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Differences of Sex Development v0.293 RXFP2 Katie Ayers edited their review of gene: RXFP2: Added comment: One individual with bilateral cryptorchidism and infertility had homozygous c.1406delT in RXFP2 (NM_130806.5), leading to a frameshift p.(Phe469Serfs*8). From consanguinous family.

Two affected brothers with homozygous missense variant c.1015A>G in RXFP2 (NM_130806.5) resulting in an amino acid substitution p.(Asn339Asp) with bilateral cryptorchidism.; Changed publications: 37208861; Changed phenotypes: Infertility, cryptorchidism, non-obstructive azoospermia
Differences of Sex Development v0.293 RXFP2 Katie Ayers edited their review of gene: RXFP2: Added comment: Homozygous non-canonical splicing variant by whole-exome sequencing and Sanger sequencing . NM_130806: c.1376-12A > G; Changed rating: GREEN; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications: 38430325; Changed phenotypes: cryptorchidism and non-obstructive azoospermia; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Differences of Sex Development v0.293 AXL Zornitza Stark gene: AXL was added
gene: AXL was added to Differences of Sex Development. Sources: Expert Review
Mode of inheritance for gene: AXL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AXL were set to 24476074
Phenotypes for gene: AXL were set to Hypogonadotropic hypogonadism, MONDO:0018555, AXL-related
Review for gene: AXL was set to RED
Added comment: Four variants reported in individuals with KS/IHH. One is non-canonical splice site variant (c.586-6 C>T) but authors demonstrate no abnormal splicing occurs. Remainder are missense. Segregation in one family only: inherited from phenotypically normal parent. Axl null mice demonstrated delay in first estrus and the interval between vaginal opening and first estrus
Sources: Expert Review
Differences of Sex Development v0.292 SEMA3A Zornitza Stark Marked gene: SEMA3A as ready
Differences of Sex Development v0.291 SEMA3A Zornitza Stark gene: SEMA3A was added
gene: SEMA3A was added to Differences of Sex Development. Sources: Expert Review
Mode of inheritance for gene: SEMA3A was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: SEMA3A were set to 28075028; 33369061; 20301509; 21059704; 24124006; 22927827
Phenotypes for gene: SEMA3A were set to Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897
Review for gene: SEMA3A was set to GREEN
Added comment: Heterozygous variants associated with isolated GnRH deficiency with or without anosmia (Kallman syndrome like). More severe phenotype with biallelic SEMA3A variants including postnatal short stature and congenital heart defects in 3/3 published, unrelated individuals.

PMID 33369061 Gileta et al 2021 - report x1 patient. Female proband was compound heterozygote for a nonsense variant and a multiexonic deletion of SEMA3A. Presents with postnatal short stature, congenital cardiac anomalies, dysmorphic features, hypogonadotrophic hypogonadism and anosmia.

PMID 28075028 Baumann et al 2017 - report x1 patient. Homozygous LoF variants identified in a proband from a consanguineous Turkish family. Noted at birth to have a high-positioned scapulae, deformed ribs and a lateral clavicular hook. The patient also had upper/lower limb contractures and aberrant right subclavian artery. Mild facial dysmorphism, micropenis and hypogonadotrophic hypogonadism also noted in the first week of life. Postnatal short stature (length 50cm at term birth)

PMID 24124006 Hofmann et al 2013 - first reported biallelic variants in a proband with postnatal short stature, skeletal anomalies of the thorax, congenital heart
defect and camptodactyly
Sources: Expert Review
Differences of Sex Development v0.289 DCAF17 Zornitza Stark Marked gene: DCAF17 as ready
Differences of Sex Development v0.287 CLPP Zornitza Stark Marked gene: CLPP as ready
Differences of Sex Development v0.286 CLPP Zornitza Stark gene: CLPP was added
gene: CLPP was added to Differences of Sex Development. Sources: Expert Review
Mode of inheritance for gene: CLPP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPP were set to 23541340; 25956234; 26970254; 27087618; 27650058; 27650058; 27899912
Phenotypes for gene: CLPP were set to Perrault syndrome 3, MIM# 614129
Review for gene: CLPP was set to AMBER
Added comment: Multiple families with Perrault syndrome, HH is an inconsistent feature.

PMID: 23541340, describes 3 consanguineous Pakistani families (PDF1, PKDF291 and DEM4395), all affected individuals had sensorineural hearing loss. Family PDF1: 3 affected sisters, 1/3 had delayed puberty, streak ovaries and hormone levels consistant with hypogonadotropic hypogonadism, 2/3 had incipient POF and 1/3 had white matter phenotype. All three had epilepsy, short stature, microcephaly (< 3 percentile), moderate learning difficulties and ataxia.
Family PKDF291: 4 affected females with primary amenorrhea and hypogonadotropic hypogonadism. 3/4 had rudimentary uterus and small ovaries, 1/4 had small uterus and normal sized ovaries. No learning disabilities, microcephaly, short stature, epilepsy or neurological deficiet in all affected females.
Family DEM4395: 1 affected male and 2 affected females. All females had normal periods but their hormone profiles were not investigated. Aside from hearing loss there were no other self reported medical problems.

PMID: 25956234. Consanguineous Saudi family with 1 affected male and 1 affected female. Both patients have hearing loss, growth retardation and mental retardation, spastic diplegia and mild-severe white matter loss. No seizures were described in the patients. There is a third sibling (8 months) with the same variant; however, he did not show any of the phenotypes seen in his siblings but he is under regular checkups from a clinical team.

PMID:26970254. Consanguineous family of Arabic descent. Proband with 4 unaffected siblings and parents. Proband has hearing loss, azoospermia, no neurological symptoms other than the foot drop (neurophysiology revealed a sensory-motor demyelinative axonal peripheral neuropathy of the lower limbs). Father has cerebellar ataxia (cause unknown).

PMID: 27087618. Non-consanguineous Turkish family; however, parents are from the same village. 2 affected siblings (1 male, 1 female). Sister has secondary amenorrhea, hearing loss, no ovaries detected, hypogonadotropic hypogonadism, no neurological problems. Brother has hearing loss but no other problems.

PMID: 27650058. Consanguineous Algerian family with 2 affected females. Both have hearing loss and secondary amenorrhea, but no other neurological symptoms.

PMID: 27899912. 3 affected families, with 5 affected individuals (all males). All had congenital deafness, psychomotor retardation, white matter phenotype and short stature. Patients were not tested for infertility.
Sources: Expert Review
Differences of Sex Development v0.285 CCDC141 Zornitza Stark Marked gene: CCDC141 as ready
Differences of Sex Development v0.284 CCDC141 Zornitza Stark gene: CCDC141 was added
gene: CCDC141 was added to Differences of Sex Development. Sources: Expert Review
Mode of inheritance for gene: CCDC141 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CCDC141 were set to 251920460; 28324054; 32520725; 27014940
Phenotypes for gene: CCDC141 were set to congenital hypogonadotropic hypogonadism, MONDO:0015770, CCDC141-related
Review for gene: CCDC141 was set to AMBER
Added comment: PMID: 251920460 describes 2 affected siblings from a consanguineous family with anosmic HH, who had homozygous variant in FEZF1 (Amber gene on this panel) and also homozyous for variant in CCDC141.

