Activity
| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
43 actions
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.32 | PPP2R3C |
Ida Ertmanska changed review comment from: PMID: 35812758 Zhang et al., 2022 24yo Chinese female (46, XY) proband with complete gonadal dysgenesis (CGD) and biallelic PPP2R3C variants: p.F229del & p.G417E. Seq method: WES. She presented with poor development of secondary sexual characteristics and primary amenorrhea. She also had short stature (148 cm tall (-3SD) at 18 years old) and received growth hormone therapy. Literature review from the paper: "Thirteen 46, XY DSD patients had been reported in three articles previously (Guran et al., 2019; Cicek et al., 2021; Altunoglu et al., 2022). All the patients came from consanguineous marriages and had homozygous PPP2R3C variants. Eleven out of thirteen 46, XY DSD patients presented with complete gonadal dysgenesis, complete female vulva with hypoplastic labium major, and hypoplastic uterus. Sex hormone levels were compatible with complete gonadal dysgenesis. One patient presented with partial testicular dysgenesis, and he had ambiguous genitalia, micropenis, and left cryptorchidism. Also, three 46, XX DSD patients presented with complete gonadal dysgenesis, recognizable facial features, and multiple extragenital malformations." Other features reported: facial dysmorphism (16/16), retardation of bone age (15/ 16), delayed development of the nervous system / Neuromotor delay (14/16), and more variable features like SNHL, renal agenesis, myopathy, impaired vision. Intellect was mostly not reported, or noted to be 'low normal' - borderline ID. PMID: 34750818 - 8 patients with gonadal dysgenesis from 4 unrelated families of Turkish and Indian descent, with 3 different homozygous PPP2R3C variants PMID: 34714774 - 4 patients from 3 unrelated Turkish families with the same homozygous p.L193S variant in PPP2R3C - one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. PMID: 30893644 - Four Turkish female probands from four unrelated families with 46, XY complete gonadal dysgenesis and three different homozygous PPP2R3C variants. PPP2R3C is associated with AR Myoectodermal gonadal dysgenesis syndrome, OMIM:618419 (OMIM accessed 26th Oct 2026). Sources: Literature; to: PMID: 35812758 Zhang et al., 2022 24yo Chinese female (46, XY) proband with complete gonadal dysgenesis (CGD) and biallelic PPP2R3C variants: p.F229del & p.G417E. Seq method: WES. She presented with poor development of secondary sexual characteristics and primary amenorrhea. She also had short stature (148 cm tall (-3SD) at 18 years old) and received growth hormone therapy. Literature review from the paper: "Thirteen 46, XY DSD patients had been reported in three articles previously (Guran et al., 2019; Cicek et al., 2021; Altunoglu et al., 2022). All the patients came from consanguineous marriages and had homozygous PPP2R3C variants. Eleven out of thirteen 46, XY DSD patients presented with complete gonadal dysgenesis, complete female vulva with hypoplastic labium major, and hypoplastic uterus. Sex hormone levels were compatible with complete gonadal dysgenesis. One patient presented with partial testicular dysgenesis, and he had ambiguous genitalia, micropenis, and left cryptorchidism. Also, three 46, XX DSD patients presented with complete gonadal dysgenesis, recognizable facial features, and multiple extragenital malformations." Other features reported: facial dysmorphism (16/16), retardation of bone age (15/ 16), delayed development of the nervous system / mild neuromotor delay (14/16), and more variable features like SNHL, renal agenesis, myopathy, impaired vision. Intellect was mostly not reported, or noted to be 'low normal' - borderline ID. PMID: 34750818 - 8 patients with gonadal dysgenesis from 4 unrelated families of Turkish and Indian descent, with 3 different homozygous PPP2R3C variants PMID: 34714774 - 4 patients from 3 unrelated Turkish families with the same homozygous p.L193S variant in PPP2R3C - one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. PMID: 30893644 - Four Turkish female probands from four unrelated families with 46, XY complete gonadal dysgenesis and three different homozygous PPP2R3C variants. PPP2R3C is associated with AR Myoectodermal gonadal dysgenesis syndrome, OMIM:618419 (OMIM accessed 26th Oct 2026). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.32 | PPP2R3C |
Ida Ertmanska changed review comment from: PMID: 35812758 Zhang et al., 2022 24yo Chinese female (46, XY) proband with complete gonadal dysgenesis (CGD) and biallelic PPP2R3C variants: p.F229del & p.G417E. Seq method: WES. She presented with poor development of secondary sexual characteristics and primary amenorrhea. She also had short stature (148 cm tall (-3SD) at 18 years old) and received growth hormone therapy. Literature review from the paper: "Thirteen 46, XY DSD patients had been reported in three articles previously (Guran et al., 2019; Cicek et al., 2021; Altunoglu et al., 2022). All the patients came from consanguineous marriages and had homozygous PPP2R3C variants. Eleven out of thirteen 46, XY DSD patients presented with complete gonadal dysgenesis, complete female vulva with hypoplastic labium major, and hypoplastic uterus. Sex hormone levels were compatible with complete gonadal dysgenesis. One patient presented with partial testicular dysgenesis, and he had ambiguous genitalia, micropenis, and left cryptorchidism. Also, three 46, XX DSD patients presented with complete gonadal dysgenesis, recognizable facial features, and multiple extragenital malformations." Other features reported: facial dysmorphism (16/16), retardation of bone age (15/ 16), delayed development of the nervous system / Neuromotor delay (14/16), and more variable features like SNHL, renal agenesis, myopathy, impaired vision. PMID: 34750818 - 8 patients with gonadal dysgenesis from 4 unrelated families of Turkish and Indian descent, with 3 different homozygous PPP2R3C variants PMID: 34714774 - 4 patients from 3 unrelated Turkish families with the same homozygous p.L193S variant in PPP2R3C - one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. PMID: 30893644 - Four Turkish female probands from four unrelated families with 46, XY complete gonadal dysgenesis and three different homozygous PPP2R3C variants. PPP2R3C is associated with AR Myoectodermal gonadal dysgenesis syndrome, OMIM:618419 (OMIM accessed 26th Oct 2026). Sources: Literature; to: PMID: 35812758 Zhang et al., 2022 24yo Chinese female (46, XY) proband with complete gonadal dysgenesis (CGD) and biallelic PPP2R3C variants: p.F229del & p.G417E. Seq method: WES. She presented with poor development of secondary sexual characteristics and primary amenorrhea. She also had short stature (148 cm tall (-3SD) at 18 years old) and received growth hormone therapy. Literature review from the paper: "Thirteen 46, XY DSD patients had been reported in three articles previously (Guran et al., 2019; Cicek et al., 2021; Altunoglu et al., 2022). All the patients came from consanguineous marriages and had homozygous PPP2R3C variants. Eleven out of thirteen 46, XY DSD patients presented with complete gonadal dysgenesis, complete female vulva with hypoplastic labium major, and hypoplastic uterus. Sex hormone levels were compatible with complete gonadal dysgenesis. One patient presented with partial testicular dysgenesis, and he had ambiguous genitalia, micropenis, and left cryptorchidism. Also, three 46, XX DSD patients presented with complete gonadal dysgenesis, recognizable facial features, and multiple extragenital malformations." Other features reported: facial dysmorphism (16/16), retardation of bone age (15/ 16), delayed development of the nervous system / Neuromotor delay (14/16), and more variable features like SNHL, renal agenesis, myopathy, impaired vision. Intellect was mostly not reported, or noted to be 'low normal' - borderline ID. PMID: 34750818 - 8 patients with gonadal dysgenesis from 4 unrelated families of Turkish and Indian descent, with 3 different homozygous PPP2R3C variants PMID: 34714774 - 4 patients from 3 unrelated Turkish families with the same homozygous p.L193S variant in PPP2R3C - one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. PMID: 30893644 - Four Turkish female probands from four unrelated families with 46, XY complete gonadal dysgenesis and three different homozygous PPP2R3C variants. PPP2R3C is associated with AR Myoectodermal gonadal dysgenesis syndrome, OMIM:618419 (OMIM accessed 26th Oct 2026). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.32 | PPP2R3C |
Ida Ertmanska changed review comment from: PMID: 35812758 Zhang et al., 2022 24yo Chinese female (46, XY) proband with complete gonadal dysgenesis (CGD) and biallelic PPP2R3C variants: p.F229del & p.G417E. Seq method: WES. She presented with poor development of secondary sexual characteristics and primary amenorrhea. She also had short stature (148 cm tall (-3SD) at 18 years old) and received growth hormone therapy. Literature review from the paper: "Thirteen 46, XY DSD patients had been reported in three articles previously (Guran et al., 2019; Cicek et al., 2021; Altunoglu et al., 2022). All the patients came from consanguineous marriages and had homozygous PPP2R3C variants. Eleven out of thirteen 46, XY DSD patients presented with complete gonadal dysgenesis, complete female vulva with hypoplastic labium major, and hypoplastic uterus. Sex hormone levels were compatible with complete gonadal dysgenesis. One patient presented with partial testicular dysgenesis, and he had ambiguous genitalia, micropenis, and left cryptorchidism. Also, three 46, XX DSD patients presented with complete gonadal dysgenesis, recognizable facial features, and multiple extragenital malformations." Other features reported: facial dysmorphism (16/16), retardation of bone age (15/ 16), delayed development of the nervous system (14/16), and more variable features like SNHL, renal agenesis, myopathy, impaired vision. PMID: 34750818 - 8 patients with gonadal dysgenesis from 4 unrelated families of Turkish and Indian descent, with 3 different homozygous PPP2R3C variants PMID: 34714774 - 4 patients from 3 unrelated Turkish families with the same homozygous p.L193S variant in PPP2R3C - one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. PMID: 30893644 - Four Turkish female probands from four unrelated families with 46, XY complete gonadal dysgenesis and three different homozygous PPP2R3C variants. PPP2R3C is associated with AR Myoectodermal gonadal dysgenesis syndrome, OMIM:618419 (OMIM accessed 26th Oct 2026). Sources: Literature; to: PMID: 35812758 Zhang et al., 2022 24yo Chinese female (46, XY) proband with complete gonadal dysgenesis (CGD) and biallelic PPP2R3C variants: p.F229del & p.G417E. Seq method: WES. She presented with poor development of secondary sexual characteristics and primary amenorrhea. She also had short stature (148 cm tall (-3SD) at 18 years old) and received growth hormone therapy. Literature review from the paper: "Thirteen 46, XY DSD patients had been reported in three articles previously (Guran et al., 2019; Cicek et al., 2021; Altunoglu et al., 2022). All the patients came from consanguineous marriages and had homozygous PPP2R3C variants. Eleven out of thirteen 46, XY DSD patients presented with complete gonadal dysgenesis, complete female vulva with hypoplastic labium major, and hypoplastic uterus. Sex hormone levels were compatible with complete gonadal dysgenesis. One patient presented with partial testicular dysgenesis, and he had ambiguous genitalia, micropenis, and left cryptorchidism. Also, three 46, XX DSD patients presented with complete gonadal dysgenesis, recognizable facial features, and multiple extragenital malformations." Other features reported: facial dysmorphism (16/16), retardation of bone age (15/ 16), delayed development of the nervous system / Neuromotor delay (14/16), and more variable features like SNHL, renal agenesis, myopathy, impaired vision. PMID: 34750818 - 8 patients with gonadal dysgenesis from 4 unrelated families of Turkish and Indian descent, with 3 different homozygous PPP2R3C variants PMID: 34714774 - 4 patients from 3 unrelated Turkish families with the same homozygous p.L193S variant in PPP2R3C - one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. PMID: 30893644 - Four Turkish female probands from four unrelated families with 46, XY complete gonadal dysgenesis and three different homozygous PPP2R3C variants. PPP2R3C is associated with AR Myoectodermal gonadal dysgenesis syndrome, OMIM:618419 (OMIM accessed 26th Oct 2026). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.31 | PPP2R3C |
