adrenal hyperplasia |
| FOXL2 | BPES | 79% | Blepharophimosis, ptosis, and epicanthus inversus |
| MAMLD1 | CG1/F18/CXORF6 | 69% | Hypospadias |
| ARX | CT121/EIEE1/ISSX | 50% | X-linked lissencephaly with ambiguous genitalia |
| Genes found to be central causes of hypogonadism | |||
| ARL6 | BBS3 | 100% | Bardet-Biedl syndrome |
| BBS2 | 100% | Bardet-Biedl syndrome | |
| BBS5 | 100% | Bardet-Biedl syndrome | |
| BBS7 | BBS2L1/FLJ10715 | 100% | Bardet-Biedl syndrome |
| BBS9 | B1/PTHB1 | 100% | Bardet-Biedl syndrome |
| BBS10 | FLJ23560 | 100% | Bardet-Biedl syndrome |
| BBS12 | FLJ35630/FLJ41559 | 100% | Bardet-Biedl syndrome |
| CHD7 | FLJ20357/FLJ20361/KIAA1416 | 100% | Kallmann syndrome (isolated GnRH deficiency with anosmia), normosmic isolated GnRH deficiency, and CHARGE syndrome |
| GNRH1 | GNRH/GRH/LHRH | 100% | Isolated abnormality in GnRH secretion or response |
| GNRHR | LHRHR | 100% | Isolated abnormality in GnRH secretion or response |
| HESX1 | ANF/RPX | 100% | Combined pituitary hormone deficiency |
| HFE | HLA-H | 100% | Hemochromatosis |
| LEP | 100% | Morbid obesity | |
| MKKS | BBS6 | 100% | Bardet-Biedl syndrome and McKusick-Kaufman syndrome |
| PROKR2 | GPR73b/GPRg2/PKR2 | 100% | Kallmann sydrome (isolated GnRH deficiency with anosmia) and normosmic isolated GnRH deficiency |
| PROP1 | 100% | Combined pituitary hormone deficiency | |
| TAC3 | NKB/ZNEUROK1 | 100% | Isolated abnormality in GnRH secretion or response |
| TACR3 | Neurokinin beta receptor/NK3R | 100% | Isolated abnormality in GnRH secretion or response |
| TRIM32 | BBS11 | 100% | Bardet-Biedl syndrome |
| TTC8 | BBS8 | 100% | Bardet-Biedl syndrome and autosomal recessive retinitis pigmentosa |
| BBS1 | 99% | Bardet-Biedl syndrome | |
| BBS4 | 99% | Bardet-Biedl syndrome | |
| FGFR1 | BFGFR/CD331/CEK/FLG | 98% | Kallmann syndrome (isolated GnRH deficiency with anosmia), normosmic isolated GnRH deficiency, and Pfeiffer syndrome |
| PCSK1 | PC1/PC3/SPC3 | 98% | Morbid obesity |
| KAL1 | Anosmin-1/KALIG-1 | 95% | Kallmann syndrome (isolated GnRH deficiency with anosmia) |
| LEPR | CD295/OBR | 95% | Morbid obesity |
| LHX3 | 87% | Combined pituitary hormone deficiency | |
| FGF8 | AIGF | 79% | Kallmann syndrome (isolated GnRH deficiency with anosmia) and normosmic isolated GnRH deficiency |
| PROK2 | BV8/KAL4/MIT1/PK2 | 76% | Kallmann syndrome (isolated GnRH deficiency with anosmia) and normosmic isolated GnRH deficiency |
| KISS1R | AXOR12/HOT7T175 | 54% | Isolated abnormality in GnRH secretion or response |