Table 2.
Identified genes and variants per patient after specific filtering.
| Patient | Gene | Chromosome: Coordinates | Type/consequence | HGVSc,HGVSp | dbSNP ID | gnomAD: MAF | CSVS: MAF | Predictors | Interpretation/classification (6) | Evidence | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Exonic predictor: CADD (1) | Exonic predictors: Functional impact (2) | Exonic predictors: conservation (3) | Splicing predictor (4) | Splicing predictors (Alamut) (5) | InterVar | ClinVar | VarSome | ACMG | HGMD: variant (7) | Gene characteristics: evidences for genotype-phenotype correlation (8) | ||||||||
| 1 | CYP1A1 | 15:75013544 | snv/missense | NM_000499.5:c.1162C>G:p.(His388Asp) | – | ND | ND | 24.9 | 13 | 6 | 0 | 5 | VUS | ND | – | VUS: PM2, PP3 | No | Association to hypospadias (ᴔvan der Zanden et al., 2012) |
| 1 | EVC | 4:5798754 | snv/missense | NM_153717.2:c.1892C>T:p.(Thr631Met) | rs139481521 | 0.0003 | ND | 23.5 | 5 | 3 | 0 | 3 | VUS | VUS | – | VUS: BP4 | No | Syndromic (Ellis–van Creveld syndrome) micropenis (D’Asdia et al., 2013; Ibarra-Ramirez et al., 2017), gonadal development? (Beverdam and Koopman, 2006; Jameson et al., 2012) |
| 1 | EVC | 4:5785368 | snv/synonymous | NM_153717.2:c.1653G>A:p.(Pro551=) | rs151293705 | 0.0003 | ND | 2.382 | NA | NA | 1 | 3 | Likely benign | other | VUS | VUS: BP7 | No | Syndromic (Ellis–van Creveld syndrome) micropenis (D’Asdia et al., 2013; Ibarra-Ramirez et al., 2017), gonadal development? (Beverdam and Koopman, 2006; Jameson et al., 2012) |
| 1 | GRID1 | 10:87966142 | snv/missense | NM_017551.2:c.499A>G:p.(Met167Val) | rs956188880 | 0.00004 | ND | 10.04 | 1 | 5 | 0 | NA | VUS | ND | – | VUS: BP4 | No | Candidate to hypospadias (van der Zanden et al., 2012) |
| 1 | NOTCH1 | 9:139399213 | snv/synonymous | NM_017617.5:c.4930C>T:p.(Leu1644=) | rs568700183 | 0.0003 | ND | 0.018 | NA | NA | 0 | 4 | Likely benign | Likely benign|Likely benign | Likely benign | Likely benign: BP6, BP7 | No | Related to SHH and FGF10 (Grinspon and Rey, 2014) |
| 1 | RET | 10:43609955 | snv/missense | NM_020975.5:c.1907C>T:p.(Thr636Met) | rs1035958105 | 0.00001 | 0 | 23.0 | 6 | 6 | 0 | NA | VUS | VUS | VUS | Likely pathogenic: PM1, PM2, PP2, PP3 | DM; thyroid carcinoma | Syndromic (CAKUT syndrome) cryptorchidism (ᴔChatterjee et al., 2012), gonadal development? (Jameson et al., 2012; Li et al., 2014) |
| 1 | RIPK4 | 21:43161468 | snv/missense | NM_020639.2:c.1885G>A:p.(Asp629Asn) | rs199669994 | 0.00004 | ND | 7.899 | 4 | 4 | NA | NA | VUS | ND | – | VUS: PM2 BP1 | No | Syndromic (Popliteal pterygium syndrome) genital hypoplasia (Mitchell et al., 2012), micropenis, hypoplastic scrotum, inguinal hernia (Kalay et al., 2012), gonadal development? (Beverdam and Koopman, 2006; Jameson et al., 2012) |
| 1 | RIPK4 | 21:43176830 | snv/missense | NM_020639.2:c.329C>T:p.(Ser110Leu) | rs200823657 | 0.00005 | ND | 22.7 | 3 | 5 | 0 | NA | VUS | NDw | – | VUS: PM2 BP1 | No | Syndromic (Popliteal pterygium syndrome) genital hypoplasia (Mitchell et al., 2012), micropenis, hypoplastic scrotum, inguinal hernia (Kalay et al., 2012), gonadal development? (Beverdam and Koopman, 2006; Jameson et al., 2012) |