Ida Ertmanska changed review comment from: PMID: 35812758 Zhang et al., 2022 24yo Chinese female (46, XY) proband with complete gonadal dysgenesis (CGD) and biallelic PPP2R3C variants: p.F229del & p.G417E. Seq method: WES. She presented with poor development of secondary sexual characteristics and primary amenorrhea. She also had short stature (148 cm tall (-3SD) at 18 years old) and received growth hormone therapy. Literature review from the paper: "Thirteen 46, XY DSD patients had been reported in three articles previously (Guran et al., 2019; Cicek et al., 2021; Altunoglu et al., 2022). All the patients came from consanguineous marriages and had homozygous PPP2R3C variants. Eleven out of thirteen 46, XY DSD patients presented with complete gonadal dysgenesis, complete female vulva with hypoplastic labium major, and hypoplastic uterus. Sex hormone levels were compatible with complete gonadal dysgenesis. One patient presented with partial testicular dysgenesis, and he had ambiguous genitalia, micropenis, and left cryptorchidism. Also, three 46, XX DSD patients presented with complete gonadal dysgenesis, recognizable facial features, and multiple extragenital malformations." Other features reported: facial dysmorphism (16/16), retardation of bone age (15/ 16), delayed development of the nervous system (14/16), and more variable features like SNHL, renal agenesis, myopathy, impaired vision. PMID: 34750818 - 8 patients with gonadal dysgenesis from 4 unrelated families of Turkish and Indian descent, with 3 different homozygous PPP2R3C variants PMID: 34714774 - 4 patients from 3 unrelated Turkish families with the same homozygous p.L193S variant in PPP2R3C - one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. PMID: 30893644 - Four Turkish female probands from four unrelated families with 46, XY complete gonadal dysgenesis and three different homozygous PPP2R3C variants Sources: Literature; to: PMID: 35812758 Zhang et al., 2022 24yo Chinese female (46, XY) proband with complete gonadal dysgenesis (CGD) and biallelic PPP2R3C variants: p.F229del & p.G417E. Seq method: WES. She presented with poor development of secondary sexual characteristics and primary amenorrhea. She also had short stature (148 cm tall (-3SD) at 18 years old) and received growth hormone therapy. Literature review from the paper: "Thirteen 46, XY DSD patients had been reported in three articles previously (Guran et al., 2019; Cicek et al., 2021; Altunoglu et al., 2022). All the patients came from consanguineous marriages and had homozygous PPP2R3C variants. Eleven out of thirteen 46, XY DSD patients presented with complete gonadal dysgenesis, complete female vulva with hypoplastic labium major, and hypoplastic uterus. Sex hormone levels were compatible with complete gonadal dysgenesis. One patient presented with partial testicular dysgenesis, and he had ambiguous genitalia, micropenis, and left cryptorchidism. Also, three 46, XX DSD patients presented with complete gonadal dysgenesis, recognizable facial features, and multiple extragenital malformations." Other features reported: facial dysmorphism (16/16), retardation of bone age (15/ 16), delayed development of the nervous system (14/16), and more variable features like SNHL, renal agenesis, myopathy, impaired vision. PMID: 34750818 - 8 patients with gonadal dysgenesis from 4 unrelated families of Turkish and Indian descent, with 3 different homozygous PPP2R3C variants PMID: 34714774 - 4 patients from 3 unrelated Turkish families with the same homozygous p.L193S variant in PPP2R3C - one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. PMID: 30893644 - Four Turkish female probands from four unrelated families with 46, XY complete gonadal dysgenesis and three different homozygous PPP2R3C variants. PPP2R3C is associated with AR Myoectodermal gonadal dysgenesis syndrome, OMIM:618419 (OMIM accessed 26th Oct 2026). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.31 | PPP2R3C |
Ida Ertmanska changed review comment from: PMID: 35812758 Zhang et al., 2022 24yo Chinese female (46, XY) proband with complete gonadal dysgenesis (CGD) and biallelic PPP2R3C variants: p.F229del & p.G417E. Seq method: WES. She presented with poor development of secondary sexual characteristics and primary amenorrhea. She also had short stature (148 cm tall (-3SD) at 18 years old) and received growth hormone therapy. Literature review from the paper: "Thirteen 46, XY DSD patients had been reported in three articles previously (Guran et al., 2019; Cicek et al., 2021; Altunoglu et al., 2022). All the patients came from consanguineous marriages and had homozygous PPP2R3C variants. Eleven out of thirteen 46, XY DSD patients presented with complete gonadal dysgenesis, complete female vulva with hypoplastic labium major, and hypoplastic uterus. Sex hormone levels were compatible with complete gonadal dysgenesis. One patient presented with partial testicular dysgenesis, and he had ambiguous genitalia, micropenis, and left cryptorchidism. Also, three 46, XX DSD patients presented with complete gonadal dysgenesis, recognizable facial features, and multiple extragenital malformations." Other features reported: facial dysmorphism (16/16), retardation of bone age (15/ 16), delayed development of the nervous system (14/16), and more variable features like SNHL, renal agenesis, myopathy, impaired vision. PMID: 34750818 - 8 patients with gonadal dysgenesis from 4 unrelated families of Turkish and Indian descent, with 3 different homozygous PPP2R3C variants PMID: 34714774 - 4 patients from 3 unrelated Turkish families with the same homozygous p.L193S variant in PPP2R3C - one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. PMID: 30893644 - Four female probands from four unrelated families with 46, XY complete gonadal dysgenesis and three different homozygous PPP2R3C variants Sources: Literature; to: PMID: 35812758 Zhang et al., 2022 24yo Chinese female (46, XY) proband with complete gonadal dysgenesis (CGD) and biallelic PPP2R3C variants: p.F229del & p.G417E. Seq method: WES. She presented with poor development of secondary sexual characteristics and primary amenorrhea. She also had short stature (148 cm tall (-3SD) at 18 years old) and received growth hormone therapy. Literature review from the paper: "Thirteen 46, XY DSD patients had been reported in three articles previously (Guran et al., 2019; Cicek et al., 2021; Altunoglu et al., 2022). All the patients came from consanguineous marriages and had homozygous PPP2R3C variants. Eleven out of