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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 v2.64 PRDM13 Ivone Leong Phenotypes for gene: PRDM13 were changed from congenital hypogonadotropic hypogonadism, MONDO:0015770 to congenital hypogonadotropic hypogonadism, MONDO:0015770; Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, OMIM:619761
Differences in sex development v2.60 CYP11A1 Arina Puzriakova Added comment: Comment on mode of inheritance: Homozygous, compound heterozygous, and heterozygous (although most rare) variants in the CYP11A1 gene have all been associated with disease. Therefore, MOI should be updated to 'Both mono- and biallelic' at the next GMS panel update.
Differences in sex development v2.55 PRDM13 Zornitza Stark gene: PRDM13 was added
gene: PRDM13 was added to Disorders of sex development. Sources: Literature
Mode of inheritance for gene: PRDM13 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRDM13 were set to 34730112
Phenotypes for gene: PRDM13 were set to congenital hypogonadotropic hypogonadism, MONDO:0015770
Review for gene: PRDM13 was set to AMBER
Added comment: Recessive disease causing ID and DSD described in three unrelated families (2 consanguineous), but all are from Malta, and all share the same 13bp deletion spanning an exon-intron boundary, so likely founder effect.

Mouse KO is embryonically lethal, and tissue specific KO failed to replicate many of the patients phenotypes, other than hypoplasia of the cerebellar vermis and hemispheres.
Sources: Literature
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 v2.52 AR Arina Puzriakova Phenotypes for gene: AR were changed from Gender Assignment Gene Panel UKGTN; Androgen insensitivity, OMIM:300068; Androgen insensitivity,partial,with/without breast cancer, OMIM:312300; Hypospadias 1,X-linked, OMIM:300633 to Androgen insensitivity, OMIM:300068; Androgen insensitivity, partial, with or without breast cancer, OMIM:312300; Hypospadias 1, X-linked, OMIM:300633
Differences in sex development v2.51 CYP19A1 Arina Puzriakova Phenotypes for gene: CYP19A1 were changed from Gender Assignment Gene Panel (UKGTN); Endocrine disorders including disorders of sexual development; Aromatase deficiency, 613546 to Aromatase deficiency, OMIM:613546
Differences in sex development v2.50 CYP11A1 Arina Puzriakova Phenotypes for gene: CYP11A1 were changed from Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN); Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, 613743 to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, OMIM:613743
Differences in sex development v2.49 ATP6V0A4 Arina Puzriakova Phenotypes for gene: ATP6V0A4 were changed from Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN); Renal tubular acidosis, distal, autosomal recessive, 602722 to Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN); Distal renal tubular acidosis 3, with or without sensorineural hearing loss, OMIM:602722
Differences in sex development v2.48 AR Arina Puzriakova Phenotypes for gene: AR were changed from Gender Assignment Gene Panel UKGTN; Androgen insensitivity,300068; Androgen insensitivity,partial,with/without breast cancer,312300; Hypospadias 1,X-linked,300633 to Gender Assignment Gene Panel UKGTN; Androgen insensitivity, OMIM:300068; Androgen insensitivity,partial,with/without breast cancer, OMIM:312300; Hypospadias 1,X-linked, OMIM:300633
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 v2.45 FGFR2 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.

After consulting with the Genomics England Clinical Team, it was decided that this gene should be rated Amber. Helen Brittain (Genomics England):
"In the fetal cases the potential DSD phentoype is very mild and eclipsed by the skeletal / craniosynostosis presentation."
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 v2.36 MYRF Ivone Leong Phenotypes for gene: MYRF were changed from Cardiac-urogenital syndrome; gonadal hypoplasia; Müllerian duct hypoplasia to Cardiac-urogenital syndrome, OMIM:618280; gonadal hypoplasia; Mullerian duct hypoplasia
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 v2.34 ESR2 Ivone Leong Phenotypes for gene: ESR2 were changed from 46,XY disorder of sex development, MONDO:0020040; Ovarian dysgenesis 8, OMIM:618187 to 46,XY disorder of sex development, MONDO:0020040; ?Ovarian dysgenesis 8, OMIM:618187
Differences in sex development v2.33 ESR2 Ivone Leong Phenotypes for gene: ESR2 were changed from 46,XY disorder of sex development; Ovarian dysgenesis 8, MIM# 618187 to 46,XY disorder of sex development, MONDO:0020040; Ovarian dysgenesis 8, OMIM:618187
Differences in sex development v2.26 GATA4 Ivone Leong Phenotypes for gene: GATA4 were changed from ?Testicular anomalies with or without congenital heart disease 615542 to ?Testicular anomalies with or without congenital heart disease, OMIM:615542
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 v2.20 PBX1 Ivone Leong Phenotypes for gene: PBX1 were changed from 46, XY gonadal dysgenesis to 46, XY gonadal dysgenesis; 46,XY partial gonadal dysgenesis, MONDO:0016674
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 v2.17 NR2F2 Ivone Leong Phenotypes for gene: NR2F2 were changed from 46,XX disorder of sex development (DSD) and congenital heart defects to 46,XX sex reversal 5, OMIM:618901; 46,XX sex reversal 5, MONDO:0030049
Differences in sex development v2.16 PAX8 Zornitza Stark gene: PAX8 was added
gene: PAX8 was added to Disorders of sex development. Sources: Literature
Mode of inheritance for gene: PAX8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PAX8 were set to 33434492
Phenotypes for gene: PAX8 were set to Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS)
Review for gene: PAX8 was set to AMBER
Added comment: Variants in this gene are associated with congenital hypothyroidism.