| 1 | ZBTB16 | 11:114027160 | snv/intronic | NM_006006.5:c.1366+4G>C | – | ND | ND | 13.81 | NA | NA | 1 | 4 | ND | ND | – | VUS: PM2 BP1 | No | Syndromic (deletion 11q23) cryptorchidism and micropenis (Fischer et al., 2008) |
| 2 | RECQL4 | 8:145738828 | snv/missense | NM_004260.3:c.2237C>T:(p.Ala746Val) | rs201883228 | 0.0002 | ND | 26.8 | 6 | 5 | NA | NA | VUS | VUS | VUs | VUS: BP1 | No | Syndromic (Rothmund–Thomson syndrome) hypospadias, bilateral inguinal hernia (Kellermayer et al., 2005) |
| 3 | GLI2 | 2:121747688 | snv/missense | NM_005270.4:c.4198G>T:p.(Gly1400Cys) | rs143914758 | 0.0001 | ND | 23.4 | 7 | 2 | NA | NA | Likely benign | ND | VUS | VUS: - | No | Increased risk of hypospadias (Carmichael et al., 2013), male gonadal development (Jameson et al., 2012), masculinization of male external genitalia (Rey et al., 2000) |
| 3 | RECQL4 | 8:145737701 | snv,missense | NM_004260.3:c.3062G>A:p.(Arg1021Gln) | rs34666647 | 0.004 | 2.375 | 2 | 0 | 0 | 4 | Likely benign | other|Benign | Benign | Likely benign: PM2, PM5, BP1, BP4 | Cancer | Syndromic (Rothmund–Thomson Syndrome) hypospadias, bilateral inguinal hernia (Kellermayer et al., 2005) | |
| 4 | CDH23 | 10:73559034 | snv/nonsense | NM_022124.5:c.7221C>A:p.(Tyr2407*) | rs779038178 | ND | 0.002 | 35 | 5 | 6 | 1 | 3 | Likely pathogenic | ND | – | Pathogenic: PVS1, PM2, PP3 | No | Gonadal development? (Jameson et al., 2012; Li et al., 2014) |
| 4 | COL9A3 | 20:61448956 | snv/missense | NM_001853.4:c.116C>G:(p.(Pro39Arg) | rs1028982816 | 0.00001 | ND | 22.7 | 12 | 5 | 0 | NA | VUS | ND | – | VUS: PP3 | No | Male gonadal development (Nef et al., 2005; Beverdam and Koopman, 2006; Jameson et al., 2012) |
| 4 | MAML1 | 5:179193385 | snv/synonymous | NM_014757.4:c.1374C>T:p.(Asp458=) | rs61748799 | 0.003 | 0.004 | 0.089 | NA | NA | 0 | 1 | Likely benign | ND | – | VUS: BP7 | No | No (MAMLD1-related) |
| 4 | NOTCH1 | 9:139401803 | snv/synonymous | NM_017617.5:c.3597C>T:p.(Leu1199=) | rs150666307 | 0.00009 | ND | 11.70 | NA | NA | 0 | 3 | Likely benign | Likely benign | Likely benign | Likely benign: BP6, BP7 | No | Related to SHH and FGF10 (Grinspon and Rey, 2014) |
| 5 | BNC2 | 9:16436324 | snv/missense | NM_017637.5:c.1868C>A:p.(Pro623His) | rs114596065 | 0.0022 | 0.002 | 5.290 | 8 | 6 | NA | NA | Benign | Benign | Benign | VUS: BP6 | No | Hypospadias (Bhoj et al., 2011; van der Zanden et al., 2012; Baxter et al., 2015; Kon et al., 2015), gonadal development? (Jameson et al, 2012) |
| 5 | FGF10 | 5:44388817 | snv/upstream/missense | NG_011446.1:c.-33G>A | rs17233910 | 0.005 | 0.002 | 19.99 | NA | NA | NA | NA | ND | ND | – | VUS: - | No | Increased risk hypospadias in human (van der Zanden et al., 2012; Carmichael et al., 2013; Svechnikov et al., 2014); development of the glans penis (Rey et al., 2000) |
