Table II.
List of genes linked to male infertility or abnormal genitourinary development phenotypes classified as moderate evidence or higher.
| Gene | Location | Disorder | Inheritance pattern | Score | Conclusion |
|---|---|---|---|---|---|
| Isolated infertility | |||||
| ADGRG2 | Xp22.13 | Congenital bilateral absence of the vas deferens; OMIM:300985 | XL | 16 | Definitive |
| AR | Xq12 | Non-obstructive azoospermia; OMIM:NA | XL | 17 | Definitive |
| ARMC2 | 6q21 | Multiple morphological abnormalities of the sperm flagella; OMIM:618433 | AR | 11 | Moderate |
| AURKC | 19q13.43 | Macrozoospermia; OMIM:243060 | AR | 17 | Definitive |
| CFAP251 | 12q24.31 | Multiple morphological abnormalities of the sperm flagella; OMIM:NA (PS258150) | AR | 17 | Definitive |
| CFAP43 | 10q25.1 | Multiple morphological abnormalities of the sperm flagella; OMIM:617592 | AR | 17 | Definitive |
| CFAP44 | 3q13.2 | Multiple morphological abnormalities of the sperm flagella; OMIM:617593 | AR | 17 | Definitive |
| CFAP65 | 2q35 | Multiple morphological abnormalities of the sperm flagella; OMIM:618664 | AR | 15 | Strong |
| CFAP69 | 7q21.13 | Multiple morphological abnormalities of the sperm flagella; OMIM:617959 | AR | 13 | Strong |
| CFAP91 | 3q13.33 | Multiple morphological abnormalities of the sperm flagella; OMIM:609910 | AR | 9 | Moderate |
| CFTR | 7q31.2 | Congenital bilateral/unilateral absence of vas deferens; OMIM:277180 | AR | 17 | Definitive |
| DMRT1 | 9p24.3 | Non-obstructive azoospermia; OMIM:NA (PS258150) | AD | 10 | Moderate |
| DNAH1 | 3p21.1 | Multiple morphological abnormalities of the sperm flagella; OMIM:617576 | AR | 17 | Definitive |
| DNAH17 | 17q25.3 | Multiple morphological abnormalities of the sperm flagella; OMIM:618643 | AR | 15 | Strong |
| DPY19L2 | 12q14.2 | Globozoospermia; OMIM:613958 | AR | 16 | Definitive |
| FANCM | 14q21.2 | Oligozoospermia; OMIM:NA (PS258150) | AR | 13 | Strong |
| FSIP2 | 2q32.1 | Multiple morphological abnormalities of the sperm flagella; OMIM:618153 | AR | 12 | Moderate |
| KLHL10 | 17q21.2 | Oligozoospermia; OMIM:615081 | AD | 10.5 | Moderate |
| M1AP | 2p13.1 | Non-obstructive azoospermia; OMIM:619108 | AR | 12 | Moderate |
| MEI1 | 22q13.2 | Non-obstructive azoospermia; OMIM:NA (PS258150) | AR | 13 | Strong |
| PLCZ1 | 12p12.3 | Fertilization failure; OMIM:617214 | AR | 16 | Definitive |
| PMFBP1 | 16q22.2 | Acephalic spermatozoa; OMIM:618112 | AR | 14 | Strong |
| QRICH2 | 17q25.1 | Multiple morphological abnormalities of the sperm flagella; OMIM:618341 | AR | 12 | Moderate |
| SEPTIN12 | 16p13.3 | Multiple morphological abnormalities of the sperm flagella; OMIM:614822 | AD | 11.5 | Moderate |
| SPEF2 | 5p13.2 | Multiple morphological abnormalities of the sperm flagella; OMIM:618751 | AR | 14.75 | Strong |
| STAG3 | 7q22.1 | Non-obstructive azoospermia; OMIM:NA (PS258150) | AR | 11.5 | Moderate |
| SUN5 | 20q11.21 | Acephalic sperm; OMIM:617187 | AR | 16.75 | Definitive |
| SYCP2 | 20q13.33 | Severe oligozoospermia; OMIM:258150 | AD | 10.75 | Moderate |
| SYCP3 | 12q23.2 | Non-obstructive azoospermia; OMIM:270960 | AD | 14 | Strong |