5 individuals identified in large cohorts with MRKHS and likely deleterious variants in PAX8. At least one of the individuals had congenital hypothyroidism together with features of MRKHS, suggesting this is phenotype expansion. Amber rating suggested due to limited case-level data.
Sources: Literature
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 v2.11 TCF12 Arina Puzriakova changed review comment from: Comment on list classification: Variants in TCF12 typically cause craniosynostosis, while evidence for an association with Kallmann Syndrome is currently based on a single study, and therefore warrants further investigation. Furthermore, the presence of incomplete penetrance must be considered.

Additional cases would help validate the pathogenicity of TCF12 variants in aberrant GnRH axis development.

Therefore, rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).; to: Comment on list classification: Variants in TCF12 typically cause craniosynostosis, while evidence for an association with Kallmann Syndrome is currently based on a single study, and therefore warrants further investigation. Furthermore, the presence of incomplete penetrance must be considered. Additional cases would help validate the pathogenicity of TCF12 variants in aberrant GnRH axis development.

Therefore, rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).
Differences in sex development v2.11 TCF12 Arina Puzriakova Added comment: Comment on list classification: Variants in TCF12 typically cause craniosynostosis, while evidence for an association with Kallmann Syndrome is currently based on a single study, and therefore warrants further investigation. Furthermore, the presence of incomplete penetrance must be considered.

Additional cases would help validate the pathogenicity of TCF12 variants in aberrant GnRH axis development.

Therefore, rating Amber in anticipation of additional publications/clinical evidence (added to watchlist).
Differences in sex development v2.10 TCF12 Arina Puzriakova gene: TCF12 was added
gene: TCF12 was added to Disorders of sex development. Sources: Literature
Mode of inheritance for gene: TCF12 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TCF12 were set to 32620954
Phenotypes for gene: TCF12 were set to Kallmann syndrome
Review for gene: TCF12 was set to AMBER
Added comment: Note monoallelic variants in this gene are a well-established cause of craniosynostosis.
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- PMID: 32620954 (2020) - 13 unrelated kindreds (11 de novo, 1 AD and 1 AR) comprising 14 affected individuals with an anosmic form of isolated GnRH deficiency (IGD) (Kallman syndrome) due to different LoF variants in TCF12.

Clinical manifestation included anosmia and pubertal failure (with reproductive phenotypes such as micropenis, bilateral cryptorchidism, hypospadias). Two unrelated individuals within the cohort additionally exhibited craniosynostosis, and a further two pedigrees had a family history of craniosynostosis (that did not affect the index cases). Multiplex cases typically presented incomplete penetrance.

Loss of tcf12 in a mutant zebrafish model perturbed GnRH neuronal patterning, with concomitant expression attenuation of tcf3a/b and stub1 (latter mutated in other syndromic forms of IGD). Furthermore, restored STUB1 expression rescued loss of tcf12 in vivo.
Sources: Literature
Differences in sex development v2.8 DHX37 Arina Puzriakova Phenotypes for gene: DHX37 were changed from 46,XY gonadal dysgenesis; testicular regression syndrome (TRS) to 46, XY sex reversal 11, 273250
Differences in sex development v2.6 PPP1R12A Arina Puzriakova Added comment: Comment on list classification: There is enough evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with significant genitourinary malformations.
Differences in sex development v2.5 PPP1R12A Arina Puzriakova gene: PPP1R12A was added
gene: PPP1R12A was added to Disorders of sex development. Sources: Literature
for-review tags were added to gene: PPP1R12A.
Mode of inheritance for gene: PPP1R12A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PPP1R12A were set to 31883643
Phenotypes for gene: PPP1R12A were set to Genitourinary and/or/brain malformation syndrome, 618820
Review for gene: PPP1R12A was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for PPP1R12A-related Holoprosencephaly Spectrum and Urogenital Malformations in G2P.