thirteen 46, XY DSD patients presented with complete gonadal dysgenesis, complete female vulva with hypoplastic labium major, and hypoplastic uterus. Sex hormone levels were compatible with complete gonadal dysgenesis. One patient presented with partial testicular dysgenesis, and he had ambiguous genitalia, micropenis, and left cryptorchidism. Also, three 46, XX DSD patients presented with complete gonadal dysgenesis, recognizable facial features, and multiple extragenital malformations." Other features reported: facial dysmorphism (16/16), retardation of bone age (15/ 16), delayed development of the nervous system (14/16), and more variable features like SNHL, renal agenesis, myopathy, impaired vision. PMID: 34750818 - 8 patients with gonadal dysgenesis from 4 unrelated families of Turkish and Indian descent, with 3 different homozygous PPP2R3C variants PMID: 34714774 - 4 patients from 3 unrelated Turkish families with the same homozygous p.L193S variant in PPP2R3C - one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. PMID: 30893644 - Four Turkish female probands from four unrelated families with 46, XY complete gonadal dysgenesis and three different homozygous PPP2R3C variants Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.31 | PPP2R3C |
Ida Ertmanska changed review comment from: PMID: 35812758 Zhang et al., 2022 PMID: 34750818 Altunoglu et al., 2022 PMID: 34714774 Cicek et al., 2021 PMID: 30893644 Guran et al., 2019 Sources: Literature; to: PMID: 35812758 Zhang et al., 2022 24yo Chinese female (46, XY) proband with complete gonadal dysgenesis (CGD) and biallelic PPP2R3C variants: p.F229del & p.G417E. Seq method: WES. She presented with poor development of secondary sexual characteristics and primary amenorrhea. She also had short stature (148 cm tall (-3SD) at 18 years old) and received growth hormone therapy. Literature review from the paper: "Thirteen 46, XY DSD patients had been reported in three articles previously (Guran et al., 2019; Cicek et al., 2021; Altunoglu et al., 2022). All the patients came from consanguineous marriages and had homozygous PPP2R3C variants. Eleven out of thirteen 46, XY DSD patients presented with complete gonadal dysgenesis, complete female vulva with hypoplastic labium major, and hypoplastic uterus. Sex hormone levels were compatible with complete gonadal dysgenesis. One patient presented with partial testicular dysgenesis, and he had ambiguous genitalia, micropenis, and left cryptorchidism. Also, three 46, XX DSD patients presented with complete gonadal dysgenesis, recognizable facial features, and multiple extragenital malformations." Other features reported: facial dysmorphism (16/16), retardation of bone age (15/ 16), delayed development of the nervous system (14/16), and more variable features like SNHL, renal agenesis, myopathy, impaired vision. PMID: 34750818 - 8 patients with gonadal dysgenesis from 4 unrelated families of Turkish and Indian descent, with 3 different homozygous PPP2R3C variants PMID: 34714774 - 4 patients from 3 unrelated Turkish families with the same homozygous p.L193S variant in PPP2R3C - one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. PMID: 30893644 - Four female probands from four unrelated families with 46, XY complete gonadal dysgenesis and three different homozygous PPP2R3C variants Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.27 | DMRT1 |
Ida Ertmanska changed review comment from: PMID: 36110220 Zidoune H, et al., 2022 Large study of developmental disorders cohort from North Africa. See suppl material for case details. P_73 - 29 days old male, het for de novo variant NM_021951.3(DMRT1):c.149G>C (p.Ser50Thr); phenotype: Genital bud, preputial orifice and perineal orifice, bifid labioscrotal folds, BC, NPG. Patient was also hemizygous for MAMLD1:NM_005491:c.C2075T:p.A692V - MAMLD1 is associated with Hypospadias 2, X-linked, OMIM:300758. Difficult to decouple the effect of each variant. PMID: 33057194 Kaplanis et al., 2020 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: P_19455: het for NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) P_24289: het for NM_021951.3(DMRT1):c.962C>A (p.Ala321Glu) These variants are not reported in gnomAD v4.1.1. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).; to: PMID: 36110220 Zidoune H, et al., 2022 Large study of developmental disorders cohort from North Africa. See suppl material for case details. P_73 - 29 days old male, het for de novo variant NM_021951.3(DMRT1):c.149G>C (p.Ser50Thr); phenotype: Genital bud, preputial orifice and perineal orifice, bifid labioscrotal folds, BC, NPG. Patient was also hemizygous for MAMLD1:NM_005491:c.C2075T:p.A692V - MAMLD1 is associated with Hypospadias 2, X-linked, OMIM:300758. Difficult to decouple the effect of each variant. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with 46,XY karyotype and variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.26 | DMRT1 | Ida Ertmanska changed review comment from: Comment on list classification: Based on available evidence, this gene can be promoted to Green on Differences in sex development at the next update, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.; to: Comment on list classification: There are now more than 3 cases reported in literature with heterozygous DMRT1 missense variants and gonadal dysgenesis. Based on available evidence, this gene can be promoted to Green on Differences in sex development at the next update, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.24 | DMRT1 |
Ida Ertmanska changed review comment from: PMID: 36110220 Zidoune H, et al., 2022 P_73 - 29 days old male, het for de novo variant NM_021951.3(DMRT1):c.149G>C (p.Ser50Thr); phenotype: Genital bud, preputial orifice and perineal orifice, bifid labioscrotal folds, BC, NPG. Patient was also hemizygous for MAMLD1:NM_005491:c.C2075T:p.A692V - MAMLD1 is associated with Hypospadias 2, X-linked, OMIM:300758. Difficult to decouple the effect of each variant. PMID: 33057194 Kaplanis et al., 2020 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: P_19455: het for NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) P_24289: het for NM_021951.3(DMRT1):c.962C>A (p.Ala321Glu) These variants are not reported in gnomAD v4.1.1. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).; to: PMID: 36110220 Zidoune H, et al., 2022 Large study of developmental disorders cohort from North Africa. See suppl material for case details. P_73 - 29 days old male, het for de novo variant NM_021951.3(DMRT1):c.149G>C (p.Ser50Thr); phenotype: Genital bud, preputial orifice and perineal orifice, bifid labioscrotal folds, BC, NPG. Patient was also hemizygous for MAMLD1:NM_005491:c.C2075T:p.A692V - MAMLD1 is associated with Hypospadias 2, X-linked, OMIM:300758. Difficult to decouple the effect of each variant. PMID: 33057194 Kaplanis et al., 2020 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: P_19455: het for NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) P_24289: het for NM_021951.3(DMRT1):c.962C>A (p.Ala321Glu) These variants are not reported in gnomAD v4.1.1. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.24 | DMRT1 |