PMID: 28324054 describes the above case and also 3 new cases (all had normal sense of smell and HH). Family 2: compound het for CCDC141 and heterozygous for DMXL2 variant. Family 3: heterozygous for CCDC141 variant and heterozygous for variants in 3 other genes (NR5A2, FSHB - Green on HH panel, IGSF10). Family 4: affected patient was heterozygous for CCDC141 variant, which the father also carried but father was unaffected.

PMID: 32520725 describes a large Chinese cohort with congenital HH looking at the contribution of CCDC141 to the disease. 12 probands had variants CCDC141 and 9 of these probands had variants in other HH-related genes (inluding PCSK1, ANOS1, PROKR2, AXL, SOX10, HS6ST1, PNPLA6 and FGFR1). The authors concluded that CCDC141 variants alone is not sufficient to cause HH.

PMID: 27014940 talks about a ccdc141 knockdown mouse model reduces GnRH neuronal migration.

Overall, insufficient evidence for gene-disease association; may be a modifier.
Sources: Expert Review
Differences of Sex Development v0.283 NR2F2 Zornitza Stark Phenotypes for gene: NR2F2 were changed from 46,XX disorder of sex development (DSD) and congenital heart defects to 46XX sex reversal 5, MIM# 618901
Differences of Sex Development v0.282 SOX11 Zornitza Stark Marked gene: SOX11 as ready
Differences of Sex Development v0.281 SOX11 Zornitza Stark gene: SOX11 was added
gene: SOX11 was added to Differences of Sex Development. Sources: Expert Review
Mode of inheritance for gene: SOX11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOX11 were set to 29459093; 24886874; 33086258; 33785884; 35642566; 35341651
Phenotypes for gene: SOX11 were set to Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, MIM# 615866
Review for gene: SOX11 was set to GREEN
Added comment: Over 40 individuals reported, e.g. PMID 35341651. The phenotype that has emerged over time is distinct from patients with mutations in ARID1B (614556) and Coffin-Siris syndrome-1 (135900). Patients with IDDMOH tend to be microcephalic and have ocular motor apraxia, abnormal eye morphology, or hypogonadotropic hypogonadism.
Sources: Expert Review
Differences of Sex Development v0.280 SLC20A1 Zornitza Stark Marked gene: SLC20A1 as ready
Differences of Sex Development v0.279 PTCH1 Zornitza Stark Marked gene: PTCH1 as ready
Differences of Sex Development v0.277 SLC20A1 Chirag Patel gene: SLC20A1 was added
gene: SLC20A1 was added to Differences of Sex Development. Sources: Literature
Mode of inheritance for gene: SLC20A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC20A1 were set to PMID: 32850778, 27013921
Phenotypes for gene: SLC20A1 were set to Bladder-Exstrophy-Epispadias Complex (BEEC)
Review for gene: SLC20A1 was set to GREEN
gene: SLC20A1 was marked as current diagnostic
Added comment: Three individuals with BEEC and animal model supporting role of this gene in urinary tract and urorectal development.
Sources: Literature
Differences of Sex Development v0.276 PTCH1 Chirag Patel gene: PTCH1 was added
gene: PTCH1 was added to Differences of Sex Development. Sources: Other
Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PTCH1 were set to Bladder exstrophy and epispadias complex (BEEC)
Review for gene: PTCH1 was set to AMBER
Added comment: ESHG 2023:
9 individuals with BEEC (WES/Sanger) with 9 x rare HTZ variants in PTCH1 (2 de novo, 7 inherited unaffected parent). No clinical features of Gorlin syndrome and variants not seen in Gorlin syndrome.

Zebrafish models:
a) knock out and knock in (1 missense variant) models showed no phenotype
b) co-injection of WT and missense variant led to altered cloaca on D5.
Proposed mechanism is dominant negative effect.
Sources: Other
Differences of Sex Development v0.276 PTCH1 Chirag Patel gene: PTCH1 was added
gene: PTCH1 was added to Differences of Sex Development. Sources: Other
Mode of inheritance for gene: PTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PTCH1 were set to Bladder exstrophy and epispadias complex (BEEC)
Review for gene: PTCH1 was set to AMBER
Added comment: ESHG 2023:
9 individuals with BEEC (WES/Sanger) with 9 x rare HTZ variants in PTCH1 (2 de novo, 7 inherited unaffected parent). No clinical features of Gorlin syndrome and variants not seen in Gorlin syndrome.

Zebrafish models:
a) knock out and knock in (1 missense variant) models showed no phenotype
b) co-injection of WT and missense variant led to altered cloaca on D5.
Proposed mechanism is dominant negative effect.
Sources: Other
Differences of Sex Development v0.275 SART3 Krithika Murali Classified gene: SART3 as Green List (high evidence)
Differences of Sex Development v0.275 SART3 Krithika Murali Gene: sart3 has been classified as Green List (High Evidence).
Differences of Sex Development v0.274 SART3 Krithika Murali Marked gene: SART3 as ready
Differences of Sex Development v0.274 SART3 Krithika Murali Gene: sart3 has been removed from the panel.
Differences of Sex Development v0.274 SART3 Daniel Flanagan gene: SART3 was added
gene: SART3 was added to Differences of Sex Development. Sources: Expert list
Mode of inheritance for gene: SART3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SART3 were set to PMID: 37296101
Phenotypes for gene: SART3 were set to Neurodevelopmental disorder (MONDO#0700092), SART3-related; 46,XY disorder of sex development (MONDO:0020040), SART3-related
Review for gene: SART3 was set to GREEN
Added comment: Nine individuals from six families presenting with intellectual disability, global developmental delay, a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Additionally, two individuals had seizures and two had epileptiform activity reported on EEG.

Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro.
Sources: Expert list
Differences of Sex Development v0.274 DAAM2 Zornitza Stark Marked gene: DAAM2 as ready
Differences of Sex Development v0.272 ARHGAP35 Zornitza Stark Marked gene: ARHGAP35 as ready
Differences of Sex Development v0.272 ARHGAP35 Zornitza Stark Gene: arhgap35 has been classified as Green List (High Evidence).
Differences of Sex Development v0.272 ARHGAP35 Zornitza Stark Phenotypes for gene: ARHGAP35 were changed from Idiopathic hypogonadotropic hypogonadism, no OMIM # to Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related
Differences of Sex Development v0.271 ARHGAP35 Zornitza Stark reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Differences of Sex Development v0.271 ARHGAP35 Chirag Patel Classified gene: ARHGAP35 as Green List (high evidence)
Differences of Sex Development v0.271 ARHGAP35 Chirag Patel Gene: arhgap35 has been classified as Green List (High Evidence).
Differences of Sex Development v0.270 ARHGAP35 Chirag Patel gene: ARHGAP35 was added
gene: ARHGAP35 was added to Differences of Sex Development. Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to PMID: 36178483
Phenotypes for gene: ARHGAP35 were set to Idiopathic hypogonadotropic hypogonadism, no OMIM #
Review for gene: ARHGAP35 was set to GREEN
Added comment: 12 patients with idiopathic hypogonadotropic hypogonadism. Rare protein-truncating variants (n = 5) and missense variants (n = 7) found in the RhoGAP domain of ARHGAP35 gene. Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a (predominant ARHGAP35 paralog in zebrafish brain), displayed decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant (Arg1284Trp) had decreased GAP activity.
Sources: Literature
Differences of Sex Development v0.268 KCNK3 Zornitza Stark Marked gene: KCNK3 as ready
Differences of Sex Development v0.267 KCNK3 Krithika Murali gene: KCNK3 was added
gene: KCNK3 was added to Differences of Sex Development. Sources: Literature
Mode of inheritance for gene: KCNK3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNK3 were set to 36195757
Phenotypes for gene: KCNK3 were set to Neurodevelopmental disorder, MONDO:0700092, KCNK3-related; developmental delay with sleep apnoea (DDSA)
Review for gene: KCNK3 was set to GREEN
Added comment: PMID 36195757 Sörmann et al 2022 report 9 unrelated individuals with de novo heterozygous KCNK3 missense variants (21 weeks to 25 years old). All 8 living probands (3-25 years) had hypotonia, global developmental delay, central and/or obstructive sleep apnoea and feeding difficulties. 7/9 probands had additional anomalies including microcephaly (at least 3/9), arthrogryposis/flexion contractures/foot deformities (7/9), scoliosis, cleft palate (2/9), and ambiguous genitalia/undescended testes (5/6) and dysmorphism. IUGR reported in 3/9 probands and polyhdramnios in 2/9.