| 5 | HSD3B2 | 1:119964831 | snv/missense | NM_000198.3:c.707T>C:p.(Leu236Ser) | rs35887327 | 0.003788 | ND | 8.277 | 3 | 3 | NA | NA | Likely benign | VUS | VUS | Likely Pathogenic: PS1, PP2, PP5, BP4 | DM?; HSD3B2 deficiency | Hypospadias (Codner et al., 2004; Kon et al., 2015; Eggers et al., 2016), sex development (Baxter and Vilain, 2013; Baxter et al., 2015), hormone synthesis (ᴔMcCartin et al., 2000) |
| 5 | IRX5 | 16:54967040 | snv/missense | NM_005853.5:c.707C>T:p.(Pro236Leu) | rs115549200 | 0.0088 | ND | 11.97 | 3 | 4 | NA | NA | Benign | ND | – | VUS: BP4 | No | Association to hypospadias (Geller et al., 2014; Grinspon and Rey, 2014), female gonadal development? (Nef et al., 2005) |
| 5 | MAML2 | 11:95826473 | snv/missense | NM_032427.3:c.722G>A:p.(Arg241Gln) | rs111958464 | 0.005 | ND | 32 | 6 | 6 | 0 | NA | VUS | ND | – | VUs: - | No | No (MAMLD1-related) |
| 5 | NOTCH2 | 1:120469147 | snv/nonsynonymous | NM_024408.3:c.3980A>G:p.(Asp1327Gly) | rs61752484 | 0.0037 | 0.004 | 20.4 | 6 | 6 | 0 | NA | Likely benign | Benign | Benign | VUS: BP6 | DM?; cardiopathy | Primary ovarian failure (Patiño et al., 2017); male gonadal development? (Jameson et al., 2012) |
| 6 | ATF3 | 1:212788544 | snv/missense | NM_001674.3:c.181G>T:p.(Ala61Ser) | – | ND | ND | 7.826 | 3 | 5 | 1 | NA | Benign | ND | – | VUS: PM2, BP4 | No | Hypospadias (Beleza-Meireles et al., 2008; van der Zanden et al., 2012), female gonadal development? (Jameson et al., 2012) |
| 6 | BNC2 | 9:16436324 | snv/missense | NM_017637.5:c.1868C>A:p.(Pro623His) | rs114596065 | 0.0022 | 0.002 | 5.290 | 8 | 6 | NA | NA | Benign | Benign | Benign | VUS: BP6 | No | Hypospadias (Bhoj et al., 2011; van der Zanden et al., 2012; Baxter et al., 2015; Kon et al., 2015), gonadal development? (Jameson et al., 2012) |
| 6 | CYP1A1 | 15:75012979 | snv/missense | NM_001319216.2:c.1303C> A:p.(Arg435Ser) | rs41279188 | 0.0047 | ND | 33 | 11 | 5 | NA | NA | VUS | ND | Benign | VUS: PP3, BP6 | No | Association to hypospadias (van der Zanden et al., 2012) |
| 6 | EYA1 | 8:72211882 | snv/synonymous | NM_000503.5:c.630T>C:p.(Ser210=) | rs373102227 | 0.00008 | ND | 10.56 | NA | NA | 1 | 4 | Likely benign | VUS | VUS | VUS: PP3, BP7 | No | Associated to hypospadias (Grinspon and Rey, 2014; Hwang et al., 2014), male gonadal development? (Jameson et al., 2012) |
| 6 | FLNA | X:153596078 | snv/synonymous | NM_001456.3:c.651C>T:p.(Asp217=) | rs34644500 | 0.0002 | ND | 5.473 | NA | NA | 1 | 3 | Likely benign | Likely benign | Likely benign | Likely benign: BP4, BP6, BP7 | No | Hypospadias, cryptorchidism, diminished androgen receptor (Carrera-García et al., 2017), female gonadal development? (Jameson et al., 2012) |
| 6 | FRAS1 | 4:79334181 | snv/missense | NM_025074.6:c.4367T>C:p.(Ile1456Thr) | rs560902495 | 0.00003 | ND | 24.6 | 12 | 5 | NA | NA | VUS | ND | – | VUS: PM2, PP3, BP1 | No | Syndromic (Fraser syndrome) abnormal genitourinary system (Retterer et al., 2016; Kornacki et al., 2017); female gonadal development? (Jameson et al., 2012) |
| 6 | GLI3 | 7:42066017 | snv/intronic | NM_000168.5:c.1029-6G>A | rs748670269 | 0.00002 | ND | 0.004 | NA | NA | 0 | 3 | NA | ND | – | VUS: BP4 | No | Increased risk of hypospadias (Carmichael et al., 2013), early genital primordia (Rey and Grinspon, 2011), female gonadal development? (Jameson et al., 2012) |
