Table 3 Clinical phenotype, hormonal profil and details of potentially pathogenic variants identified by WES in a cohort of individuals with 46,XY DSD
nDSD case | Age/sex of rearing | FSH (UI/l)/ Normal range | LH (UI/l)/ Normal range | Testosterone (ng/ml)/ Normal range | Genitourinary | Somatic features | Gene/Variant/Zygosity/inheritance | MAF and population (gnomAD)/ Predicted effect on protein | Clinical significance: ACMG/ ClinVar/ GV, Ref | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
External genitalia | Internal genitalia | Gonad position | Gonad Histology | |||||||||
DSD1 | 17Y/F | 8.92 (6.3–24) | 8.81 (9.6–80) | 4.06 (0.7–19) | Micropenis, absence of labia minora, no vagina | Absent MD, presence of seminal vesicles, hypotrophic testis | R: inguinal, L: inguinal | Testis/ NA | - | SRD5A2:NM_000348:c.G344A:p.G115D,Hom, parents | 0.0001964 Latino-Admixed American/ SIFT: D (0.03), PP2: PrD (0.993), REVEL: NA | P/NA / P [Lavinia vija et al 2014, Laurent Maimoun 2011] |
DSD2 | 28Y/F | NA | NA | NA | Micropenis, absence of labia minora and majora, vaginal aplasia | Absent MD, atrophic testes | R: inguinal, L: inguinal | Testis /Sertoli cells, no germ cells, Leydig cell hyperplasia | - | SRD5A2:NM_000348:c.A622C:P.T208P, Hom, parents | Novel/SIFT: SIFT: D(0.01), PP2: PrD (0.913), REVEL: NA | LP/ NA/ NA |
DSD3 | 30 Y/F | 7 (1.7–12) | 15.5 (1.1–7) | NA | F | Absent uterus, hypoplasic gonads | NA | NA | - | AR:NM_000044:c.G2231A:p.G744E, Hemi, maternal | NA/ SIFT: D(0.00), PP2: PrD(1.00), REVEL: 0.935 (LDC) | P/ P/ NA |
DSD4 | 8Mo/F | NA | 0.8 (2–12) | < 0.1(0.2–0.8) | F, bilateral inguinal hernia | Absent MD, presence of testes in hernia sac | Hernia sac | Testis/Sertoli cells with seminiferous tubes, no germ cells | - | AR:NM_000044:c.G2231A:p.G744E, Hemi,NA | NA/ SIFT: D(0.00), PP2: PrD(1.00), REVEL: 0.935 (LDC) | P/ P/ NA |
DSD5 | 4D/F | NA | NA | NA | Hypertrophy of the clitoris and labia majora | NA | NA | NA | - | AR:NM_000044:c.A1742G:p.K581R, Hemi, maternal | Novel/ SIFT: D (0.00), PP2: PrD (0.998), REVEL: NA | LP/ NA/ NA |
DSD6 | 18Y/F | NA | NA | NA | F | Absent MD, presence of bilateral gonadal mass with epididymes | NA | Two atrophic testes, presence of Sertoli cells, no germ cells | - | AR:NM_000044:c.G1597T:p.G533*, Hemi, matneral | Novel/LOF | P/ NA/NA |
DSD7 DSD8 (sibs) | 25Y/F | 28.7 (1.1–7) | 5.6(1.1–7) | NA | F, bilateral inguinal hernia | Vagina present, absent MD | NA | no residual gonad | - | AR:NM_000044:c.C1277A::p.S426*, Hemi, De novo | Novel/LOF | P/ NA/ NA |
15Y/F | 7.38(1.7–12) | 10.46(1.1–7) | 0.23(0.1–0.9) | F | Absent MD, presence of gonadal mass | R:Inguinal,L: no residual gonad | NA | - | ||||
DSD9 | 1Y and half/M | NA | NA | NA | Hypospadias, cryptorchidism, incomplete foreskin | NA | NA | NA | - | AR:NM_000044:c.T170A::p.L57Q, Hemi, maternal | Novel/ SIFT:D (0.001), PP2: unknown, REVEL: 0.150(B) | B/LB/NA |
DSD10 | 14Y | 39(1.7–12) | NA | NA | F | Absent gonads and uterus | No residual gonad | NA | - | LHCGR:NM_000233:c.C1573T:p.Q525*, Hom, parents | NA/ LOF | P/NA/P [Imen Et al 2015] |