KCNK3 encodes the TASK-1 K2P channel expressed throughout the central nervous system. All identified variants clustered near the X-gate and are involved in inter- or intra-subunit interaction likely to hold the X-gate closed. Individuals with variants located in the M2 transmembrane helix had a more severe phenotype than those with variants in the M4 helix. Functional studies support a gain of function disease mechanism with increased channel activation. TASK-1 K+ channel inhibitors (some in clinical use) have been raised as a possible therapeutic strategy.

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Heterozygous LoF variants associated with a different disorder - primary pulmonary arterial hypertension
Sources: Literature
Differences of Sex Development v0.265 PBX1 Bryony Thompson Phenotypes for gene: PBX1 were changed from 46, XY gonadal dysgenesis to 46, XY gonadal dysgenesis; congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay MONDO:0060549
Differences of Sex Development v0.262 PBX1 Bryony Thompson reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35451537, 31302614, 31058389, 32141698; Phenotypes: congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay MONDO:0060549; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Differences of Sex Development v0.262 PRDM13 Zornitza Stark Phenotypes for gene: PRDM13 were changed from congenital hypogonadotropic hypogonadism, MONDO:0015770 to Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761
Differences of Sex Development v0.261 PRDM13 Zornitza Stark reviewed gene: PRDM13: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, MIM# 619761; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Differences of Sex Development v0.261 MAP3K1 Zornitza Stark Marked gene: MAP3K1 as ready
Differences of Sex Development v0.258 DUSP6 Zornitza Stark Marked gene: DUSP6 as ready
Differences of Sex Development v0.254 HSD3B2 Zornitza Stark Marked gene: HSD3B2 as ready
Differences of Sex Development v0.251 RSPO1 Zornitza Stark Marked gene: RSPO1 as ready
Differences of Sex Development v0.251 RSPO1 Zornitza Stark Phenotypes for gene: RSPO1 were changed from to Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal MIM#610644; Palmoplantar hyperkeratosis and true hermaphroditism MIM#610644
Differences of Sex Development v0.248 RSPO1 Belinda Chong reviewed gene: RSPO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17041600, 18085567, 18250098, 18250097; Phenotypes: Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal MIM#610644, Palmoplantar hyperkeratosis and true hermaphroditism MIM#610644; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Differences of Sex Development v0.248 SRD5A2 Zornitza Stark Marked gene: SRD5A2 as ready
Differences of Sex Development v0.245 STAR Zornitza Stark Marked gene: STAR as ready
Differences of Sex Development v0.245 STAR Zornitza Stark Gene: star has been classified as Green List (High Evidence).
Differences of Sex Development v0.245 STAR Zornitza Stark Phenotypes for gene: STAR were changed from to Lipoid adrenal hyperplasia (MIM#201710)
Differences of Sex Development v0.244 STAR Zornitza Stark Publications for gene: STAR were set to
Differences of Sex Development v0.243 STAR Zornitza Stark Mode of inheritance for gene: STAR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Differences of Sex Development v0.242 STAR Zornitza Stark reviewed gene: STAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 7892608, 8634702; Phenotypes: Lipoid adrenal hyperplasia (MIM#201710); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Differences of Sex Development v0.242 PPP2R3C Zornitza Stark Marked gene: PPP2R3C as ready
Differences of Sex Development v0.240 PPP2R3C Chirag Patel gene: PPP2R3C was added
gene: PPP2R3C was added to Differences of Sex Development. Sources: Literature
Mode of inheritance for gene: PPP2R3C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP2R3C were set to PMID: 30893644, 34714774, 34750818
Phenotypes for gene: PPP2R3C were set to Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy, OMIM # 618419
Review for gene: PPP2R3C was set to GREEN
Added comment: Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy (GDRM) is characterized by 46,XY complete gonadal dysgenesis in association with extragonadal anomalies, low birth weight, typical facial gestalt, rod and cone dystrophy, sensorineural hearing loss, omphalocele, anal atresia, renal agenesis, skeletal abnormalities, dry and scaly skin, severe myopathy, and neuromotor delay.