| TEX11 | Xp11 | Non-obstructive azoospermia; OMIM:309120 | XL | 16 | Definitive |
| TEX14 | 17q22 | Non-obstructive azoospermia; OMIM:617707 | AR | 10 | Moderate |
| TEX15 | 8p12 | Non-obstructive azoospermia; OMIM:617960 | AR | 13.5 | Strong |
| TSGA10 | 2q11.2 | Acephalic spermatozoa; OMIM:617961 | AR | 10.25 | Moderate |
| TTC29 | 4q31.22 | Multiple morphological abnormalities of the sperm flagella; OMIM:618745 | AR | 14.5 | Strong |
| USP26 | Xq26.2 | Azoospermia or oligozoospermia; OMIM:NA (PS258150) | XL | 9.5 | Moderate |
| XRCC2 | 7q36.1 | Non-obstructive azoospermia; OMIM: 617247 | AR | 10 | Moderate |
| Syndromic infertility | |||||
| APOA1 | 11q23.3 | Testicular amyloidosis; OMIM:105200 | AD | 12 | Moderate |
| CATSPER2 | 15q15.3 | Deafness infertility syndrome; OMIM: 611102 | AR | 11 | Moderate |
| CCDC39 | 3q26.33 | Primary ciliary dyskinesia; OMIM:613807 | AR | 13 | Strong |
| CCDC40 | 17q25.3 | Primary ciliary dyskinesia; OMIM:613808 | AR | 13.25 | Strong |
| CDC14A | 1p21.2 | Oligoasthenoteratozoospermia OMIM:608653 | AR | 9 | Moderate |
| CEP290 | 12q21.32 | Leber congenital amaurosis; OMIM:611755 | AR | 9 | Moderate |
| DNAAF2 | 14q21.3 | Primary ciliary dyskinesia; OMIM:612518 | AR | 12.25 | Moderate |
| DNAAF4 | 15q21.3 | Primary ciliary dyskinesia; OMIM:615482 | AR | 13 | Strong |
| DNAAF6 | Xq22.3 | Primary ciliary dyskinesia: OMIM:300991 | XL | 15 | Strong |
| FANCA | 16q24.3 | Occult Fanconi anaemia; OMIM:NA (PS227650) | AR | 10 | Moderate |
| LRRC6 | 8q24.22 | Primary ciliary dyskinesia; OMIM:614935 | AR | 13.5 | Strong |
| MNS1 | 15q21.3 | Asthenoteratozoospermia; OMIM:NA (PS258150) | AR | 9.5 | Moderate |
| NLRP3 | 1q44 | Muckle-Wells Syndrome; OMIM:191900 | AD | 9 | Moderate |
| PKD1 | 16p13.3 | Polycystic kidney disease and asthenozoospermia; OMIM:173900 | AD | 11.25 | Moderate |
| RSPH3 | 6q25.3 | Primary ciliary dyskinesia; OMIM:616481 | AR | 10.25 | Moderate |
| SPEF2 | 5p13.2 | Primary ciliary dyskinesia with multiple morphological abnormalities of the sperm flagellum; OMIM:618751 | AR | 12 | Moderate |
| TRIM37 | 17q22 | Mulibrey nanism; OMIM:253250 | AR | 10 | Moderate |
| Reproductive system syndrome/endocrine disorder | |||||
| AMH | 19p13.3 | Persistent Müllerian duct syndrome; OMIM:261550 | AR | 17 | Definitive |
| AMHR2 | 12q13.13 | Persistent Müllerian duct syndrome; OMIM:261550 | AR | 17 | Definitive |
| ANOS1 | Xp22.31 | Kallmann syndrome; OMIM:308700 | XL | 16 | Definitive |
| ANOS1 | Xp22.31 | Isolated hypogonadotropic hypogonadism (normosmic); OMIM:308700 | XL | 13 | Strong |
| AR | Xq12 | Partial androgen insensitivity syndrome; OMIM:312300/300633 | XL | 17 | Definitive |
| BMP4 | 14q22.2 | Hypospadias; OMIM:NA (PS300633). Micropenis; OMIM:NA | AD | 10.25 | Moderate |
| BMP7 | 20q13.31 | Hypospadias; OMIM:NA (PS300633) | AD | 10.25 | Moderate |
| BNC2 | 9p22.3-p22.2 | Hypospadias; OMIM:NA (PS300633) | AD | 10 | Moderate |
| CCDC141 | 2q31.2 | Kallmann syndrome; OMIM:NA (PS147950) | AR | 12 | Moderate |
| CHD7 | 8q12.2 | Kallmann syndrome without CHARGE phenotype; OMIM:612370 | AD | 16 | Definitive |