Ida Ertmanska changed review comment from: PMID: 33057194 Kaplanis et al., 2020 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: P_19455: het for NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) P_24289: het for NM_021951.3(DMRT1):c.962C>A (p.Ala321Glu) These variants are not reported in gnomAD v4.1.1. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).; to: PMID: 36110220 Zidoune H, et al., 2022 P_73 - 29 days old male, het for de novo variant NM_021951.3(DMRT1):c.149G>C (p.Ser50Thr); phenotype: Genital bud, preputial orifice and perineal orifice, bifid labioscrotal folds, BC, NPG. Patient was also hemizygous for MAMLD1:NM_005491:c.C2075T:p.A692V - MAMLD1 is associated with Hypospadias 2, X-linked, OMIM:300758. Difficult to decouple the effect of each variant. PMID: 33057194 Kaplanis et al., 2020 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: P_19455: het for NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) P_24289: het for NM_021951.3(DMRT1):c.962C>A (p.Ala321Glu) These variants are not reported in gnomAD v4.1.1. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.24 | DMRT1 |
Ida Ertmanska changed review comment from: PMID: 33057194 Kaplanis et al., 2021 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).; to: PMID: 33057194 Kaplanis et al., 2020 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: P_19455: het for NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) P_24289: het for NM_021951.3(DMRT1):c.962C>A (p.Ala321Glu) These variants are not reported in gnomAD v4.1.1. PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.24 | DMRT1 |
Ida Ertmanska changed review comment from: PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).; to: PMID: 33057194 Kaplanis et al., 2021 Large exome seq study of Developmental Disorders cohort. 2 patients identified with gonadal dysgenesis and DMRT1 variants: NM_021951.3(DMRT1):c.673C>A (p.Leu225Ile) PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.24 | DMRT1 |
Ida Ertmanska changed review comment from: DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026).; to: PMID: 31745530 Buonocore et al., 2019 Study of a patient cohort with complete gonadal dysgenesis (CGD) (n = 27) and partially virilized 46,XY DSD (pvDSD) (n = 25). A patient with CGD and female genital phenotype was heterozygous for variant in DMRT1: c.240G>C, p.Arg80Ser - not reported in gnomAD v4.1.1, inheritance listed as sporadic. Some support for pathogenicity from protein computer modelling. PMID: 27711951 Chauhan et al., 2017 Study of 10 patients with variable DSD. Method: direct sequencing of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes. One patient with complete gonadal dysgenesis was found to be heterozygous for DMRT1: c.416T>A, p.Leu139Gln. PMID: 28295047 Fan et al., 2017 P19 - diagnosed with CGD, 46, XY karyotype with normal SRY; harboured het DMRT1 variant c.251A > G, p.Tyr84Cys - maternally inherited, labelled VUS. As DMRT1 is only expressed in male-specific gonads, authors hypothesise the variant would not be expected to cause a phenotype in the mother. This variant has total of 7 hets reported in gnomAD v4. DMRT1 association with AD "46 XY differences of sex development" has been classified as Definitive in ClinGen (Reproduction and Infertility Expert Panel, 03/18/2026). A separate Definitive association was made between DMRT1 and AD spermatogenic failure. DMRT1 is not yet associated with a disease entity in OMIM (accessed 25th Sept 2026). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.22 | TBX6 |
Luke Stuart gene: TBX6 was added gene: TBX6 was added to Differences in sex development. Sources: Literature Mode of inheritance for gene: TBX6 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TBX6 were set to 36049007; 23954021 Phenotypes for gene: TBX6 were set to Mullerian aplasia (MONDO:0019128); Mayer-Rokitansky-Kuster-Hauser syndrome (MONDO:0017771) Review for gene: TBX6 was set to AMBER Added comment: Ma et al. 2022 (PMID 36049007): 622 Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) probands, 16 rare heterozygous TBX6 variants, all single alleles with no biallelic or in-trans genotypes. Several variants were supported by in vitro functional evidence (splice/frameshift c.423G>A p.Leu141Leu, c.839+5G>A; reduced protein c.422T>C p.Leu141Pro, c.745G>A Val249Met; reduced transactivation c.10C>T, c.400G>A; mislocalisation c.356G>A p.Arg119His plus one prior canonical splice variant c.621+1G>A. Against diagnostic-grade rating: segregation studies showed multiple non manifesting female carriers suggesting incomplete penetrance (unaffected carrier mother, c.10C>T p.Pro4Ser; two of three carrier sisters with normal uterus, c.356G>A p.Arg119His), penetrance of the Müllerian phenotype is low among TBX6 LoF and 16p11.2-deletion carriers generally, and no second in-trans allele was found. The authors propose an digenic/oligogenic model in which TBX6 confers risk of urogenital phenotypes. No family showed penetrant monogenic segregation. Sandbacka et al. 2013 (PMID 23954021): ascertained series of 112 mullerain aplasia (MA) patients vs 200 controls. Heterozygous whole-gene TBX6/16p11.2 deletion in 5/112, three of whom also had skeletal/vertebral findings; this recurrent deletion is found in unaffected and non-reproductive-phenotype carriers elsewhere, indicating low penetrance of this phenotype. Splice variant c.622-2A>T in two patients was predicted LoF but RT-PCR was inconclusive. Two recurrent missense variants (p.Gly162Ser, p.Arg272Gln) were enriched in affecteds but also frequent in controls. No segregation data was shown. Two patients were homozygous for both recurrent TBX6 missense variants (p.Gly162Ser, p.Arg272Gln): one also carried a heterozygous missense variant in LHX1 (p.Pro312His), another a candidate gene for MRKHS, the other an 11q13.4 deletion. A third patient, heterozygous for both TBX6 recurrent missense variants, also carried LHX1 p.Pro312His. Overall: both studies support risk association and complex/oligogenic inheritance, but neither provides segregation, completed functional validation of a penetrant effect, or convincing evidence free of confounding co-occurring variants. The evidence does not meet criteria for penetrant monogenic disease reportable in a diagnostic setting; amber rating is appropriate. This phenotype regarding TBX6 is not cited in OMIM. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.15 | FGFR1 | Ida Ertmanska Added comment: Comment on list classification: There is only one individual reported in literature with a biallelic FGFR1 variant and a diagnosed difference in sex development (ambiguous genitalia - PMID: 27055092). Other reported cases are more aligned with diagnosis of Hypogonadotropic hypogonadism (FGFR1 is already Green on that panel). Hence, this gene can only be rated Red on Differences in sex development given the evidence available. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.14 | TACR3 |
Rabina Akhtar gene: TACR3 was added gene: TACR3 was added to Differences in sex development. Sources: Research,Literature Mode of inheritance for gene: TACR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TACR3 were set to PMID: 22031817; 20332248; 40101754 Phenotypes for gene: TACR3 were set to HYPOGONADOTROPIC HYPOGONADISM 11 WITH OR WITHOUT ANOSMIA; HH11 (OMIM: 614840) Penetrance for gene: TACR3 were set to Complete Review for gene: TACR3 was set to GREEN gene: TACR3 was marked as current diagnostic Added comment: PMID:22031817 reports a 19 year old patient with small testes, micropenis and bilateral cryptorchidism, compound heterozygous TACR3 variant (c.824G>A and c.1003C>T) PMID: 20332248 reports proband 3 of the study with micropenis and was found to be homozygous for TACR3 c.824G>A p.Trp275* variant PMID: 40101754 performed a systematic review of the literature (245 publications) to extract clinical data and the association with gene variants from 775 males with delayed or arrested puberty due to CHH. The characteristics of the genitalia in patients with causal variants in the TACR3 was summarized in this paper. A total of 17 disease causing TACR3 variants were identified. Of those, 3 patients had cryptorchidism, 10 patients had micropenis, 2 patients had microorchidism, 3 patients had cryptorchidism and micropenis, and 2 patients had micropenis and microorchidism. Additional male patient identified at WMGL with cryptorchidism and micropenis with a homozygous likely pathogenic TACR3 c.1057C>T p.(Pro353Ser) Sources: Research, Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.14 | FGFR1 |
Rabina Akhtar gene: FGFR1 was added gene: FGFR1 was added to Differences in sex development. Sources: Literature,Research Mode of inheritance for gene: FGFR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FGFR1 were set to (PMID: 41108094; 34589657; 32853167) Phenotypes for gene: FGFR1 were set to Hypogonadotropic hypogonadism 2 with out without anosmia Penetrance for gene: FGFR1 were set to Complete Review for gene: FGFR1 was set to GREEN gene: FGFR1 was marked as current diagnostic Added comment: PMID:41108094 reports a 14 year old male patient with micropenis, hypoplasia of the testes and angulation of the penis and was found to have a likely pathogenic FGFR1 c.263_264del p.Val88Alafs*22. PMID:34589657 reports a 7 year old male patient with history of bilateral cryptorchidism and was found to have a pathogenic FGFR1 c.1955A>C p.His652pro. PMID: 32853167 reports a 16 year old male with micropenis and bilateral cryptorchidism and was found to have a FGFR1 c.1864C>T p.Arg622* Additional male patient identified at WMGL with bilateral cryptorchidism and micropenis was found to have FGFR1 c.2008G>A p.Glu670Lys Sources: Literature, Research |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.12 | CYP11A1 | Ida Ertmanska edited their review of gene: CYP11A1: Added comment: Comment on mode of inheritance: There are only two potentially plausible reports of heterozygous CYP11A1 variants and adrenal insufficiency / differences in sex development (PMIDs: 29995203, 11502818). In contrast, there are at least 44 biallelic CYP11A1 cases with adrenal insufficiency and/or differences in sex development. Studies have shown that severe CYP11A1 LOF variants in conjunction with common, 'likely benign' variants (e.g., rs6161 in European populations) may underlie unsolved cases of PAI (PMID:30620006). Hence, the mode of inheritance should be changed to BIALLELIC, autosomal or pseudoautosomal, for Differences in sex development.; Changed rating: GREEN; Changed publications to: 11502818, 29995203, 30620006, 35418949, 39457196; Changed phenotypes to: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM: 613743, Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, MONDO:0013400; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v4.11 | DMRT1 | Sarah Leigh edited their review of gene: DMRT1: Added comment: Variants affecting DMRT1 have been reported in cases with 46,XY disorders/differences of sex development. PMID: 24934491 reports NM_021951.3(DMRT1):c.671A>G (p.Asn224Ser) in 2 unrelated azoospermic men with complete bilateral Sertoli cell-only syndrome and decreased testicular volume by ultrasound. PMID: 26139570 reports NM_021951.2 c.-223_-219CGAAA>T in the promoter of DMRT1, which is a region shown to be involved in the repression of Dmrt1 expression in rat and mouse Sertoli cells (PMID:11870074). Therefore this promoter variants could result in disruption of DMRT1 regulation. PMID: 39936125 reports four different deletions, which all encompass the DMRT1 region (9p24.3p23 - 9p24) in four unrelated cases with gonadal dysgenesis and .; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.66 | PRDM13 |
