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Fetal anomalies v6.131 WSB2 Achchuthan Shanmugasundram gene: WSB2 was added
gene: WSB2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WSB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WSB2 were set to 40374945
Phenotypes for gene: WSB2 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: WSB2 was set to GREEN
Added comment: PMID:40374945 reported five patients from four unrelated families with developmental delays, brain anomalies, and dysmorphic features with or without intrauterine growth restriction (IUGR) and hypotonia. They were all identified with homozygous predicted loss-of-function (pLoF) or missense variants in WSB2 gene (c.128G>A/ p.Trp43Ter, p.Gln134ArgfsTer14, c.1121G>A/ p.Arg374Gln & c.1187_1188delAA/ p.Lys396ArgfsTer19) inherited from asymptomatic consanguineous parents.

Intrauterine growth restriction (IUGR) was reported in two unrelated patients and Oligohydramnios was reported in a different unrelated patient.

There is also functional evidence available from Wsb2-mutant mice, which exhibited several neurological findings that included hyperactivity, altered exploration, and hyper alertness. They also weighed less, had a lower heart rate, and presented an abnormal retinal blood vessel morphology and vasculature pattern along with decreased total thickness of the retina.

This gene has not been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen.
Sources: Literature
Fetal anomalies v6.128 PAN2 Achchuthan Shanmugasundram Phenotypes for gene: PAN2 were changed from syndromic disease MONDO:0002254 to Developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, OMIM:621384
Fetal anomalies v6.103 PLD1 Arina Puzriakova commented on gene: PLD1: This gene was previously downgraded from Green to Amber following review by Jesse Hayesmoore highlighting the presence of homozygotes in population databases, including some patient variants. However, additional cases have continued to be published albeit often with limited information and no extensive functional studies. This gene-condition has been reviewed by multiple resources including:

- ClinGen: definitive (classified on 12-02-2024) - https://search.clinicalgenome.org/CCID:008897
- G2P: definitive (classified on 19-02-2025) - https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03704
- PanelApp Australia: green on multiple panels - https://panelapp-aus.org/panels/entities/PLD1
- OMIM (last updated on 30-09-2022) - https://www.omim.org/entry/212093