| 6 | HOXA13 | 7:27239079 | snv/missense | NM_000522.4:c.618C>G:p.(Phe206Leu) | rs774388075 | 0.00002 | ND | 22.3 | 5 | 5 | NA | NA | VUS | ND | – | VUS: - | No | Associated to hypospadias (Beleza-Meireles et al., 2007; van der Zanden et al., 2012; syndromic, Hand-foot-genital)/Guttmacher syndrome) hypospadias (Innis et al., 2002), small penis (Goodman et al., 2000), genital tubercle development (Grinspon and Rey, 2014) |
| 6 | IRX5 | 16:54965347 | deletion/inframe | NM_005853.5:c.240_242delCTC:p.(Ser81del) | rs1057518726 | ND | ND | – | NA | NA | NA | NA | NA | VUS | VUS | VUS: PM4: nonframeshift deletion | No | Association to hypospadias (Geller et al., 2014; Grinspon and Rey, 2014), female gonadal development? (Nef et al., 2005) |
| 6 | IRX6 | 16:55362842 | snv/missense | NM_024335.2:c.952T>A:p.(Phe318Ile) | rs61743419 | 0.0014 | ND | 5.599 | 3 | 4 | 0 | NA | VUS | ND | – | VUS: - | No entry for this gene | Associated to hypospadias (Grinspon and Rey, 2014) |
| 6 | MAML1 | 5:179193168 | snv/missense | NM_014757.4:c.1157G>T:p.(Gly386Val) | rs777367230 | 0.0001 | 0.003 | 22.9 | 9 | 5 | 0 | NA | VUS | ND | – | VUS: - | No | No (MAMLD1-related) |
| 6 | MAML3 | 4:140811687 NOT CONFIRMED |
snv/synonymous | NM_018717.5:c.903C>T:p.(Asp301=) | rs76066862 | 0.0015 | 0.002 | 2.445 | NA | NA | NA | 2 | Likely benign | ND | – | VUS: - | No | Female gonadal development? (Jameson et al., 2012) |
| 6 | NRP1 | 10:33469272 | snv/missense | NM_003873.5:c.2504G>A:p.(Gly835Asp) | – | ND | ND | 5.556 | 6 | 4 | NA | NA | VUS | ND | – | VUS: PM2 | No | DSD (Baxter et al., 2015), gonadal development? (Jameson et al., 2012) |
| 6 | PROP1 | 5:177421299 | deletion/frameshift | NM_006261.4:c.150delA:p.(Arg53Aspfs*112) | rs587776683 | ND | ND | – | NA | NA | NA | NA | NA | Pathogenic | Likely pathogenic | VUS: PVS1, PP5 | DM; pituitary hormone deficiency | No, hypogonadotropic hipogonadism (Reynaud et al., 2005; Reynaud et al., 2005; Baxter and Vilain, 2013; Baxter et al., 2015; Eggers et al., 2016) |
| 6 | PTPN11 | 12:112856827 | snv/upstream | NM_002834.4:c.-89G>A | – | ND | ND | 16.23 | NA | NA | NA | NA | NA | ND | – | VUS: PM2, PP3 | No | Syndromic (Noonan syndrome) cryptorchidism (Tartaglia et al., 2002) |
| 6 | WDR11 | 10:122668121 | snv/missense | NM_018117.11:c.3571G>A:p.(Gly1191Ser) | rs149486212 | 0.0001 | 0.004 | 34 | 14 | 5 | NA | NA | VUS | ND | – | VUS : PP2, PP3 | No | Hypospadias (ᴔEggers et al., 2016, Fan et al., 2017), small testes (ᴔFan et al., 2017) |
| 7 | EVC | 4:5800455 | snv/missense | NM_153717.2:c.2240C>T:p.(Ala747Val) | rs151091776 | 0.0002 | ND | 18.37 | 5 | 4 | 0 | NA | VUS | ND | – | VUS: BP4 | No | Syndromic (Ellis–van Creveld syndrome) hypospadias (D’Asdia et al., 2013) and micropenis (Ibarra-Ramirez et al., 2017), gonadal development? (Beverdam and Koopman, 2006; Jameson et al., 2012) |
| 7 | MAML3 | 4:140811709 | snv/missense | NM_018717.5:c.881A>G:p.(Asn294Ser) | rs115966590 | 0.0028 | ND | 13.26 | 7 | 6 | NA | NA | VUS | ND | – | VUS: - | No | Female gonadal development? (Jameson et al., 2012) |