Ivone Leong Added comment: Comment on publications: New publication: 35390279. Publication reported eight individuals from four families of different origins with loss-of-function PRDM13 variants. Phenotypic findings included cerebellar hypoplasia and perinatal lethality associated with severe brainstem dysfunctions (e.g., feeding and respiratory difficulties, central apnea, bradycardia). The patients were too young to determine if disorders of sexual development was present. Therefore gene should still stay Amber. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.65 | PRDM13 | Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. Based on the expert review and evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.53 | HHAT | Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber but with a recommendation for green rating following GMS review. 2 cases reported with 46, XY karyotype and sex reversal, plus a supportive mouse model. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.46 | WNT2B |
Ivone Leong gene: WNT2B was added gene: WNT2B was added to Disorders of sex development. Sources: Literature Mode of inheritance for gene: WNT2B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WNT2B were set to 29909964; 33526876 Phenotypes for gene: WNT2B were set to Diarrhoea 9, OMIM:618168; 46,XX testicular disorder of sex development, MONDO:0100249 Review for gene: WNT2B was set to RED Added comment: This gene is associated with a phenotype in OMIM but not Gene2Phenotype. This gene is also present on the Intestinal failure panel (Version 1.28). Review submitted by Zornitza Stark on the Intestinal failure panel: "Diarrhoea-9 is a form of neonatal-onset chronic diarrhoea characterized by an osmotic diarrhoea that is not substrate specific, abnormal crypt and villus architecture, and significant fat malabsorption. Three probands from two unrelated families and functional data suggesting severe intestinal dysregulation due to decreased intestinal stem cell number and function. Borderline Green/Amber. Sources: Expert Review Zornitza Stark (Australian Genomics), 4 Jan 2021" PMID: 33526876 reports an additional unrelated case. Patient is of Haitian descent (previous cases described in PMID:29909964 are of Vietnamese and Kuwaiti origins). Patient has neonatal onset diarrhoea with metabolic acidosis and failure to thrive. Patient also has bilateral microcornea and corneal clouding. Patient also presented with ambiguous genitalia and diagnosed with 46,XX testicular DSD. The authors reviewed the clinical findings of the previous patients they had reported on (PMID:29909964) and found that the Kuwaiti patients had bilateral microcornea, corneal neovascularization and thick corneas (I-2), and bilateral iridocorneal adhesions, congenital cataract, and iris coloboma (I-3). The gonadal findings in the Haitian patient was not seen in any of the other affected patients. As there is only 1 case, this gene has been added as Red on this panel. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.43 | NR3C1 |
Ivone Leong changed review comment from: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. PMID:30158362 reviewed 23 index cases of patients with variants in NR3C1. There are 33 index cases as of June 2019 (PMID:31995340). PMID:30158362 found that 63% of cases showed hyperandrogenism and impaired fertility (ambiguous genitalia, hirsutism and oligomenorrhoea in females; precocious puberty and oligospermia in males). 50% cases showed hyperaldosteronism, with or without hypertensionand/or hypokalemia. There are also 4 biallelic cases (PMID:19933394; 7683692; 11932321; 31145715). There is enough evidence to support a gene-disease association. Therefore this gene should be rated Green at the next review.; to: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. PMID:30158362 reviewed 23 index cases of patients with variants in NR3C1. There are 33 index cases as of June 2019 (PMID:31995340). PMID:30158362 found that 63% of cases showed hyperandrogenism and impaired fertility (ambiguous genitalia, hirsutism and oligomenorrhoea in females; precocious puberty and oligospermia in males). 50% cases showed hyperaldosteronism, with or without hypertensionand/or hypokalemia. There is enough evidence to support a gene-disease association. Therefore this gene should be rated Green at the next review. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.39 | NR3C1 |
Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark. This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. PMID:30158362 reviewed 23 index cases of patients with variants in NR3C1. There are 33 index cases as of June 2019 (PMID:31995340). PMID:30158362 found that 63% of cases showed hyperandrogenism and impaired fertility (ambiguous genitalia, hirsutism and oligomenorrhoea in females; precocious puberty and oligospermia in males). 50% cases showed hyperaldosteronism, with or without hypertensionand/or hypokalemia. There are also 4 biallelic cases (PMID:19933394; 7683692; 11932321; 31145715). There is enough evidence to support a gene-disease association. Therefore this gene should be rated Green at the next review. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.37 | MYRF | Ivone Leong Added comment: Comment on list classification: This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association and this gene should be promoted to Green at the next review. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.35 | ESR2 | Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is currently not enough evidence to support a gene-disease association. Therefore, this gene has been given an Amber rating. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.28 | GATA4 | Ivone Leong Added comment: Comment on list classification: This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be promoted to Green at the next review. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.25 | HOXA13 | Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.23 | PAX8 | Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. This gene has been given an Amber rating as more evidence is required to support a gene-disease association. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.19 | PBX1 | Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM and Gene2Phenotype. As there is currently not enough evidence to support a gene-disease association, this gene has been given an Amber rating. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.18 | NR2F2 | Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. Therefore this gene should be Green at the next review. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.14 | TSPYL1 | Eleanor Williams Added comment: Comment on list classification: Leaving rating as amber, but there are 3 cases now reported and so this gene should be reviewed at the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.4 | FGFR2 |