Given the classification on Genomics England PanelApp currently conflicts with multiple other resources, this gene will be flagged for additional expert review during the next GMS panel release.
Fetal anomalies v6.24 SEL1L Anna de Burca reviewed gene: SEL1L: Rating: AMBER; Mode of pathogenicity: ; Publications: 37943610, 37943617; Phenotypes: Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v6.21 SEL1L Arina Puzriakova gene: SEL1L was added
gene: SEL1L was added to Fetal anomalies. Sources: Expert Review Amber
Mode of inheritance for gene: SEL1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SEL1L were set to 37943617; 37943610
Phenotypes for gene: SEL1L were set to Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia
Fetal anomalies v5.60 SMOC2 Achchuthan Shanmugasundram Phenotypes for gene: SMOC2 were changed from DENTIN DYSPLASIA, TYPE I, WITH MICRODONTIA AND MISSHAPEN TEETH; Dentin dysplasia, type I, with microdontia and misshapen teeth, OMIM:125400 to Dentin dysplasia, type I, with microdontia and misshapen teeth, OMIM:125400
Fetal anomalies v5.56 SETD1A Achchuthan Shanmugasundram Phenotypes for gene: SETD1A were changed from INTELLECTUAL DISABILITY; Neurodevelopmental disorder with speech impairment and dysmorphic facies, OMIM:619056 to Neurodevelopmental disorder with speech impairment and dysmorphic facies, OMIM:619056
Fetal anomalies v5.42 ITCH Achchuthan Shanmugasundram Phenotypes for gene: ITCH were changed from Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385; AUTOIMMUNE DISEASE, SYNDROMIC MULTISYSTEM to Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385
Fetal anomalies v5.34 FTO Achchuthan Shanmugasundram Phenotypes for gene: FTO were changed from Growth retardation, developmental delay, facial dysmorphism; Growth retardation, developmental delay, facial dysmorphism, OMIM: 612938 to Growth retardation, developmental delay, facial dysmorphism, OMIM: 612938
Fetal anomalies v5.19 BPTF Achchuthan Shanmugasundram Phenotypes for gene: BPTF were changed from Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features; Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, OMIM:617755 to Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, OMIM:617755
Fetal anomalies v5.16 SMOC2 Achchuthan Shanmugasundram commented on gene: SMOC2
Fetal anomalies v5.15 WBP4 Vicki Harrison reviewed gene: WBP4: Rating: GREEN; Mode of pathogenicity: ; Publications: 37963460, 37425688; Phenotypes: Neurodevelopmental disorder with hypotonia, feeding difficulties, facial dysmorphism, and brain abnormalities, MIM#620852; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.15 U2AF2 Sarah Graham reviewed gene: U2AF2: Rating: GREEN; Mode of pathogenicity: ; Publications: 34112922, 36747105, 37092751, 37134193; Phenotypes: Developmental delay, dysmorphic facies, and brain anomalies MIM#620535; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.15 SMOC2 Sunayna Best reviewed gene: SMOC2: Rating: RED; Mode of pathogenicity: ; Publications: 22152679, 23317772; Phenotypes: Dentin dysplasia, type I, with microdontia and misshapen teeth, MIM#125400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.15 SETD1A Stephanie Allen reviewed gene: SETD1A: Rating: GREEN; Mode of pathogenicity: ; Publications: 37000069; Phenotypes: Neurodevelopmental disorder with speech impairment and dysmorphic facies, MIM#619056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v5.15 RAP1B Soo-Mi Park reviewed gene: RAP1B: 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: 37850357, 35451551, 32627184; Phenotypes: Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, MIM#620654; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.15 PUM1 Soo-Mi Park reviewed gene: PUM1: Rating: GREEN; Mode of pathogenicity: ; Publications: 25768905, 30903679, 29474920, 31859446, 35386260; Phenotypes: Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism, MIM#620719; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.15 PKDCC Sarah Graham reviewed gene: PKDCC: Rating: GREEN; Mode of pathogenicity: ; Publications: 30478137, 19097194; Phenotypes: Rhizomelic limb shortening with dysmorphic features, MIM#618821; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.15 ITCH Natalie Canham reviewed gene: ITCH: Rating: RED; Mode of pathogenicity: ; Publications: 20170897, 31091003; Phenotypes: Autoimmune disease, multisystem, with facial dysmorphism, MIM#613385; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.15 GNB2 Natalie Canham reviewed gene: GNB2: Rating: GREEN; Mode of pathogenicity: ; Publications: 31698099, 36658419, 34183358; Phenotypes: Neurodevelopmental disorder with hypotonia and dysmorphic facies, MIM#619503; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.15 FTO Natalie Bibb reviewed gene: FTO: Rating: GREEN; Mode of pathogenicity: ; Publications: 19559399, 19234441, 26697951, 26378117, 26740239; Phenotypes: Growth retardation, developmental delay, facial dysmorphism, MIM#612938; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.15 FILIP1 Anna de Burca reviewed gene: FILIP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 36943452, 37163662; Phenotypes: Neuromuscular disorder, congenital, with dysmorphic facies, MIM#620775; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.15 CNOT2 Elizabeth Scotchman reviewed gene: CNOT2: Rating: GREEN; Mode of pathogenicity: ; Publications: 31145527, 28135719, 31512373; Phenotypes: Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies, MIM#618608; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.15 BPTF Alice Gardham reviewed gene: BPTF: Rating: RED; Mode of pathogenicity: ; Publications: 36153657, 33522091; Phenotypes: Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, MIM#617755; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v5.13 WBP4 Achchuthan Shanmugasundram gene: WBP4 was added