DSD11 | 19Y/F | 25(6.3–24) | 44(29.6–60) | NA | F | Absent uterus, vagina present, R ovary:18 mm/L ovary:26 mm | NA | Ovarian-like tissue | - | ZNRF3:NM_001206998:c.A1014G:p.I338M, Het, NA | Novel/ SIFT:D (0.01)/PP2:PD(0.519)/ REVEL:0.461(LB) | LP /NA/NA |
DSD12 | 40D/F | NA | NA | NA | F | NA | NA | NA | Hydrocephalus,skeletal malformations,bilateral anophtalmos,agenesis of the corpus callosum | HHAT:NM_018194.6:c.C934A:p.R312S, Hom, parents | 0.00006482 European/ SIFT:T(0.06)/PP2: PD(0.459) /REVEL:0.159(B) | LP/NA/NA |
DSD13 | 3 Mo/M | NA | NA | NA | Micropenis, hypospadias, crytorchidism | NA | NA | NA | Dysmoprphic features,daibetes,epileptic seizures,atrophy of the supra tentorial level | IER3IP1: NM_016097.5:c.T62G:p.V21G,Hom, AR parents | 0.0001491Latino admixed Americain /SIFT:D(0.00)/PP2:PD(0.583)/REVEL:0.886(LDC) | P/VUS/Khouloud et al. 2021] |
DSD14 | 23Y/F | 103.53(17–95 | 15.99(8–33) | NA | F | No ovaries, small uterus | No residual gonad | NA | NO | NSMF:exon3:c.134-4C > T, Het, NA | Novel/LOF | LB/NA/NA |
SEMA3A:c.G391A:p.A131T,Het, NA | European 0.0001176/ SIFT:T(0.16)/PP2:B(0.121) /REVEL:0.187(B) | B/NA/NA | ||||||||||
DSD15 | 1Y/M | NA | NA | NA | Micropenis, hypospadias, small testes | NA | NA | NA | Dysmorphic features,psychomotor delay,hypotrophy | POR:NM_000941c.G1736A:p.R579Q, Het, NA | SIFT:T (0.13)/PP2:B(0.2)./REVEL:0.319(B) | B/NA/NA |
KDM3A:NM_001146688:c.C1535T:p.S512L, Het, NA | African American: 0.00004826/ SIFT:D(0.0)/PP2: PrD(0.98)/REVEL: 0.371(B) | LB/NA/NA | ||||||||||
DSD16 | 16Y/F | 48.33(6.3–24) | 20.20(29.6–60) | NA | F | Infantile uterus, no ovaries | No residual gonad | NA | - | SOX9:NM_000346:c.C920G:p.P307R, Het, NA | European 0.00001470 / SIFT:T(0.05)/PP2:B(0.009)/REVEL: 0.426(LB) | LP/NA/NA |
DSD17 | 2Y/M | NA | NA | NA | Left testicular ectopy | NA | NA | NA | Dysmorphic features/partial agenesis of the corpus callosum/microcephaly | PEX1:NM_000466:c.G2528A:p.G843D, Hom, parents | African American 0.00009653/ SIFT:D(0.0)/PP2: PrD(1.0)/REVEL: 0.984(LDC) | P/P/NA |
DSD18 | 1Y and 1Mo/M | NA | NA | NA | Hypospadias,micropenis, unilateral cryptorchidism | R: in place L: in the abdomen | Testes/NA | Dysmorphic features,CIV,intra-uterine growth delay | POLE:NM_006231:c.C1707G:p.F569L,Het, parents | Latino/American 0.00006545 / SIFT:T(0.11)/PP2: B(0.04) /REVEL:0.171(B) | B/VUS/NA | |
ANOS1:NM_000216:c.C1283T:p.P428L, Hemi, parents | european 0.00005634/ SIFT: T(0.73)/PP2:B(0.00)/REVEL:0.081(B) | LB/LB/NA | ||||||||||
DSD19 | 4Mo/M | NA | NA | NA | Micropenis, cryptorchidism, small smooth scrotum | NA | NA | - | MAMLD1:NM_005491:c.A862C:p.M288L, Hemi, maternal | 0.00005637 european/SIFT:T(0.17)/PP2:B(0.053)/REVEL:0.057(B) | B/NA/NA | |
DSD20 | 15D/M | NA | NA | NA | Anterior interscrotal hypospadias, micropenis, hypoplasic scrotum, left testicular ectopy | Bilateral hydrocele | R: no residual gonad, L:inguinal region | Testis/NA | - | FGF17:NM_001304478:c.C32T:pT11I, Het, NA | 0.00001470 european/ SIFT:T(0.17)/ PP2:B(0.053)/ REVEL:0.256(B) | VUS/NA/NA |
