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| Disorders of 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. |
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| Disorders of 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Disorders of 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Disorders of 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 |
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| Disorders of 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. |
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| Disorders of 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. |
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| Disorders of 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Disorders of 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Disorders of 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Disorders of 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Disorders of 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Disorders of 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Disorders of 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Disorders of 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Disorders of 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 |
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| Disorders of 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 |
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| Disorders of 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 |
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| Disorders of 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 |
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| Disorders of 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 |
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| Disorders of 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 |
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| Disorders of 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 |
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| Disorders of sex development v1.32 | POR | Ivone Leong reviewed gene: POR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Disorders of sex development | POR | Sarah Leigh marked POR as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Disorders of sex development | POR | Sarah Leigh commented on POR | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||