11 unrelated families with syndromic complete gonadal dysgenesis. 9 families had 46,XY females with complete gonadal dysgenesis, but 2 families had 46,XX patients with hypergonadotropic hypogonadism, nonvisualized gonads, primary amenorrhea, and absence of secondary sexual characteristics. Variants segregated with disease in each family and were not found in ethnically matched controls or in public variant databases. The heterozygous fathers exhibited morphologic abnormalities of spermatozoa and reduced fertility.
Sources: Literature
Differences of Sex Development v0.239 NHLH2 Zornitza Stark Marked gene: NHLH2 as ready
Differences of Sex Development v0.239 NHLH2 Zornitza Stark gene: NHLH2 was added
gene: NHLH2 was added to Differences of Sex Development. Sources: Expert Review
Mode of inheritance for gene: NHLH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NHLH2 were set to 35066646
Phenotypes for gene: NHLH2 were set to Hypogonadotropic hypogonadism 27 without anosmia , MIM# 619755
Review for gene: NHLH2 was set to RED
Added comment: Single individual reported homozygous for a missense variant in this gene. Two other individuals heterozygous for missense variants identified as part of this cohort; however, had alternative diagnoses.
Sources: Expert Review
Differences of Sex Development v0.237 MAMLD1 Zornitza Stark Marked gene: MAMLD1 as ready
Differences of Sex Development v0.234 PRDM13 Seb Lunke Marked gene: PRDM13 as ready
Differences of Sex Development v0.233 PRDM13 Seb Lunke gene: PRDM13 was added
gene: PRDM13 was added to Differences 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 supposedly unrelated families (2 consanguine), but all are from Malta, and all share the same 13bp deletion spanning an exon-intron boundary. 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 at P21.
Sources: Literature
Differences of Sex Development v0.232 CYP17A1 Zornitza Stark Marked gene: CYP17A1 as ready
Differences of Sex Development v0.229 CYP11B1 Zornitza Stark Marked gene: CYP11B1 as ready
Differences of Sex Development v0.226 CYP11A1 Zornitza Stark Marked gene: CYP11A1 as ready
Differences of Sex Development v0.226 CYP11A1 Zornitza Stark Phenotypes for gene: CYP11A1 were changed from to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, MIM# 613743
Differences of Sex Development v0.223 CYP11A1 Zornitza Stark reviewed gene: CYP11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12161514, 16705068, 18182448, 28425981; Phenotypes: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, MIM# 613743; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Differences of Sex Development v0.223 HSD17B3 Zornitza Stark Marked gene: HSD17B3 as ready
Differences of Sex Development v0.220 ANOS1 Zornitza Stark Marked gene: ANOS1 as ready
Differences of Sex Development v0.217 COG6 Zornitza Stark Marked gene: COG6 as ready
Differences of Sex Development v0.215 CPE Zornitza Stark Marked gene: CPE as ready
Differences of Sex Development v0.213 CDKN1C Zornitza Stark Marked gene: CDKN1C as ready
Differences of Sex Development v0.211 CDKN1C Zornitza Stark Mode of pathogenicity for gene: CDKN1C was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Differences of Sex Development v0.209 CDKN1C Zornitza Stark reviewed gene: CDKN1C: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 22634751, 33076988, 31976094, 31497289; Phenotypes: IMAGe syndrome, MIM# 614732; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Differences of Sex Development v0.209 IGF2 Zornitza Stark Marked gene: IGF2 as ready
Differences of Sex Development v0.208 SEMA3F Zornitza Stark Marked gene: SEMA3F as ready
Differences of Sex Development v0.208 PLXNA3 Zornitza Stark Marked gene: PLXNA3 as ready
Differences of Sex Development v0.207 SEMA3F Chirag Patel gene: SEMA3F was added
gene: SEMA3F was added to Differences of Sex Development. Sources: Literature
Mode of inheritance for gene: SEMA3F was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA3F were set to PMID: 33495532
Phenotypes for gene: SEMA3F were set to Hypogonadotropic hypogonadism
Review for gene: SEMA3F was set to GREEN
Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 10 individuals from 7 families with heterozygous SEMA3F missense variants. In 4 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Provide unequivocal human embryonic data showing the expression of SEMA3F along the developing human GnRH migratory pathway. SEMA3Fs harboring the P452T, T29M, and T724M missense variants showed impaired SEMA3F secretion in whole cell lysates.
Sources: Literature
Differences of Sex Development v0.207 PLXNA3 Chirag Patel gene: PLXNA3 was added
gene: PLXNA3 was added to Differences of Sex Development. Sources: Literature
Mode of inheritance for gene: PLXNA3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PLXNA3 were set to PMID: 33495532
Phenotypes for gene: PLXNA3 were set to Hypogonadotropic hypogonadism
Added comment: Screened 216 patients with Idiopathic hypogonadotropic hypogonadism by exome sequencing. Identified 7 individuals from 5 families with hemizygous PLXNA3 missense variants.
In 2 of the kindreds, there was at least one more gene known to be associated with IHH (oligogenecity). Data provided with evidence that PLXNA3, a key component of the SEMA3F holoreceptor complex,31 is expressed by the human GnRH and olfactory/vomeronasal systems. S646P variant showed PLXNA3 localization exclusively in the ER, indicating that the variant S646P disrupts cell surface localization of PLXNA3.
Sources: Literature
Differences of Sex Development v0.206 LHCGR Zornitza Stark Marked gene: LHCGR as ready
Differences of Sex Development v0.203 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Differences of Sex Development v0.200 DLK1 Zornitza Stark Marked gene: DLK1 as ready
Differences of Sex Development v0.197 MKRN3 Natasha Brown Marked gene: MKRN3 as ready
Differences of Sex Development v0.197 MKRN3 Natasha Brown changed review comment from: PMID: 31687022 4 novel missense, c.1138G > A (p.Glu380Lys), c.1420T > A (p.Leu474Met), c.673C > G (p.Leu225Val), and c.1071C > G (p.Ile357Met) in two sporadic cases and three familial cases. ACMG: (p.Glu380Lys and p.Ile357Met) = LP, but (p.Leu474Met) (p.Leu225Val) are VUS.
PMID: 31636607 3 novel promotor variants found in 6 unrelated females; significant reduction of MKRN3 promoter activity using luciferase assays.
PMID: 32480405 - 2 females with whole gene deletions of MKRN3
PMID: 31041429 systematic review/meta analysis: "Patients with MKRN3 mutations presented with signs and symptoms of early reactivation of the hypothalamic-pituitary-gonadal axis, represented by precocious development of sexual characteristics, BA advancement, and pubertal levels of basal or poststimulated LH"
Sources: Literature; to: PMID: 23738509: four (3fs; 1missense) novel heterozygous mutations in MKRN3, in 5 of the 15 families; both sexes were affected; mouse model confirms low expression.
PMID: 31687022 4 novel missense, c.1138G > A (p.Glu380Lys), c.1420T > A (p.Leu474Met), c.673C > G (p.Leu225Val), and c.1071C > G (p.Ile357Met) in two sporadic cases and three familial cases. ACMG: (p.Glu380Lys and p.Ile357Met) = LP, but (p.Leu474Met) (p.Leu225Val) are VUS.
PMID: 31636607 3 novel promotor variants found in 6 unrelated females; significant reduction of MKRN3 promoter activity using luciferase assays.
PMID: 32480405 - 2 females with whole gene deletions of MKRN3
PMID: 31041429 systematic review/meta analysis: "Patients with MKRN3 mutations presented with signs and symptoms of early reactivation of the hypothalamic-pituitary-gonadal axis, represented by precocious development of sexual characteristics, BA advancement, and pubertal levels of basal or poststimulated LH"
Sources: Literature
Differences of Sex Development v0.197 MKRN3 Natasha Brown gene: MKRN3 was added
gene: MKRN3 was added to Differences of Sex Development. Sources: Literature
Mode of inheritance for gene: MKRN3 was set to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Publications for gene: MKRN3 were set to PMID: 31687022; 31041429; 31636607; 32480405
Phenotypes for gene: MKRN3 were set to central precocious puberty
Penetrance for gene: MKRN3 were set to unknown
Review for gene: MKRN3 was set to GREEN
Added comment: PMID: 31687022 4 novel missense, c.1138G > A (p.Glu380Lys), c.1420T > A (p.Leu474Met), c.673C > G (p.Leu225Val), and c.1071C > G (p.Ile357Met) in two sporadic cases and three familial cases. ACMG: (p.Glu380Lys and p.Ile357Met) = LP, but (p.Leu474Met) (p.Leu225Val) are VUS.
PMID: 31636607 3 novel promotor variants found in 6 unrelated females; significant reduction of MKRN3 promoter activity using luciferase assays.
PMID: 32480405 - 2 females with whole gene deletions of MKRN3
PMID: 31041429 systematic review/meta analysis: "Patients with MKRN3 mutations presented with signs and symptoms of early reactivation of the hypothalamic-pituitary-gonadal axis, represented by precocious development of sexual characteristics, BA advancement, and pubertal levels of basal or poststimulated LH"
Sources: Literature
Differences of Sex Development v0.195 CYP19A1 Zornitza Stark Marked gene: CYP19A1 as ready
Differences of Sex Development v0.195 CYP19A1 Zornitza Stark Phenotypes for gene: CYP19A1 were changed from to Aromatase deficiency (MIM#613546), AR; Aromatase excess syndrome (MIM#139300), AD
Differences of Sex Development v0.192 CYP19A1 Teresa Zhao reviewed gene: CYP19A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 17164303, 25264451; Phenotypes: Aromatase deficiency (MIM#613546), AR, Aromatase excess syndrome (MIM#139300), AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Differences of Sex Development v0.192 AMH Seb Lunke Marked gene: AMH as ready
Differences of Sex Development v0.192 AMH Seb Lunke Added comment: Comment when marking as ready: 64 different alleles have been discovered in 79 families. There is a common 27-bp deletion in the kinase domain in caucasians.
Differences of Sex Development v0.189 PAX8 Zornitza Stark Marked gene: PAX8 as ready
Differences of Sex Development v0.188 PAX8 Zornitza Stark gene: PAX8 was added
gene: PAX8 was added to Differences 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: 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.