PMID: 31883643 (2020) - Screening cohorts of patients with holoprosencephaly and patients with disorders of sex development revealed 12 unrelated individuals with de novo LoF variants in the PPP1R12A gene. Variants were associated with a broad spectrum of manifestations, and a clear genotype-phenotype correlation was not observed - most commonly presentation included either malformations of the brain or the genitourinary tract (two individuals exhibited both brain and genitourinary anomalies). Out of the 12 patients, 4 were XY females and 3 were XY males with significant anomalies.
Sources: Literature
Differences in sex development v2.4 HOXA13 Zornitza Stark gene: HOXA13 was added
gene: HOXA13 was added to Disorders of sex development. Sources: Expert list
Mode of inheritance for gene: HOXA13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HOXA13 were set to 10839976; 9020844
Phenotypes for gene: HOXA13 were set to Hand-foot-uterus syndrome, MIM# 140000
Review for gene: HOXA13 was set to GREEN
gene: HOXA13 was marked as current diagnostic
Added comment: Hypospadias/bifid scrotum in males, Mullerian duct fusion defects in females (double uterus, double cervix, longitudinal vaginal septum).
Sources: Expert list
Differences in sex development v2.4 GATA4 Zornitza Stark reviewed gene: GATA4: Rating: GREEN; Mode of pathogenicity: None; Publications: 21220346, 31962012; Phenotypes: Testicular anomalies with or without congenital heart disease, MIM#615542; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
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 MYRF Zornitza Stark reviewed gene: MYRF: Rating: GREEN; Mode of pathogenicity: None; Publications: 30985895, 29446546, 31069960, 30070761, 30532227; Phenotypes: Cardiac-urogenital syndrome, gonadal hypoplasia, Müllerian duct hypoplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
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 v1.37 Ivone Leong List of related panels changed from to R146
Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Differences in sex development v1.36 ZFPM2 Ivone Leong Added comment: Comment on list classification: Demoted from green to amber based on the evidence provided by Martina Owens (Exeter Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust).
Differences in sex development v1.34 TSPYL1 Ivone Leong Added comment: Comment on list classification: Promoted from red to amber. TSPYL1 is associated with a phenotype in OMIM but not Gene2Phenotype. As there are only 2 unrelated cases with different variants in the gene, it was decided that there is currently not enough evidence to promote to green status. There was agreement to promote this gene to amber by experts in GMS Endocrinology Specialist Test Group. Until further evidence is available, TSPYL1 will be promoted to amber.
Differences in sex development v1.33 SGPL1 Ivone Leong Added comment: Comment on list classification: Promoted from amber to green. There was agreement to promote to green because experts in paediatric endocrinology agreed that ambiguous genitalia may be the presenting feature in some cases, and an early diagnosis may significantly reduce the chance of adverse clinical outcomes
Differences in sex development v1.32 STAR Ivone Leong reviewed gene: STAR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Differences in sex development v1.32 ARX Ivone Leong reviewed gene: ARX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Differences in sex development v1.32 AR Ivone Leong reviewed gene: AR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Differences in sex development v1.31 AMHR2 Ivone Leong Added comment: Comment on list classification: Promoted from red to green as recommended by Martina Owens (Exeter Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust). There are >3 unrelated cases of patients with variants in AMHR2 who have Persistent Mullerian duct syndrome, type II (PMID: 28528332).
Differences in sex development v1.30 AMH Ivone Leong Added comment: Comment on list classification: Promoted from red to green as recommended by Martina Owens (Exeter Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust). There are >3 unrelated cases of patients with variants in AMH who have Persistent Mullerian duct syndrome, type I (PMID: 28528332).
