TABLE 2.
Clinical phenotype, hormonal profile and details of variants identified in 12 individuals with disorders of gonadal development.
| Case, Age, Sex rearing | FSH (UI/L) | LH (UI/L) | Testosterone (ng/ml) | AMH (ng/ml) | Genitourinary | Variant | MAF and Population (gnomAD)/Predicted effect on Protein | Zyg | PoGI/transmission of Variant | Clinical Significance: ACMG/ClinVar/GV, ref | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Value/NR | Value/NR | Value/NR | Value-HCG Stimulation test/NR | Value/NR | External genitalia | Internal genitalia | Gonadal Position | Gonad/histology | ||||||
| 1 2D M | NA | NA | 0.08 [0.12–0.21] (3D) | NA | NA | Phallus (<1 cm), BC, NPG | No Müllerian ducts, posterior cavity present, male urethra | No residual gonad | No residual gonad | DHH:NM_021044:c.G913A:p.G305R | Novel/SIFT: tolerated (0.14), PolyPhen2: possibly damaging (0.993), REVEL: 0.528 (LDC) | Het | AR Paternal | VUS/NA/NA |
| GPRC6A:NM_148963:c.2323dupT:p.Y775fs | 0.2768- African/African-American/LOF | Het | Maternal | B/B/VUS Dawson et al. (2020) | ||||||||||
| 2 2D M | NA | NA | 0.09 [<0.03] (14D) | <0.025 [0.03–0.38] (3.5Y) | 0.01 [1.0–10.6] (3Mo) | Micropenis (1 × 0.5 cm), urogenital sinus closed, urethral orifice, hypoplastic scrotum, BC, NPG | No Müllerian ducts | R: inguinal, L: inguinal | R:hypotrophic hypoechoic testis (10.6 × 4mm)/NA, L: testis (11 × 6mm)/NA | PROK2:NM_001126128:c.96+4A > G | Novel/LOF | Het | AD | VUS/NA/NA |
| 3 40D F | NA | NA | <0.03 [0.03–0.32] (4Y) | NA | 1.44 [12.6–167] (4.5Y) | Micropenis (3 cm), perineal hypospadias, labia majora, BC, NGP | Hypoplastic uterus, Müllerian ducts present | R: abdominal, L: abdominal | R: ovary/NA, L: ovary/NA | RNF216:NM_207111:c.G785A:p.R262H | 0.0005534- Other/SIFT: tolerated low confidence (0.05), PolyPhen2: B (0.169), REVEL: 0.016 (B) | Het | AR | VUS/NA/NA |
| 4 3Y M | 2.9 [1–8] (3Y) | 0.2 [0.6–12] (3Y) | 0.026 [3.0–12.0] (3Y) | 0.34 [3.0–12.0] (3Y) | 0.08 [3.8–159.8] (3Y) | Genital bud (4 cm), posterior orifice, poorly developed labioscrotal folds, BC, NPG | No Müllerian ducts | R: abdominal, L: no residual gonad | R: nodular structure (11 × 17 mm)/NA, L: no residual gonad | ANOS1:NM_000216:c.C1187T:p.S396L | 0.003935- Ashkenazi Jewish/SIFT: deleterious (0), PolyPhen2: B (0.085), REVEL: 0.462 (B) | Hem | XLR | VUS/P/LP Dodé et al. (2006) |
| WT1:NM_024424:c.C299G:p.A100G | Novel/SIFT: tolerated low confidence (0.59), PolyPhen2: B (0.007), REVEL: 0.219 (B) | Het | AD Parental | LB/NA/B McCarthy et al. (2013) | ||||||||||
| 5 # 1D M | 4.33 [<5.0] (6Mo) | 1.09 [<1.0] (6Mo) | 0.12 [0.12–0.22] (6Mo) | 2.57 [0.12–0.22] (6Mo) | 67.6 [39.1–91.1] (6Mo) | Micropenis (2 cm), 2 orifices, anogenital distance of 4cm, PG | Müllerian ducts present, oblong posterior cavity (18 mm) communicating with the bulbar urethra | R: inguinal, L: inguinal | R:hypotrophic testis/NA, L: hypotrophic testis/NA | NR5A1:NM_004959:c.A1223C:p.H408P | Novel/SIFT: tolerated (0.24), PolyPhen2: possibly damaging (0.641), REVEL: 0.769 (LDC) | Het | AD De novo | P/NA/NA |
| MAP3K1:NM_005921:c.A3418G:p.M1140V | 0.001024- East Asian/SIFT: deleterious (0.04), PolyPhen2: B (0.01), REVEL: 0.180 (B) | Het | AD | VUS/NA/NA | ||||||||||