Variants in this gene are associated with congenital hypothyroidism.
Sources: Literature
Differences of Sex Development v0.187 BMP7 Zornitza Stark Marked gene: BMP7 as ready
Differences of Sex Development v0.187 BMP7 Zornitza Stark gene: BMP7 was added
gene: BMP7 was added to Differences of Sex Development. Sources: Literature
Mode of inheritance for gene: BMP7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BMP7 were set to 33434492
Phenotypes for gene: BMP7 were set to Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS)
Review for gene: BMP7 was set to RED
Added comment: Two individuals with likely deleterious variants identified in a cohort of individuals with MRKHS.
Sources: Literature
Differences of Sex Development v0.185 POR Zornitza Stark Marked gene: POR as ready
Differences of Sex Development v0.182 BMP15 Zornitza Stark Marked gene: BMP15 as ready
Differences of Sex Development v0.182 BMP15 Zornitza Stark Phenotypes for gene: BMP15 were changed from to Ovarian dysgenesis 2, MIM# 300510; Premature ovarian failure 4, MIM# 300510
Differences of Sex Development v0.179 BMP15 Zornitza Stark reviewed gene: BMP15: Rating: GREEN; Mode of pathogenicity: None; Publications: 15136966, 16508750, 16464940; Phenotypes: Ovarian dysgenesis 2, MIM# 300510, Premature ovarian failure 4, MIM# 300510; Mode of inheritance: Other
Differences of Sex Development v0.179 GATA4 Zornitza Stark Marked gene: GATA4 as ready
Differences of Sex Development v0.179 GATA4 Zornitza Stark Phenotypes for gene: GATA4 were changed from to Testicular anomalies with or without congenital heart disease, MIM# 615542
Differences of Sex Development v0.175 GATA4 Michelle Torres reviewed gene: GATA4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 21220346, 30455927, 29735817, 27899157, 26490186, 29670578, 32992319; Phenotypes: ?Testicular anomalies with or without congenital heart disease 615542 AD, Atrial septal defect 2 607941 AD, Atrioventricular septal defect 4 614430 AD, Tetralogy of Fallot 187500 AD, Ventricular septal defect 1 614429 AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Differences of Sex Development v0.175 NR5A1 Zornitza Stark Marked gene: NR5A1 as ready
Differences of Sex Development v0.175 NR5A1 Zornitza Stark Phenotypes for gene: NR5A1 were changed from to Adrenocortical insufficiency, (MIM#612964); 46, XX sex reversal 4, (MIM# 617480); Premature ovarian failure 7, (MIM#612964); Spermatogenic failure 8, (MIM#613957); 46XY sex reversal 3, (MIM#612965)
Differences of Sex Development v0.172 NR5A1 Ain Roesley edited their review of gene: NR5A1: Added comment: 188 variants from 238 cases. No genotype-phenotype correlation establised; Changed phenotypes: Adrenocortical insufficiency, (MIM#612964), 46, XX sex reversal 4, (MIM# 617480), Premature ovarian failure 7, (MIM#612964), Spermatogenic failure 8, (MIM#613957), 46XY sex reversal 3, (MIM#612965)
Differences of Sex Development v0.172 NR5A1 Ain Roesley reviewed gene: NR5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31513305; Phenotypes: Adrenocortical insufficiency, (MIM#612964), 46, XX sex reversal 4, (MIM# 617480), Premature ovarian failure 7, (MIM#612964), Spermatogenic failure 8, (MIM#613957), 46XY sex reversal 3, (MIM#612965), Autosomal dominant; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Differences of Sex Development v0.171 IGSF10 Zornitza Stark Marked gene: IGSF10 as ready
Differences of Sex Development v0.170 IGSF10 Zornitza Stark gene: IGSF10 was added
gene: IGSF10 was added to Disorders of Sex Differentiation. Sources: Expert list
Mode of inheritance for gene: IGSF10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IGSF10 were set to 27137492; 31042289
Phenotypes for gene: IGSF10 were set to delayed puberty; hypogonadotropic hypogonadism; primary ovary insufficiency
Added comment: PMID: 27137492 - 4 Finnish families segregating p.Glu161Lys, but Finnish MAF in ExAC is 2%. Another six additional families with a possible missense, but variants are seen in ExAC suggesting incomplete penetrance. Supporting in vitro functional assays and zebrafish model. PMID: 31042289 - 2 unrelated consanguineous families with homozygous variants and family with a heterozygous frameshift and apparent incomplete penetrance.
Sources: Expert list
Differences of Sex Development v0.169 TCF12 Zornitza Stark Marked gene: TCF12 as ready
Differences of Sex Development v0.168 TCF12 Zornitza Stark gene: TCF12 was added
gene: TCF12 was added to Disorders of Sex Differentiation. 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 GREEN
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 case). 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.