| CHD7 | 8q12.2 | Isolated hypogonadotropic hypogonadism (normosmic) without CHARGE phenotype; OMIM:612370 | AD | 17 | Definitive |
| CYP11A1 | 15q24.1 | Congenital adrenal insufficiency with partial 46,XY sex reversal (Prader stage 4; 5 or 6); OMIM:613743 | AR | 16 | Definitive |
| CYP11B1 | 8q24.3 | 46,XX Disorders of sexual development (Prader scale 4; 5 or 6) due to congenital adrenal hyperplasia (11-beta-hydroxylase deficiency); OMIM: 202010 | AR | 17 | Definitive |
| CYP17A1 | 10q24.32 | 46,XY Disorders of sexual development (Prader stage 4, 5 or 6) due to 17-alpha-hydroxylase/17,20-lyase deficiency; OMIM:202110 | AR | 16 | Definitive |
| CYP19A1 | 15q21.2 | Aromatase excess syndrome with gynaecomastia; OMIM:139300 | AD | 17 | Definitive |
| CYP19A1 | 15q21.2 | 46,XX Disorders of sexual development (Prader scale 4; 5 or 6) due to aromatase deficiency; OMIM:613546 | AR | 16 | Definitive |
| CYP19A1 | 15q21.2 | Male infertility in 46,XY men due to aromatase deficiency; OMIM:613546 | AR | 9.5 | Moderate |
| CYP21A2 | 6p21.33 | Classic congenital adrenal hyperplasia; OMIM:201910 | AR | 17 | Definitive |
| CYP21A2 | 6p21.33 | Non-classic adrenal hyperplasia (late onset or no CAH symptoms); OMIM: 201910 | AR | 17 | Definitive |
| DHX37 | 12q24.31 | 46,XY Disorders of sexual development (Prader scale 4; 5 or 6); OMIM:273250 | AD | 11 | Moderate |
| FGF17 | 8p21.3 | Kallmann syndrome; OMIM:615270 | AD | 9 | Moderate |
| FGF8 | 10q24.32 | Kallmann syndrome; OMIM: 612702 | AD | 10 | Moderate |
| FGF8 | 10q24.32 | Isolated hypogonadotropic hypogonadism (normosmic); OMIM:612702 | AD | 14 | Strong |
| FGFR1 | 8p11.23 | Kallmann syndrome; OMIM:147950 | AD | 17 | Definitive |
| FGFR1 | 8p11.23 | Isolated hypogonadotropic hypogonadism (normosmic); OMIM:147950 | AD | 17 | Definitive |
| FSHB | 11p14.1 | Isolated hypogonadotropic hypogonadism; OMIM:229070 | AR | 12.25 | Moderate |
| FSHR | 2p16.3 | Hypergonadotropic hypogonadism; OMIM:NA (PS147950) | AR | 11 | Moderate |
| GATA4 | 8p23.1 | 46,XY Disorders of sexual development (Prader scale 4; 5 or 6) resulting in anomalies of testicular development; OMIM:615542 | AD | 13 | Strong |
| GNRH1 | 8p21.2 | Isolated hypogonadotropic hypogonadism; OMIM:614841 | AR | 13.5 | Strong |
| GNRHR | 4q13.2 | Isolated hypogonadotropic hypogonadism; OMIM:146110 | AR | 17 | Definitive |
| HS6ST1 | 2q14.3 | Kallmann syndrome; OMIM:614880 | AD | 9.5 | Moderate |
| HSD17B3 | 9q22.32 | 46,XY Disorders of sexual development (Prader scale 4; 5 or 6) resulting in anomalies of testicular development; OMIM:264300 | AR | 16 | Definitive |
| HSD3B2 | 1p12 | Adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency; OMIM:201810 | AR | 16.5 | Definitive |
| IGSF10 | 3q25.1 | Delayed puberty; OMIM:NA (PS147950) | AD | 9.25 | Moderate |
| IL17RD | 3p14.3 | Kallmann syndrome with hearing loss; OMIM:615267 | AD | 14.5 | Strong |
| INSL3 | 19p13.11 | Cryptorchidism; OMIM:219050 | AD | 12 | Moderate |
| KISS1R | 19p13.3 | Kallmann syndrome; OMIM:614837 | AR | 9 | Moderate |