| 7 | NOTCH2 | 1:120458982 | snv/missense | NM_024408.3:c.6363G>C:p.(Lys2121Asn) | rs144047610 | 0.0004 | 0.002 | 23.4 | 9 | 5 | NA | NA | VUS | VUS | VUS | VUS: - | DM?, Bicuspid aortic valve | Primary ovarian failure (Patiño et al., 2017); male gonadal development? (Jameson et al., 2012) |
| 7 | PPARGC1B | 5:149219653 | snv/missense | NM_133263.3:c.2668G>A:p.(Ala890Thr) | rs150637009 | 0.0056 | ND | 19.13 | 5 | 5 | 0 | NA | VUS | ND | – | VUS: BP4 | No | Candidate to hypospadias (van der Zanden et al., 2012) |
| 7 | WDR11 | 10:122637900 | snv/missense | NM_018117.11:c.1592C>G:p.(Ser531Cys) | rs775506715 | 0.00004 | ND | 24.1 | 14 | 6 | 1 | NA | VUS | ND | – | VUS: PP2, PP3 | No | Hypospadias (ᴔEggers et al., 2016, Fan et al., 2017), small testes (ᴔFan et al., 2017) |
| 8 | CUL4B | X:119708447 | snv/missense | NM_003588.3:c.26G>A:p.(Gly9Glu) | rs149016283 | 0.0002 | ND | 18.73 | 1 | NA | 1 | NA | Likely benign | Likely benign | Likely benign | Likely benign: BP4, BP6 | No | Abnormal genitourinary system (Retterer et al., 2016) |
| 8 | DAPK1 | 9:90321476 | snv/missense | NM_004938.3:c.3490G>A:p.(Asp1164Asn) | rs937952689 | 0.00007 | ND | 24.3 | 8 | 5 | NA | NA | VUS | ND | – | VUS: - | No | Female gonadal development? (Jameson et al., 2012) |
| 8 | EMX2 | 10:119305133 | snv/intronic | NM_004098.3:c.407-10C >T | – | 0.000004 | ND | 9.098 | NA | NA | 1 | 4 | ND | ND | – | VUS: BP4 | No | 46,XX DSD (Liu et al., 2015), sex determination (Biason-Lauber, 2010; Jakob and Lovell-Badge, 2011; Eggers and Sinclair, 2012), (female) gonadal development (Rey et al., 2000; Jameson et al., 2012; Grinspon and Rey, 2014), (Jameson et al., 2012); 46,XY DSD (Piard et al., 2014) |
| 8 | FREM2 | 13:39454885 | insertion/frameshift | NM_207361.5:c.9472dupC:p.(Gln3160Thrfs*6) | – | ND | ND | – | NA | NA | NA | NA | ND | ND | – | Likely pathogenic: PVS1, PM2 | No | Syndromic (Fraser syndrome) abnormal genitalia (De Bernardo et al., 2015), female gonadal development (Jameson et al., 2012) |
| 8 | IGFBP2 | 2:217526593 | snv/missense | NM_000597.3:c.685C>A:p.(Gln229Lys) | – | ND | ND | 23.7 | 8 | 6 | 0 | NA | VUS | ND | – | VUS: PM2, PP3 | No entry for this gene | Candidate gene in ovary development (Clement et al., 2007), female gonadal development? (Jameson et al., 2012; Munger et al., 2013). |
| 8 | MAML2 | 11:95826575 | snv/missense | NM_032427.3:c.620G>A:p.(Arg207His) | rs191391876 | 0.0002 | ND | 24.4 | 9 | 5 | 0 | NA | VUS | ND | – | VUS: - | No | No (MAMLD1-related) |
| 8 | MAML3 | 4:140811709 | snv/missense | NM_018717.5:c.881A>G:p.(Asn294Ser) | rs115966590 | 0.0028 | 0.004 | 13.26 | 7 | 6 | NA | NA | VUS | ND | – | VUS: - | No | Female gonadal development? (Jameson et al., 2012) |
| 8 | MYO7A | 11:76883787 | delins/intronic | NM_000260:c.1798-7_1798-6delCCinsAT | – | ND | ND | – | NA | NA | NA | NA | ND | ND | – | – | No | Male gonadal development? (Jameson et al., 2012; Li et al., 2014) |
| 8 | MYO7A | 11:76883790 | delins/intronic-exonic | NM_000260: c.1798-4_1801delinsGGCTGCT | – | ND | ND | – | NA | NA | NA | NA | ND | ND | – | – | No | Male gonadal development? (Jameson et al., 2012; Li et al., 2014) |