Green for mono-allelic variants, caution with bi-allelic variants.
Sources: Literature
Differences of Sex Development v0.167 NR0B1 Zornitza Stark Marked gene: NR0B1 as ready
Differences of Sex Development v0.161 HOXA13 Zornitza Stark Marked gene: HOXA13 as ready
Differences of Sex Development v0.161 PROKR2 Zornitza Stark Marked gene: PROKR2 as ready
Differences of Sex Development v0.157 NSMF Zornitza Stark Marked gene: NSMF as ready
Differences of Sex Development v0.157 NSMF Zornitza Stark gene: NSMF was added
gene: NSMF was added to Disorders of Sex Differentiation. Sources: Expert list
Mode of inheritance for gene: NSMF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NSMF were set to 15362570; 17235395; 21700882
Phenotypes for gene: NSMF were set to Hypogonadotropic hypogonadism 9 with or without anosmia, MIM# 614838
Review for gene: NSMF was set to RED
Added comment: Rare variants reported in individuals with IHH; however, variants in other IHH genes also present, and at least one of the variants has a very high population frequency in gnomad (intronic 8-bp deletion ending 14 bp before exon 10 (1159-14_-22del), present in 258 individuals).
Sources: Expert list
Differences of Sex Development v0.156 SPRY4 Zornitza Stark Marked gene: SPRY4 as ready
Differences of Sex Development v0.155 SPRY4 Zornitza Stark gene: SPRY4 was added
gene: SPRY4 was added to Disorders of Sex Differentiation. Sources: Expert list
Mode of inheritance for gene: SPRY4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPRY4 were set to 23643382
Phenotypes for gene: SPRY4 were set to Hypogonadotropic hypogonadism 17 with or without anosmia, MIM# 615266
Review for gene: SPRY4 was set to AMBER
Added comment: 14 unrelated individuals reported originally. Three of these had variants in other IHH genes. The p.Lys177Arg variant is present in 454 individuals in gnomad, p.Ser241Tyr is present in 1279 individuals including 6 homozygotes, p.Val304Ile is present in 457 individuals. These population frequencies cast doubt on the gene-disease relationship.
Sources: Expert list
Differences of Sex Development v0.154 KISS1 Zornitza Stark Marked gene: KISS1 as ready
Differences of Sex Development v0.153 KISS1 Zornitza Stark gene: KISS1 was added
gene: KISS1 was added to Disorders of Sex Differentiation. Sources: Expert list
Mode of inheritance for gene: KISS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KISS1 were set to 22335740; 25783047; 22766261; 17563351
Phenotypes for gene: KISS1 were set to Hypogonadotropic hypogonadism 13 with or without anosmia, MIM# 614842
Review for gene: KISS1 was set to AMBER
Added comment: Reported in Turkish families, supportive mouse model, but no variants identified in other cohorts. Role of KISS1 receptor much more established.
Sources: Expert list
Differences of Sex Development v0.152 TACR3 Zornitza Stark Marked gene: TACR3 as ready
Differences of Sex Development v0.150 INSL3 Zornitza Stark Marked gene: INSL3 as ready
Differences of Sex Development v0.146 IL17RD Zornitza Stark Marked gene: IL17RD as ready
Differences of Sex Development v0.142 HSD17B4 Zornitza Stark Marked gene: HSD17B4 as ready
Differences of Sex Development v0.139 HS6ST1 Zornitza Stark Marked gene: HS6ST1 as ready
Differences of Sex Development v0.132 HESX1 Zornitza Stark Marked gene: HESX1 as ready
Differences of Sex Development v0.132 HESX1 Zornitza Stark Phenotypes for gene: HESX1 were changed from to Pituitary hormone deficiency, combined, 5, MIM# 182230
Differences of Sex Development v0.130 HESX1 Zornitza Stark reviewed gene: HESX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 5, MIM# 182230; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Differences of Sex Development v0.130 GNRH1 Zornitza Stark Marked gene: GNRH1 as ready
Differences of Sex Development v0.127 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Rare Disease
Differences of Sex Development v0.125 TSPYL1 Zornitza Stark Marked gene: TSPYL1 as ready
Differences of Sex Development v0.121 WDR11 Zornitza Stark Marked gene: WDR11 as ready
Differences of Sex Development v0.118 KISS1R Zornitza Stark Marked gene: KISS1R as ready
Differences of Sex Development v0.115 LEP Zornitza Stark Marked gene: LEP as ready
Differences of Sex Development v0.112 LEPR Zornitza Stark Marked gene: LEPR as ready
Differences of Sex Development v0.109 FGF17 Zornitza Stark Marked gene: FGF17 as ready
Differences of Sex Development v0.109 FGF17 Zornitza Stark Added comment: Comment when marking as ready: Borderline Green/Amber: contribution may not be monogenic.
Differences of Sex Development v0.107 LHB Zornitza Stark Marked gene: LHB as ready
Differences of Sex Development v0.104 FEZF1 Zornitza Stark Marked gene: FEZF1 as ready
Differences of Sex Development v0.100 ESR2 Zornitza Stark Marked gene: ESR2 as ready
Differences of Sex Development v0.100 ESR2 Zornitza Stark Phenotypes for gene: ESR2 were changed from 46,XY Disorders of Sex Development to 46,XY Disorders of Sex Development; Ovarian dysgenesis 8, MIM# 618187
Differences of Sex Development v0.97 ESR2 Zornitza Stark reviewed gene: ESR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 30113650; Phenotypes: Ovarian dysgenesis 8, MIM# 618187; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Differences of Sex Development v0.97 ERAL1 Zornitza Stark Marked gene: ERAL1 as ready
Differences of Sex Development v0.96 MKKS Zornitza Stark reviewed gene: MKKS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Bardet-Biedl syndrome 6 (MIM#605231), McKusick-Kaufman syndrome (MIM#236700); Mode of inheritance: None
Differences of Sex Development v0.96 MKKS Zornitza Stark Marked gene: MKKS as ready
Differences of Sex Development v0.96 MKKS Zornitza Stark Phenotypes for gene: MKKS were changed from to Bardet-Biedl syndrome 6 (MIM#605231); McKusick-Kaufman syndrome (MIM#236700)
Differences of Sex Development v0.92 DMRT1 Zornitza Stark Marked gene: DMRT1 as ready
Differences of Sex Development v0.91 DHCR24 Zornitza Stark Marked gene: DHCR24 as ready
Differences of Sex Development v0.87 CYB5A Zornitza Stark Marked gene: CYB5A as ready
Differences of Sex Development v0.85 LHX3 Zornitza Stark Marked gene: LHX3 as ready
Differences of Sex Development v0.84 LHX3 Zornitza Stark Phenotypes for gene: LHX3 were changed from to Pituitary hormone deficiency, combined, 3 (MIM#221750)
Differences of Sex Development v0.82 CUL4B Zornitza Stark Marked gene: CUL4B as ready
Differences of Sex Development v0.80 CBX2 Zornitza Stark Marked gene: CBX2 as ready
Differences of Sex Development v0.76 MCM5 Zornitza Stark Marked gene: MCM5 as ready
Differences of Sex Development v0.73 ATF3 Zornitza Stark Marked gene: ATF3 as ready
Differences of Sex Development v0.72 ERAL1 Elena Savva gene: ERAL1 was added
gene: ERAL1 was added to Disorders of Sex Differentiation. Sources: Expert list
Mode of inheritance for gene: ERAL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERAL1 were set to PMID: 28449065
Phenotypes for gene: ERAL1 were set to Perrault syndrome 6 617565
Review for gene: ERAL1 was set to AMBER
Added comment: PMID: 28449065 - 3 unrelated patient with perrault syndrome with the same founder missense (p.Asn236Ile). Symptoms included hearing loss, premature ovarian failure, primary amenorrhea
Supported by functional analysis on patient cells, and transfected yeast reciprocating the phenotype.
Sources: Expert list
Differences of Sex Development v0.72 DMRT1 Elena Savva gene: DMRT1 was added
gene: DMRT1 was added to Disorders of Sex Differentiation. Sources: Expert list
Mode of inheritance for gene: DMRT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DMRT1 were set to PMID: 31479588; 24934491; 29527098
Phenotypes for gene: DMRT1 were set to Azoospermia
Review for gene: DMRT1 was set to RED
Added comment: PMID: 31479588 - 1 patient with azoospermia and XY genotype. Also carries an additional variant in KLHL10

PMID: 24934491 - 6 patients with male infertility, however the 4 identified variants were also found in 2 controls and have a high frequency in the population (gnomAD). No functional studies.

PMID: 23555275 - Identifies CNVs in azoospermia patients, calls the gene a risk factor
Sources: Expert list
Differences of Sex Development v0.72 CYB5A Elena Savva gene: CYB5A was added
gene: CYB5A was added to Disorders of Sex Differentiation. Sources: Expert list
Mode of inheritance for gene: CYB5A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYB5A were set to PMID: 22170710; 32051920
Phenotypes for gene: CYB5A were set to Methemoglobinemia and ambiguous genitalia 250790
Review for gene: CYB5A was set to GREEN
Added comment: PMID: 22170710 - 3 siblings with 46,XY DSD, sex steroid deficiency, female genitalia and a homozygous missense variant. Supported by LOF functional studies. Mineralocorticoids and glucocorticoids were normal.