Zornitza Stark gene: FGFR2 was added gene: FGFR2 was added to Disorders of sex development. Sources: Expert list Mode of inheritance for gene: FGFR2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FGFR2 were set to 26362256; 18155190 Phenotypes for gene: FGFR2 were set to LADD syndrome 149730; Bent bone dysplasia syndrome 614592 Review for gene: FGFR2 was set to GREEN Added comment: PMID: 26362256 - 1 individual with craniosynostosis and XY sex reversal and a missense variant. Phenotype recapitulated using mouse model, concludes a LOF mechanism. PMID: 18155190 - partial null mutant mouse model shows XY sex reversal PMID: 2238701 - 4 fetuses with de novo mutations and a skeletal disorder 3/4 had clitoromegaly, last fetus only had radiograph available. p.(Met391Arg) is recurring, variants are supported by functional studies showing protein mislocalization Mutations reported for all other FGFR2-related conditions have a GOF mechanism Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.4 | ESR2 |
Zornitza Stark gene: ESR2 was added gene: ESR2 was added to Disorders of sex development. Sources: Expert list Mode of inheritance for gene: ESR2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: ESR2 were set to 29261182; 9861029; 30113650 Phenotypes for gene: ESR2 were set to 46,XY disorder of sex development; Ovarian dysgenesis 8, MIM# 618187 Review for gene: ESR2 was set to AMBER Added comment: A homozygous indel (Asn181del) was identified in a syndromic case with 46,XY DSD, and 2 heterozygous missense variants were identified in 2 non-syndromic cases with 46,XY DSD. Asn181del and Leu426Arg were found to have significantly increased transcriptional activation in in vitro luciferase assays. Esrb null male mice showed no overt abnormalities and reproduced normally. Older mutant males displayed signs of prostate and bladder hyperplasia. A further individual reported with 46,XX karyotype and ovarian dysgenesis (PMID: 30113650) Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.4 | NR3C1 |
Zornitza Stark gene: NR3C1 was added gene: NR3C1 was added to Disorders of sex development. Sources: Expert list Mode of inheritance for gene: NR3C1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NR3C1 were set to 30158362 Phenotypes for gene: NR3C1 were set to Glucocorticoid resistance (MIM#615962) Review for gene: NR3C1 was set to GREEN gene: NR3C1 was marked as current diagnostic Added comment: Features include hyperandrogenism with features of ambiguous genitalia, precocious puberty, advanced bone age, infertility, amenorrhea, clitoromegaly, oligospermia. PMID: 30158362: Review of >5 patients reported with the associated phenotype. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.4 | PBX1 |
Zornitza Stark gene: PBX1 was added gene: PBX1 was added to Disorders of sex development. Sources: Literature Mode of inheritance for gene: PBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PBX1 were set to 31302614; 31058389 Phenotypes for gene: PBX1 were set to 46, XY gonadal dysgenesis Review for gene: PBX1 was set to AMBER Added comment: Two individuals reported with mono allelic variants in this gene and 46,XY gonadal dysgenesis. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.4 | NR2F2 |
Zornitza Stark gene: NR2F2 was added gene: NR2F2 was added to Disorders of sex development. Sources: Expert list Mode of inheritance for gene: NR2F2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NR2F2 were set to 29478779; 31687637 Phenotypes for gene: NR2F2 were set to 46,XX disorder of sex development (DSD) and congenital heart defects Review for gene: NR2F2 was set to GREEN Added comment: Four unrelated individuals reported. Note two had the same 7bp deletion, c.97_103delCCGCCCG, NM_021005.3, and the third individual had an adjacent deletion, c.103_109delGGCGCCC, NM_021005.3. All three were of very different ancestries, making founder effect unlikely. Fourth individual had a larger deletion encompassing this gene. Gene is also linked with isolated CHD (Congenital heart defects, multiple types, 4, MIM# 615779) Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.4 | DHX37 |
Zornitza Stark gene: DHX37 was added gene: DHX37 was added to Disorders of sex development. Sources: Literature Mode of inheritance for gene: DHX37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DHX37 were set to 31337883; 31745530 Phenotypes for gene: DHX37 were set to 46,XY gonadal dysgenesis; testicular regression syndrome (TRS) Review for gene: DHX37 was set to GREEN gene: DHX37 was marked as current diagnostic Added comment: Seventeen individuals reported in two studies. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v2.0 | MYRF |
Martina Owens gene: MYRF was added gene: MYRF was added to Disorders of sex development. Sources: Literature Mode of inheritance for gene: MYRF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MYRF were set to 30985895; 29446546; 31069960; 30070761; 30532227 Phenotypes for gene: MYRF were set to Cardiac-urogenital syndrome; gonadal hypoplasia; Müllerian duct hypoplasia Penetrance for gene: MYRF were set to unknown Review for gene: MYRF was set to AMBER Added comment: Hamanaka et al 2019 (PMID:30985895): enrichment study plus an independent cohort. Identified 3 de novo MYRF truncating variants in 4 DSD cases (3 families - 2 cases were monozygotic twins) and a de novo missense variant in 1 DSD case. Pinz et al 2018 (PMID: 29446546) reported de novo truncating MYRF variants in 2 male cases with genitourinary anomalies with congenital heart defects. Chitayat et al 2018 (PMID: 30070761) reported truncating variant in a patient with ambiguous genitalia and hypoplastic left heart syndrome. Qi et al 2018 (PMID: 30532227) reported 7 de novo patients with DSD, congenital heart defects and congenital diaphragmatic hernia. Rossetti et al 2019 (PMID: 31069960) reported above patients and 2 further patients with genitourinary anomalies and congenital diaphragmatic hernia. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development v1.32 | POR | Ivone Leong reviewed gene: POR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development | POR | Sarah Leigh marked POR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Differences in sex development | POR | Sarah Leigh commented on POR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||