DSD21 | 36Y/M | 116(1.5–10) | NA | 0.52(2.5–10) | Small left testis | R: no testis L: atrophic testis | Testis/NA | - | NSMF:NM_015537:c.A125G:p.N42S, Het, NA | Novel/ SIFT:D(0.005)/PP2:B(0.417)/REVEL: 0.069(B) | B/NA/NA | |
DSD22 | 4Y and 9Mo/M | NA | NA | NA | Micropenis, small scrotum | Testis in the inguinal region | R:inguinal,L:inguinal | Testis/NA | Epilepsy,coortical atrophy | PDYN:NM_024411:c.34delC:p:L12fs, Het, NA | Novel | VUS/NA/NA |
MAMLD1:NM_001177465:c.C2573T:p.P858L, Het, maternal | European 0.0001506/SIFT:D/PP2:PD/REVEL: 0.188(B) | VUS/VUS/NA | ||||||||||
DSD23 | 21Y/M | NA | NA | NA | Hypospadias, small testis | Testis in scrotum | NA | Testis | Hypothyroidism/low hairness | ARID1B:NM_001346813:c.1053_1054insGGC:p.G351delinsGG,Het, NA | Novel/LOF | VUS/VUS/NA |
, INSR:NM_000208:c.T3410C:p.I1137T, Het, NA | European 0.000008790/SIFT:D/PP2:PD/REVEL:NA | VUS/VUS/NA | ||||||||||
INSR:NM_000208:c.G3034A:p.V1012M, Het, NA | East Asian 0.0001930 SIFT:D(0.02)/PP2:PD(0.546)/REVEL: 0.634(LDC) | VUS/VUS/NA | ||||||||||
DSD 24 | 4Y and 6Mo/M | NA | NA | NA | Hypospadias, cryptorchidism | NA | L & R: abdomen | Testis/NA | - | FLNA:NM_001110556:c.G1019T:p.R340L, Hemi, maternal | Africain/Americain 0.00008078/ SIFT:D(0.01)/PP2:PrD(0.966)/REVEL:0.538(LDC) | LP/VUS/NA |
DSD25 | 15Y/F | NA | NA | NA | F | Immature uterus without uterine cavity, vagina | No residual gonad | NA | - | NBN:NM_002485.5:c.C798T: p.R215W, Het, NA | European 0.001985/ SIFT:D(0.00)/PP2:PrD(0.977)/REVEL: 0.343(B) | LB/VUS/NA |
DSD26 | 1Y and half/M | NA | NA | NA | Micropenis, cryptorchidism | NA | NA | NA | Dysmorphic features | AMH:NM_000479:c.C553G:p.Q185E, Het, NA | European 0.0002059// SIFT: D(0.01)/PP2: PrD(0.925) /REVEL:0.492(B) | LB/LB/NA |
DSD27 | 39Y/M | NA | NA | NA | Micropenis | No testes | NA | NA | - | POR:NM_000941:c.C344T:p.A115V, Het, NA | European 0.0001911/ SIFT:T(0.04) /PP2:B(0.408) /REVEL:0.481(LB) | LB/LB/NA |
DSD28 | 1Y and half/M | NA | NA | NA | Unilateral crytorchidism | NA | R:abdomen L: scrotum | NA | Dysmorphic features,mental retardation,clinodactyly, | FRAS1:NM_025074:c.A7622G:p.N2541S, Hom, parents | European 0.0005442/ SIFT: D(0.03)/polyphen2: PrD(0.997) /REVEL:0.177(B) | B /LB/NA |
DSD29 | 8Mo/M | NA | NA | NA | Hypospadias/cryptorchidism | Testes in inguinal region | L & R: inguinal region | Testes/NA | Dysmorphic features/hypotonia/microcephaly/fallot tetralogy/brachycaphaly | ANKRD11:NM_001256183:c.C5578T:p.P1860S, Het, NA | European 0.0005580/ SIFT: T(0.07)/PP2: LB(0.348) /REVEL:0.148(B) | LB/LB/NA |
DSD30 | 21Y/F | 32.6(3–15) | 53.3(1.2–12.5) | NA | F | Absent vagina and uterus | No residual gonad | NA | - | SOX8:NM_014587:c.A676C:p.T226P, Het, NA | Novel/ SIFT:D(0.04)/PP2: ¨PrD(0.99)/REVEL:0.812(LDC) | LP/NA/NA |
DSD31⃰ | 33Y/F | 57 (3–12) | 11.7 (1.1–7) | 0.4 (3–12) | F | Bilateral gonadal agenesis | No residual gonad | Small impubertal uterus, Fallopian tubes | - | SRY:NM_003140.3c.C188A:p.P63H, Hemi, NA | Novel/ SIFT: D(0.00)/PP2: PrD(1.00)/REVEL: 0.720(LDC) | LP/NA/NA |