gene: WBP4 was added to Fetal anomalies. Sources: NHS GMS,Expert Review Amber
Mode of inheritance for gene: WBP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WBP4 were set to 37963460; 37425688
Phenotypes for gene: WBP4 were set to Neurodevelopemental disorder with hypotonia, feeding difficulties, facial dysmorphism, and brain abnormalities, OMIM:620852
Fetal anomalies v5.13 U2AF2 Achchuthan Shanmugasundram gene: U2AF2 was added
gene: U2AF2 was added to Fetal anomalies. Sources: NHS GMS,Expert Review Amber
Mode of inheritance for gene: U2AF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: U2AF2 were set to 34112922; 37134193; 37092751; 36747105
Phenotypes for gene: U2AF2 were set to Developmental delay, dysmorphic facies, and brain anomalies OMIM:620535
Fetal anomalies v5.13 SMOC2 Achchuthan Shanmugasundram Source NHS GMS was added to SMOC2.
Source Expert Review Red was added to SMOC2.
Added phenotypes Dentin dysplasia, type I, with microdontia and misshapen teeth, OMIM:125400 for gene: SMOC2
Publications for gene: SMOC2 were updated from to 22152679; 23317772
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Fetal anomalies v5.13 SETD1A Achchuthan Shanmugasundram Source NHS GMS was added to SETD1A.
Added phenotypes Neurodevelopmental disorder with speech impairment and dysmorphic facies, OMIM:619056 for gene: SETD1A
Publications for gene: SETD1A were updated from to 37000069
Fetal anomalies v5.13 PUM1 Achchuthan Shanmugasundram gene: PUM1 was added
gene: PUM1 was added to Fetal anomalies. Sources: NHS GMS,Expert Review Amber
Mode of inheritance for gene: PUM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PUM1 were set to 30903679; 29474920; 25768905; 35386260; 31859446
Phenotypes for gene: PUM1 were set to Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism, OMIM:620719
Fetal anomalies v5.13 PKDCC Achchuthan Shanmugasundram gene: PKDCC was added
gene: PKDCC was added to Fetal anomalies. Sources: NHS GMS,Expert Review Amber
Mode of inheritance for gene: PKDCC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PKDCC were set to 19097194; 30478137
Phenotypes for gene: PKDCC were set to Rhizomelic limb shortening with dysmorphic features, OMIM:618821
Fetal anomalies v5.13 ITCH Achchuthan Shanmugasundram Source NHS GMS was added to ITCH.
Source Expert Review Red was added to ITCH.
Added phenotypes Autoimmune disease, multisystem, with facial dysmorphism, OMIM:613385 for gene: ITCH
Publications for gene: ITCH were updated from to 20170897; 31091003
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Fetal anomalies v5.13 FTO Achchuthan Shanmugasundram Source NHS GMS was added to FTO.
Added phenotypes Growth retardation, developmental delay, facial dysmorphism, OMIM: 612938 for gene: FTO
Publications for gene: FTO were updated from 19559399; 26378117; 31130284 to 19234441; 26697951; 26378117; 19559399; 26740239; 31130284
Fetal anomalies v5.13 FILIP1 Achchuthan Shanmugasundram gene: FILIP1 was added
gene: FILIP1 was added to Fetal anomalies. Sources: NHS GMS,Expert Review Amber
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452; 37163662
Phenotypes for gene: FILIP1 were set to Neuromuscular disorder, congenital, with dysmorphic facies, OMIM:620775
Fetal anomalies v5.13 CNOT2 Achchuthan Shanmugasundram gene: CNOT2 was added
gene: CNOT2 was added to Fetal anomalies. Sources: NHS GMS,Expert Review Amber
Mode of inheritance for gene: CNOT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CNOT2 were set to 31512373; 31145527; 28135719
Phenotypes for gene: CNOT2 were set to Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies, OMIM:618608
Fetal anomalies v5.13 BPTF Achchuthan Shanmugasundram Source NHS GMS was added to BPTF.
Source Expert Review Red was added to BPTF.
Mode of inheritance for gene BPTF was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, OMIM:617755 for gene: BPTF
Publications for gene: BPTF were updated from to 33522091; 36153657
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Fetal anomalies v5.6 CACHD1 Achchuthan Shanmugasundram gene: CACHD1 was added
gene: CACHD1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: CACHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACHD1 were set to 38158856
Phenotypes for gene: CACHD1 were set to syndromic complex neurodevelopmental disorder, MONDO:0800439
Review for gene: CACHD1 was set to AMBER
Added comment: PMID:38158856 reported six affected individuals from four unrelated families with biallelic (either homozygous or compound heterozygous) CACHD1 variants (3 splice, 2 frameshift and 1 nonsense variant).