PMID: 32051920 - 1 female with a homozygous missense, no DSD but methemoglobinemia. All female genitalia are normal and she has had a normal female child.
Paper reviews prior reports and notes an additional 2 unrelated homozygous reports of 46 XY DSD patients with normal Methemoglobin. All variants were rare/absent (gnomAD) and PTCs.
Sources: Expert list
Differences of Sex Development v0.72 LHX3 Crystle Lee reviewed gene: LHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: 28302169, 17327381, 30262920; Phenotypes: Pituitary hormone deficiency, combined, 3 (MIM#221750); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Differences of Sex Development v0.72 CUL4B Elena Savva gene: CUL4B was added
gene: CUL4B was added to Disorders of Sex Differentiation. Sources: Expert list
Mode of inheritance for gene: CUL4B was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: CUL4B were set to PMID: 25385192
Phenotypes for gene: CUL4B were set to Mental retardation, X-linked, syndromic 15 (Cabezas type) 300354
Review for gene: CUL4B was set to GREEN
Added comment: PMID: 25385192 - 25 patients (11 families) with syndromic features including hypogonadism (85%) and gynecomastia (33%)
Sources: Expert list
Differences of Sex Development v0.72 NR3C1 Zornitza Stark Marked gene: NR3C1 as ready
Differences of Sex Development v0.69 MCM5 Crystle Lee gene: MCM5 was added
gene: MCM5 was added to Disorders of Sex Differentiation. Sources: Expert Review
Mode of inheritance for gene: MCM5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM5 were set to 28198391
Phenotypes for gene: MCM5 were set to ?Meier-Gorlin syndrome 8 (MIM#617564)
Review for gene: MCM5 was set to RED
Added comment: Only single patient reported in 2017. Patient presented with microstomia, thick lips, micrognathia, bilateral microtia, low set ears and bilateral cryptorchidism.
Sources: Expert Review
Differences of Sex Development v0.69 MKKS Crystle Lee reviewed gene: MKKS: Rating: AMBER; Mode of pathogenicity: None; Publications: 10973251, 26900326, 10973238; Phenotypes: Bardet-Biedl syndrome 6 (MIM#605231), McKusick-Kaufman syndrome (MIM#236700); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Differences of Sex Development v0.69 PCSK1 Zornitza Stark Marked gene: PCSK1 as ready
Differences of Sex Development v0.66 PROK2 Zornitza Stark Marked gene: PROK2 as ready
Differences of Sex Development v0.66 PROK2 Zornitza Stark Added comment: Comment when marking as ready: Evidence supporting association between bi-allelic variants causing IHH is stronger than for mono-allelic disease.
Differences of Sex Development v0.63 PROP1 Zornitza Stark Marked gene: PROP1 as ready
Differences of Sex Development v0.63 PROP1 Zornitza Stark Phenotypes for gene: PROP1 were changed from to Pituitary hormone deficiency, combined, 2 (MIM#262600)
Differences of Sex Development v0.60 RPL10 Zornitza Stark Marked gene: RPL10 as ready
Differences of Sex Development v0.59 SAMD9 Zornitza Stark Marked gene: SAMD9 as ready
Differences of Sex Development v0.58 SEMA3E Zornitza Stark Marked gene: SEMA3E as ready
Differences of Sex Development v0.57 SGPL1 Zornitza Stark Marked gene: SGPL1 as ready
Differences of Sex Development v0.56 SOX10 Zornitza Stark Marked gene: SOX10 as ready
Differences of Sex Development v0.56 SOX10 Zornitza Stark Phenotypes for gene: SOX10 were changed from PCWH syndrome (MIM#609136); Waardenburg syndrome, type 2E, with or without neurologic involvement (MIM#611584); Waardenburg syndrome, type 4C (MIM#613266) to Kallman syndrome; PCWH syndrome (MIM#609136); Waardenburg syndrome, type 2E, with or without neurologic involvement (MIM#611584); Waardenburg syndrome, type 4C (MIM#613266)
Differences of Sex Development v0.54 TAC3 Zornitza Stark Marked gene: TAC3 as ready
Differences of Sex Development v0.51 TOE1 Zornitza Stark Marked gene: TOE1 as ready
Differences of Sex Development v0.50 PROP1 Crystle Lee reviewed gene: PROP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15941866, 11549703; Phenotypes: Pituitary hormone deficiency, combined, 2 (MIM#262600); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Differences of Sex Development v0.50 AKR1C4 Zornitza Stark Marked gene: AKR1C4 as ready
Differences of Sex Development v0.46 AKR1C2 Zornitza Stark Marked gene: AKR1C2 as ready
Differences of Sex Development v0.42 RPL10 Crystle Lee gene: RPL10 was added
gene: RPL10 was added to Disorders of Sex Differentiation. Sources: Expert Review
Mode of inheritance for gene: RPL10 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: RPL10 were set to 25316788; 26290468; 25846674; 29066376
Phenotypes for gene: RPL10 were set to Mental retardation, X-linked, syndromic, 35 (MIM#300998)
Review for gene: RPL10 was set to GREEN
Added comment: At least 3 variants have been reported. Urogenital anomalies are a feature of the associated condition.

PMID: 25316788: Variant reported in 3 members of a family. Genitourinary abnormalities (ie cryptorchidism) reported in all 3 affected individuals.

PMID: 26290468: Reported in a family with two affected cousins presenting with X-linked ID, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia. Only one of the affected males presented with cryptorchidism.

PMID: 25846674: 3 of 4 affected males in the family presented with urogenital anomalies
Sources: Expert Review
Differences of Sex Development v0.42 SAMD9 Crystle Lee gene: SAMD9 was added
gene: SAMD9 was added to Disorders of Sex Differentiation. Sources: Expert Review
Mode of inheritance for gene: SAMD9 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SAMD9 were set to 27182967
Phenotypes for gene: SAMD9 were set to MIRAGE syndrome (MIM#617053)
Review for gene: SAMD9 was set to GREEN
Added comment: At least 10 families ( 8 diff variants) reported in one publication. External genital abnormalities observed in all 46, XY patients.
Sources: Expert Review
Differences of Sex Development v0.42 SEMA3E Crystle Lee gene: SEMA3E was added
gene: SEMA3E was added to Disorders of Sex Differentiation. Sources: Expert Review
Mode of inheritance for gene: SEMA3E was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEMA3E were set to 25985275
Phenotypes for gene: SEMA3E were set to ?CHARGE syndrome (MIM#214800)
Review for gene: SEMA3E was set to RED
Added comment: Only one variant reported in 2 sibling with Kallman syndrome. Mouse model supports involvement of this gene with the phenotype. Variant not present in gnomad in homozygosity.
Sources: Expert Review
Differences of Sex Development v0.42 SGPL1 Crystle Lee gene: SGPL1 was added
gene: SGPL1 was added to Disorders of Sex Differentiation. Sources: Expert Review
Mode of inheritance for gene: SGPL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGPL1 were set to 28165339; 28165343; 28181337
Phenotypes for gene: SGPL1 were set to Nephrotic syndrome, type 14 (MIM#617575)
Review for gene: SGPL1 was set to GREEN
Added comment: >5 families reported. Cryptorchidism and hypogonadism are features of the associated phenotype.
Sources: Expert Review
Differences of Sex Development v0.42 SOX10 Crystle Lee gene: SOX10 was added
gene: SOX10 was added to Disorders of Sex Differentiation. Sources: Expert Review
Mode of inheritance for gene: SOX10 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SOX10 were set to 23643381; 15004559
Phenotypes for gene: SOX10 were set to PCWH syndrome (MIM#609136); Waardenburg syndrome, type 2E, with or without neurologic involvement (MIM#611584); Waardenburg syndrome, type 4C (MIM#613266)
Mode of pathogenicity for gene: SOX10 was set to Other
Review for gene: SOX10 was set to GREEN
Added comment: Well reported gene disease association. Cryptorchidism and hypogonadism is a feature of Kallman Syndrome and WS4C

PMID: 23643381: Reported 6 variants in individuals with Kallman syndrome which is associated with hypogonadotropic hypogonadism. Functional studies performed.