| CTU2:NM_001012759:c.C710T:p.A237V | 0.0009344- European (Finnish)/SIFT: deleterious (0), PolyPhen2: possibly damaging (0.581), REVEL: 0.184 (B) | Het | AD | VUS/NA/NA | ||||||||||
| 6 # 45D M | 8.88 [1.1–25] (2Mo) | 0.2 [1.5–11.8] (2Mo) | 1.70 [2.2–10.5] (2D) | NA | <0.03 [42–203] (3Mo) | Micropenis (<0.5 cm), posterior hypospadia, hypoplastic labia, BC, NPG | Müllerian ductspresent | No residual gonad | No residual gonad | DHX37:NM_032656:c.G923A:p.R308Q | Novel/SIFT: deleterious (0), PolyPhen2: probably damaging (1), REVEL: 0.451 (B) | Het | AD De novo | P/NA/P McElreavey et al. (2020) |
| GLI2:NM_005270:c.C1289G:p.A430G | Novel/SIFT: deleterious (0.01), Polyphen2: B (0.205), REVEL: 0.095 (B) | Het | AD | VUS/NA/NA | ||||||||||
| CCDC141:NM_173648:c.C3782T:p.A1261V | 0.0003274- Other/SIFT: tolerated (0.26), PolyPhen2: B (0.029), REVEL: 0.056 (B) | Het | AR | VUS/NA/NA | ||||||||||
| 7 2D M | NA | NA | <0.10 [3.0–10.6] (18Mo) | NA | 46.3 [51.3–88.3] (22Mo) | Genital bud (2 cm), perineal hypospadias, bifid scrotum, BC, NPLG | Uterus remnant present, uterovaginal cavity present | R: inguinal, L: no residual gonad | R: testis/NA, L: no residual gonad | MYRF:NM_001127392:c.A1222G:p.I408V | 0.001779- Latino/Admixed American/SIFT: tolerated (0.19), PolyPhen2: B (0.241), REVEL score: 0.062 (B) | Het | AD Maternal | VUS/NA/NA |
| CCDC141:NM_173648:c.G1131T:p.K377N | 0.001264- Ashkenazi Jewish/SIFT: deleterious (0), PolyPhen2: probably damaging (0.982), REVEL: 0.110 (B) | Het | AR Maternal | VUS/NA/NA | ||||||||||
| TGIF1:NM_170695:c.239dupC:p.A80fs | Novel/LOF | Het | AD Maternal | VUS/NA/NA | ||||||||||
| 8 # 20Mo M | 86.76 (6Mo) | 11.38 (6Mo) | 0.03 [3.0–12.0] (6Mo) | 0.17 [3.0–12.0] (6.5Mo) | 0.01 [2.0–6.8] (6Mo) | Micropenis (0.5 cm), fused pigmented labia, fusion of labia minora, BC, NPG | No Müllerian ducts | No residual gonad | No residual gonad | DHX37:NM_032656:c.G923A:p.R308Q | Novel/SIFT: deleterious (0), PolyPhen2: probably damaging (1), REVEL: 0.451 (B) | Het | AD Maternal | P/NA/P McElreavey et al. (2020) |
| SLC29A3:NM_018344:c.C971T:p.P324L | 0.0004349- East Asian/SIFT: deleterious (0), PolyPhen2: probably pathogenic, REVEL: 0.899 (LDC) | Het | AR Paternal | VUS/LP/VUS Molho-Pessach et al. (2014) | ||||||||||
| CCDC141:NM_173648:c.G1979A:p.R660Q | Novel/SIFT: deleterious (0.04), PolyPhen2: tolerated (0.121), REVEL: 0.074 (B) | Het | AR Maternal | VUS/NA/NA | ||||||||||
| 9 2D F | NA | NA | 0.35 [0–2.31] (2.5Mo) | NA | 3.6 [3.8–159.8] (14D) | Clitoromegaly (1.5 cm), bifid poorly developed labiscrotal folds | Presence of a left structure correspond probably to a Müllerian ducts | R: inguinal, L: inguinal | R: testis/NA, L: testis/NA | FGFR2:NM_000141:c.A1132G:p.I378V | Novel/SIFT: tolerated (0.37), PolyPhen2: possibly damaging (0.503), REVEL: 0.290 (B) | Het | AD Paternal | VUS/NA/NA |
| FANCD2:NM_033084:c.C2965G:p.P989A | 0.0004573- South Asian/SIFT: deleterious (0.02), PolyPhen2: B (0.311), REVEL: 0.091 (B) | Het | AR Paternal | VUS/VUS/NA | ||||||||||
| 10 4.5Mo M | NA | NA | 0.1 [3.0–12.0] (2.5Mo) | 0.5 [3.0–12.0] (9Mo) | 18.7 [51.3–88.3] (13Mo) | Micropenis (<1 cm), UC | No Müllerian ducts | R: scrotum, L: inguinal | R:oscillating testis/NA, L: testis/NA | RXFP2:NM_130806:c.G184A:p.A62T | 0.001524- Other/SIFT: tolerated (0.43), PolyPhen2: B (0.035), SIFT: 0.281 (B) | Het | AR | VUS/NA/NA |