Differences in sex development v1.29 AMH Ivone Leong Added comment: Comment on list classification: Promoted from red to green as recommended by Martina Owens (Exeter Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust). There are >3 unrelated cases of patients with variants in AMH who have Persistent Mullerian duct syndrome, type I (PMID: 28528332).
Differences in sex development v1.25 Ellen McDonagh List of related panels changed from to
Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual
Differences in sex development v1.24 ISCA-37401-Loss Louise Daugherty Region: ISCA-37401-Loss was added
Region: ISCA-37401-Loss was added to Disorders of sex development. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37401-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37401-Loss were set to Wilms tumor, aniridia, genitourinary anomalies and mental retardation syndrome; 194072
Differences in sex development TOE1 Helen Brittain marked TOE1 as ready
Differences in sex development SAMD9 Helen Brittain marked SAMD9 as ready
Differences in sex development ATRX Sarah Leigh marked ATRX as ready
Differences in sex development NR0B1 Sarah Leigh marked NR0B1 as ready
Differences in sex development INPP5E Sarah Leigh marked INPP5E as ready
Differences in sex development CUL4B Sarah Leigh marked CUL4B as ready
Differences in sex development GLI2 Sarah Leigh marked GLI2 as ready
Differences in sex development CHD7 Sarah Leigh marked CHD7 as ready
Differences in sex development TSPYL1 Sarah Leigh marked TSPYL1 as ready
Differences in sex development ZFPM2 Sarah Leigh marked ZFPM2 as ready
Differences in sex development TSPYL1 Sarah Leigh marked TSPYL1 as ready
Differences in sex development TAF4B Sarah Leigh marked TAF4B as ready
Differences in sex development MAP3K1 Sarah Leigh marked MAP3K1 as ready
Differences in sex development HSD17B2 Sarah Leigh marked HSD17B2 as ready
Differences in sex development HHAT Sarah Leigh marked HHAT as ready
Differences in sex development DMRT1 Sarah Leigh marked DMRT1 as ready
Differences in sex development DGKQ Sarah Leigh marked DGKQ as ready
Differences in sex development PAX6 Sarah Leigh marked PAX6 as ready
Differences in sex development CDKN1C Sarah Leigh marked CDKN1C as ready
Differences in sex development ARX Sarah Leigh marked ARX as ready
Differences in sex development ARX Sarah Leigh commented on ARX
Differences in sex development CYB5A Sarah Leigh marked CYB5A as ready
Differences in sex development AKR1C2 Sarah Leigh marked AKR1C2 as ready
Differences in sex development SRD5A2 Sarah Leigh marked SRD5A2 as ready
Differences in sex development RSPO1 Sarah Leigh marked RSPO1 as ready
Differences in sex development MAMLD1 Sarah Leigh marked MAMLD1 as ready
Differences in sex development GATA4 Sarah Leigh marked GATA4 as ready
Differences in sex development DHH Sarah Leigh marked DHH as ready
Differences in sex development CYP21A2 Sarah Leigh marked CYP21A2 as ready
Differences in sex development CBX2 Sarah Leigh marked CBX2 as ready
Differences in sex development ATP6V0A4 Sarah Leigh marked ATP6V0A4 as ready
Differences in sex development AR Sarah Leigh marked AR as ready
Differences in sex development AR Sarah Leigh classified AR as green
Differences in sex development AR Sarah Leigh commented on AR
Differences in sex development STAR Sarah Leigh marked STAR as ready
Differences in sex development STAR Sarah Leigh commented on STAR
Differences in sex development WT1 Sarah Leigh marked WT1 as ready
Differences in sex development SRY Sarah Leigh marked SRY as ready
Differences in sex development SOX9 Sarah Leigh marked SOX9 as ready
Differences in sex development POR Sarah Leigh marked POR as ready
Differences in sex development NR5A1 Sarah Leigh marked NR5A1 as ready
Differences in sex development LHCGR Sarah Leigh marked LHCGR as ready
Differences in sex development HSD3B2 Sarah Leigh marked HSD3B2 as ready
Differences in sex development HSD17B3 Sarah Leigh marked HSD17B3 as ready
Differences in sex development DHCR7 Sarah Leigh marked DHCR7 as ready
Differences in sex development CYP19A1 Sarah Leigh marked CYP19A1 as ready
Differences in sex development CYP17A1 Sarah Leigh marked CYP17A1 as ready
Differences in sex development CYP11B1 Sarah Leigh marked CYP11B1 as ready
Differences in sex development CYP11A1 Sarah Leigh marked CYP11A1 as ready