PMID: 15004559: PCWH is caused by dominant-negative mutations (truncating variants) whereas NMD and thus haploinsufficiency results in WS4C
Sources: Expert Review
Differences of Sex Development v0.42 TOE1 Crystle Lee gene: TOE1 was added
gene: TOE1 was added to Disorders of Sex Differentiation. Sources: Expert Review
Mode of inheritance for gene: TOE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOE1 were set to 28092684
Phenotypes for gene: TOE1 were set to Pontocerebellar hypoplasia, type 7 (MIM#614969)
Review for gene: TOE1 was set to GREEN
Added comment: >10 families with pontocerebellar hypoplasia type 7 (PCH7) reported with biallelic variants.MRI showed reduced cerebellar volume in these families. Ambiguous genitalia is a feature of this condition.
Sources: Expert Review
Differences of Sex Development v0.42 WNT4 Zornitza Stark Marked gene: WNT4 as ready
Differences of Sex Development v0.38 ZFPM2 Zornitza Stark Marked gene: ZFPM2 as ready
Differences of Sex Development v0.34 FLRT3 Zornitza Stark Marked gene: FLRT3 as ready
Differences of Sex Development v0.34 FLRT3 Zornitza Stark Added comment: Comment when marking as ready: Oligogenic inheritance postulated. I also note one of the variants, Gln69Lys is present in 7 individuals in gnomad.
Differences of Sex Development v0.34 FLRT3 Zornitza Stark Marked gene: FLRT3 as ready
Differences of Sex Development v0.31 ESR2 Bryony Thompson gene: ESR2 was added
gene: ESR2 was added to Disorders of Sex Differentiation. Sources: Literature
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
Phenotypes for gene: ESR2 were set to 46,XY Disorders of Sex Development
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.
Sources: Literature
Differences of Sex Development v0.30 NR2F2 Zornitza Stark Marked gene: NR2F2 as ready
Differences of Sex Development v0.29 NR2F2 Zornitza Stark gene: NR2F2 was added
gene: NR2F2 was added to Disorders of Sex Differentiation. 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 of Sex Development v0.28 KLB Zornitza Stark Marked gene: KLB as ready
Differences of Sex Development v0.26 NDNF Zornitza Stark Marked gene: NDNF as ready
Differences of Sex Development v0.25 NDNF Zornitza Stark gene: NDNF was added
gene: NDNF was added to Disorders of Sex Differentiation. Sources: Literature
Mode of inheritance for gene: NDNF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NDNF were set to 31883645
Phenotypes for gene: NDNF were set to Congenital hypogonadotropic hypogonadism (CHH)
Review for gene: NDNF was set to GREEN
Added comment: Three heterozygous protein-truncating variants and one heterozygous missense variant identified in a cohort of 240 unrelated IHH patients. The authors also provided supporting evidence from animal models.
Sources: Literature
Differences of Sex Development v0.24 MYRF Zornitza Stark Marked gene: MYRF as ready
Differences of Sex Development v0.23 DHX37 Zornitza Stark Marked gene: DHX37 as ready
Differences of Sex Development v0.22 DHX37 Zornitza Stark gene: DHX37 was added
gene: DHX37 was added to Disorders of Sex Differentiation. 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
Added comment: Seventeen individuals reported in two studies.
Sources: Literature
Differences of Sex Development v0.21 MYRF Ain Roesley gene: MYRF was added
gene: MYRF was added to Disorders of Sex Differentiation. Sources: Literature
Mode of inheritance for gene: MYRF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MYRF were set to PMID: 30985895
Phenotypes for gene: MYRF were set to disorders of sex development
Review for gene: MYRF was set to GREEN
Added comment: PMID: 30985895; 4 unrelated families with de novo variants. 1 family includes monozygotic twins
Sources: Literature
Differences of Sex Development v0.21 RXFP2 Zornitza Stark Marked gene: RXFP2 as ready
Differences of Sex Development v0.17 DHH Zornitza Stark Marked gene: DHH as ready
Differences of Sex Development v0.17 DHH Zornitza Stark Phenotypes for gene: DHH were changed from to 46XY partial gonadal dysgenesis, with minifascicular neuropathy, MIM# 607080
Differences of Sex Development v0.14 DHH Naomi Baker reviewed gene: DHH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31018998, 29471294, 11017805.; Phenotypes: gonadal dysgenesis, minifascicular neuropathy.; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Differences of Sex Development v0.14 GNRHR Zornitza Stark Marked gene: GNRHR as ready
Differences of Sex Development v0.11 CYP21A2 Zornitza Stark Marked gene: CYP21A2 as ready
Differences of Sex Development v0.9 SOX3 Zornitza Stark Marked gene: SOX3 as ready
Differences of Sex Development v0.8 SOX3 Zornitza Stark gene: SOX3 was added
gene: SOX3 was added to Disorders of Sex Differentiation. Sources: Expert Review
SV/CNV tags were added to gene: SOX3.
Mode of inheritance for gene: SOX3 was set to Other
Publications for gene: SOX3 were set to 21183788; 22678921; 25781358; 31523625
Phenotypes for gene: SOX3 were set to XX male sex reversal
Mode of pathogenicity for gene: SOX3 was set to Other
Review for gene: SOX3 was set to AMBER
Added comment: Multiple individuals reported; animal model: association is with structural variants, primarily duplications.
Sources: Expert Review
Differences of Sex Development v0.5 PPP1R12A Zornitza Stark Marked gene: PPP1R12A as ready
Differences of Sex Development v0.5 PPP1R12A Zornitza Stark Added comment: Comment when marking as ready: Now published; 12 individuals, upgraded to Green.
Differences of Sex Development v0.4 PBX1 Zornitza Stark Marked gene: PBX1 as ready
Differences of Sex Development v0.3 PBX1 Zornitza Stark gene: PBX1 was added
gene: PBX1 was added to Disorders of Sex Differentiation_VCGS. 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 of Sex Development v0.2 PPP1R12A Zornitza Stark Marked gene: PPP1R12A as ready
Differences of Sex Development v0.0 STAR Zornitza Stark gene: STAR was added
gene: STAR was added to Disorders of Sex Differentiation_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: STAR was set to Unknown
Differences of Sex Development v0.0 ARX Zornitza Stark gene: ARX was added
gene: ARX was added to Disorders of Sex Differentiation_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: ARX was set to Unknown
Differences of Sex Development v0.0 AR Zornitza Stark gene: AR was added
gene: AR was added to Disorders of Sex Differentiation_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: AR was set to Unknown