| 12 30Mo M | NA | NA | NA | 0.639 [0.0–0.9] (30Mo) | 116.0 [3.8–159.8] (30Mo) | Micropenis (1 cm), phimosis, urethral orifice, developed scrotum, UC | No Müllerian ducts | R: scrotum, L: no residual gonad | R: testis (15 × 9 mm)/NA, L: no residual gonad | MAP3K1:NM_005921:c.A3557G:p.E1186G | Novel/SIFT: deleterious (0.01), Polyphen2: probably damaging (0.986), REVEL: 0.259 (B) | Het | AD | VUS/NA/NA |
| MYRF:NM_001127392:c.A1222G:p.I408V | 0.001779- Latino/Admixed American/SIFT: tolerated (0.19), PolyPhen2: B (0.241), REVEL: 0.062 (B) | Het | AD Maternal | VUS/NA/NA | ||||||||||
| 15 22Y M | 69.26 [1–8] (22Y) | 36.36 [2–12] (22Y) | 0.32 [3–10.6] (22Y) | 0.34 [0.7–8.53] (22Y) | 0.04 [0.8–14.6] (22Y) | Penis (5 cm), urogenital sinus closed, urethral orifice, developed scrotum, BC, NPG | No Müllerian ducts, atrophic prostate present | No residual gonad | No residual gonad | SOX8:NM_014587:c.G1264A:p.G422S | 0.0001749- Other/SIFT: tolerated (1), PolyPhen2: B (0.003), REVEL: 0.194 (B) | Het | AD | VUS/NA/NA |
| PROKR2:NM_144773:c.C868T:p.P290S | 0.0003668- Latino/Admixed American/SIFT: deleterious (0), PolyPhen2: probably damaging (1), REVEL: 0.939 (LDC) | Het | AD | VUS/VUS/VUS Cox et al. (2018) | ||||||||||
| PLXNA3:NM_017514:c.787_796del:p.V263fs | Novel/LOF | Hem | AR | VUS/NA/NA | ||||||||||
| FLNA:NM_001110556:c.C2449T:p.P817S | Novel/SIFT: deleterious (0.02), PolyPhen2: B (0.439), REVEL: 0.320 (B) | Hem | XLD | VUS/NA/NA | ||||||||||
| NIPBL:NM_015384:c.6954+3A > G | 0.0001693- African/African-American/LOF | Het | AD | VUS/NA/NA | ||||||||||
| SLC29A3:NM_001174098:c.G325A:p.V109I | 0.0003252- European (non-Finnish)/SIFT: tolerated (1), PolyPhen2: B (0.007), REVEL: 0.052 (B) | Het | AR | VUS/VUS/NA | ||||||||||
| GLI3:NM_000168:c.G1527C:p.E509D | Novel/SIFT: deleterious (0.02), PolyPhen2: B (0.038), REVEL: 0.122 (B) | Het | AD | VUS/NA/NA | ||||||||||
ACMG, american college of medical genetics; AD, autosomal dominant; AMH, anti-Müllerian hormone; AR, autosomal recessive, B benign, BC, bilateral cryptorchidism, D day, DSD, disorders/differences of sex development, F female, FSH, follicle stimulating hormone; GD, gonadal dysgenesis, gnomAD genome aggregation database; GV, gene variants previously associated with the disease; HCG, human chorionic gonadotropins, Hem hemizygous, Het heterozygous, Hom homozygous; I.D., initial diagnosis, L left, LB, likely benign; LDC, likely disease causing; LH, luteinizing hormone; LOF, loss-of-function, LP, likely pathogenic; LPG, left palpable gonad, M male, MAF, minor allele frequency, Mo month, NA not available; NPG, non palpable gonads; NPLG, non palpable left gonad; NPRG, non palpable right gonad; NR, normal range, P pathogenic, PG, palpable gonads; PGD, partial gonadal dysgenesis, PoGI, pattern of disease inheritance usually associated with the gene, R right, Ref reference, REVEL, rare exome variant ensemble learner; RPG, right palpable gonad; TRS, testicular regression syndrome; UC, unilateral cryptorchidism; VUS, variant of uncertain significance, Y year. #A definitive genetic diagnosis was achieved.