| KISS1R | 19p13.3 | Isolated hypogonadotropic hypogonadism (normosmic); OMIM:614837 | AR | 17 | Definitive |
| LHB | 19q13.33 | Isolated Hypogonadotropic hypogonadism; OMIM:228300 | AR | 16.5 | Definitive |
| LHCGR | 2p16.3 | Leydig cell dysfunction with hypogonadism; OMIM:238320 | AR | 16.5 | Definitive |
| LHCGR | 2p16.3 | Male precocious puberty; OMIM:176410 | AD | 17 | Definitive |
| MAMLD1 | Xq28 | 46,XY Disorders of Sex Development (Prader scale 4; 5 or 6); OMIM:300758 | XL | 15 | Strong |
| MYRF | 11q12.2 | 46XY Disorders of Sex Development, OMIM gene 608329 | AD | 14.5 | Strong |
| NR0B1 | Xp21.2 | Congenital adrenal hypoplasia; OMIM:300200 | XL | 17 | Definitive |
| NR0B1 | Xp21.2 | Late-onset adrenal failure or isolated hypogonadotropic hypogonadism; OMIM:NA (PS147950) | XL | 17 | Definitive |
| NR5A1 | 9q33.3 | 46,XY Disorders of sexual development (Prader scale 4; 5 or 6); OMIM:612965 | AD | 17 | Definitive |
| NR5A1 | 9q33.3 | 46,XX Disorders of sexual development (Prader scale 4; 5 or 6); OMIM:617480 | AD | 16 | Definitive |
| NR5A1 | 9q33.3 | Isolated spermatogenic failure; OMIM:184757 | AD | 14 | Strong |
| PLXNA1 | 3q21.3 | Kallmann syndrome; OMIM:NA (PS147950) | AD | 13.5 | Strong |
| POU1F1 | 3p11.2 | Combined pituitary hormone deficiency; OMIM:613038 | AR | 16 | Definitive |
| PROK2 | 3p13 | Kallmann syndrome; OMIM:610628 | AR | 11.5 | Moderate |
| PROKR2 | 20p12.3 | Kallmann syndrome; OMIM:244200 | AR | 17 | Definitive |
| PROP1 | 5q35.3 | Pituitary hormone deficiency; OMIM:262600 | AR | 17 | Definitive |
| RSPO1 | 1p34.3 | Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal; OMIM:610644 | AR | 12 | Moderate |
| SEMA3A | 7q21.11 | Kallmann syndrome; OMIM:614897 | AD | 16 | Definitive |
| SOX10 | 22q13.1 | Kallmann syndrome; OMIM:NA (PS147950) | AD | 16 | Definitive |
| SOX2 | 3q26.33 | Isolated hypogonadotropic hypogonadism (normosmic); OMIM:NA (PS147950) | AD | 16 | Definitive |
| SOX3 | Xq27.1 | 46,XX Disorders of sexual development (Prader scale 4; 5 or 6); OMIM:NA | XL | 13 | Strong |
| SOX9 | 17q24.3 | 46,XY Disorders of sexual development (Prader scale 4; 5 or 6); OMIM:NA | AD | 13.5 | Strong |
| SRD5A2 | 2p23.1 | 46,XY Disorders of sexual development (Prader scale 4; 5 or 6); OMIM:264600 | AR | 17 | Definitive |
| SRY | Yp11.2 | 46,XX Disorders of sexual development (Prader scale 4; 5 or 6); OMIM:400045 | YL | 17 | Definitive |
| SRY | Yp11.2 | 46,XY Disorders of sexual development (Prader scale 4; 5 or 6); OMIM:400044 | YL | 17 | Definitive |
| STAR | 8p11.23 | Lipoid adrenal hyperplasia; OMIM:201710 | AR | 10 | Moderate |
| TACR3 | 4q24 | Kallmann syndrome; OMIM:614840 | AR | 16.5 | Definitive |
| WDR11 | 10q26.12 | Hypogonadotropic hypogonadism; OMIM:614858 | AD | 12 | Moderate |
| WDR11 | 10q26.12 | Kallmann syndrome; OMIM:614858 | AD | 11 | Moderate |
| WT1 | 11p13 | 46,XY Disorders of sexual development (Prader scale 4; 5 or 6) without Wilm's tumour; OMIM:NA (PS400044) | AD | 14.25 | Strong |
We note that recent studies are identifying digenic/oligogenic causes for hypogonadotropic hypogonadism presentations including Kallman syndrome.