| 8 | NOTCH1 | 9:139405111 | snv/missense | NM_017617.5:c.2734C>T:p.(Arg912Trp) | rs201620358 | 0.002 | ND | 31 | 12 | 6 | 0 | 3 | Likely benign | VUS | VUS | VUS: PP3 | No | Related to SHH and FGF10 (Grinspon and Rey, 2014) |
| 8 | PIK3R3 | 1:46521570 | snv/missense | NM_003629.3:c.838G>A:p.(Asp280Asn) | rs186728731 | 0.0001 | ND | 25.5 | 6 | 6 | 0 | 2 | VUS | ND | – | VUS: PP3 | No | Female gonadal development? (Beverdam and Koopman, 2006; Jameson et al., 2012) |
| 8 | TGFBI | 5:135398870 | snv/intronic | NM_000358.2:c.2012-5T>C | rs147650812 | 0.004 | 0.007 | 4.531 | NA | NA | 0 | 4 | ND | ND | – | VUS: - | No | Gonadal development? (Jameson et al., 2012, Clement et al., 2007, Beverdam and Koopman, 2006) |
| 8 | WNT9A | 1:228109247 | snv/missense | NM_003395.3:c.1070G>A:p.(Arg357His) | rs145836311 | 0.0010 | 0.004 | 34 | 11 | 5 | NA | NA | VUS | ND | – | VUS: - | No | Female gonadal development? (Nef et al., 2005; Beverdam and Koopman, 2006) |
| 8 | WNT9B | 17:44949939 | snv/missense | NM_003396.2:c.134C>T:p.(Pro45Leu) | rs530502749 | 0.00002 | ND | 21.1 | 5 | 4 | 0 | NA | VUS | ND | – | VUS: PM2 | No | Mayer–Rokitansky–Küster–Hauser syndrome (Waschk et al., 2016); bicornuate uterus (Waschk et al., 2016), organogenesis urogenital system (Carroll et al., 2005; Grinspon and Rey, 2014) |
All patients were heterozygote for these variants and were checked and confirmed through IGV software (alignment with human genome hg19/grch37; https://www.broadinstitute.org/igv/, Broad Institute, Cambridge, MA, USA). (1) Combined exonic predictor CADD: Combined Annotation Dependent Depletion (cutoff score: consensus ≥20; deleterious for DSD ≥18; contained in ANNOVAR). (2) Exonic predictors (funcional impact) (ANNOVAR, 15): SIFT, PolyPhen2 HumDiv, PolyPhen2 HumVar, LRT, MutationTaster, MutationAssessor, FATHEMM, Fathmm-MKL, PROVEAN, VEST3 (Variant Effect Scoring Tool), MetaSVM, MetaLR, MCAP, DANN, fitCons. (3) Exonic predictors (evolutionary conservation) (ANNOVAR, 6): GERP++, phyloP (vertebrate and mammalians), phastCons (vertebrate and mammalians), SiPhy. (4) Splicing predictors (ANNOVAR, 3): splicing predictor from dbscSNV ADA and RF, and SPIDEX splicing predictor (DPSI). (5) Splicing predictors (Alamut software, 5): SSF, MaxEnt, NNSPLICE, GeneSplicer, Ex-Skip. (6) InterVar: Clinical Interpretation of genetic Variants by ACMG/AMP guideline (http://wintervar.wglab.org/); ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/); VarSome: The Human Genomics Search Engine (https://varsome.com/); ACMG: ACMG classification from VarSome search engine. (7) Human Gene Mutation Database Biobase (HGMD® Professional 2018.2, http://www.biobase-international.com/product/hgmd): reported variant: variant class, reference, clinical association Human Gene Mutation Database Biobase. (8) Gene characteristics: evidences for genotype-phenotype correlation. Data obtained from pubmed, HGMD and String. ND, not detected; -, not shown; NA, not analysed; no, not previously related to DSD.