Of these, two cases from the fourth family are fetal cases. Excluding these two fatal cases, all others were affected by syndromic neurodevelopmental abnormalities, multiple organ systems featuring global impairment of psychomotor development, dysmorphic facial features, genitourinary abnormalities, oculo-auricular and congenital malformation. Cognitive impairment was reported to be mild in three cases from three different families, while the fourth case had no cognitive impairment. Psychomotor delay was reported in two unrelated cases and seizure was reported in one.

Facial dysmorphism and ear and genitourinary abnormalities were reported in the two fetal cases, while congenital malformations of the digestive tract was reported in one of them.

Functional evidence from human stem cell-derived neural models and zebrafish mutants are also available in support of the disease association.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Fetal anomalies v4.179 DDX6 Achchuthan Shanmugasundram Phenotypes for gene: DDX6 were changed from INTELLECTUAL DISABILITY; Intellectual developmental disorder with impaired language and dysmorphic facies, OMIM:618653 to Intellectual developmental disorder with impaired language and dysmorphic facies, OMIM:618653
Fetal anomalies v4.125 CTDP1 Achchuthan Shanmugasundram Phenotypes for gene: CTDP1 were changed from CONGENITAL CATARACTS FACIAL DYSMORPHISM AND NEUROPATHY SYNDROME to Congenital cataracts, facial dysmorphism, and neuropathy, OMIM:604168
Fetal anomalies v4.115 ASXL2 Achchuthan Shanmugasundram Phenotypes for gene: ASXL2 were changed from Developmental delay, macrocephaly, and dysmorphic features; Shashi-Pena syndrome, OMIM:617190 to Shashi-Pena syndrome, OMIM:617190
Fetal anomalies v4.104 TRRAP Achchuthan Shanmugasundram Phenotypes for gene: TRRAP were changed from multiple congenital anomalies; Developmental delay with or without dysmorphic facies and autism, OMIM:618454 to Developmental delay with or without dysmorphic facies and autism, OMIM:618454; multiple congenital anomalies
Fetal anomalies v4.81 PHF21A Achchuthan Shanmugasundram Phenotypes for gene: PHF21A were changed from POTOCKI-SHAFFER SYNDROME; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, OMIM:618725 to Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, OMIM:618725
Fetal anomalies v4.80 PGAP1 Achchuthan Shanmugasundram Phenotypes for gene: PGAP1 were changed from Intellectual disability, encephalopathy, impaired GPI-anchor maturation to Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities, OMIM:615802
Fetal anomalies v4.76 OTUD6B Achchuthan Shanmugasundram Phenotypes for gene: OTUD6B were changed from Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features to Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, OMIM:617452
Fetal anomalies v4.35 ZMIZ1 Denise Williams reviewed gene: ZMIZ1: Rating: GREEN; Mode of pathogenicity: ; Publications: 30639322, 31879022; Phenotypes: Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies, OMIM:618659; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v4.35 TUBGCP2 Lyn Chitty reviewed gene: TUBGCP2: Rating: AMBER; Mode of pathogenicity: ; Publications: 31630790; Phenotypes: Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, OMIM:618737; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v4.35 TRRAP Anna de Burca reviewed gene: TRRAP: Rating: GREEN; Mode of pathogenicity: ; Publications: 30827496; Phenotypes: multiple congenital anomalies, Developmental delay with or without dysmorphic facies and autism, OMIM:618454; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v4.35 RHOA Esther Kinning reviewed gene: RHOA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, somatic mosaic, OMIM:618727; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v4.35 PPP2R3C Lyn Chitty reviewed gene: PPP2R3C: Rating: GREEN; Mode of pathogenicity: ; Publications: 30893644, 34714774, 34750818; Phenotypes: Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy, OMIM:618419; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v4.35 PHF21A Anna de Burca reviewed gene: PHF21A: Rating: GREEN; Mode of pathogenicity: ; Publications: 31649809, 30487643, 22770980; Phenotypes: Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, MIM# 618725; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v4.35 PGAP1 Denise Williams reviewed gene: PGAP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 24482476, 25823418, 25804403, 26050939, 24784135; Phenotypes: Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities, OMIM:615802; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v4.35 OTUD6B Anna de Burca reviewed gene: OTUD6B: Rating: GREEN; Mode of pathogenicity: ; Publications: 31147255, 32924626, 28343629; Phenotypes: Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, OMIM #617452; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v4.35 MYOD1 Natalie Bibb reviewed gene: MYOD1: Rating: GREEN; Mode of pathogenicity: ; Publications: 30403323, 26733463, 31260566; Phenotypes: Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies, OMIM:618975; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v4.35 MAPKAPK5 Natalie Chandler reviewed gene: MAPKAPK5: Rating: GREEN; Mode of pathogenicity: ; Publications: 35575217, 33442026; Phenotypes: Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v4.35 KAT5 Achchuthan Shanmugasundram reviewed gene: KAT5: Rating: AMBER; Mode of pathogenicity: ; Publications: 32822602; Phenotypes: Neurodevelopmental disorder wtih dysmorphic facies, sleep disturbance, and brain abnormalities, OMIM:619103; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v4.35 INTS1 Natalie Chandler reviewed gene: INTS1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28542170, 31428919, 30622326; Phenotypes: Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, OMIM:61857; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v4.35 HERC1 Natalie Bibb reviewed gene: HERC1: Rating: AMBER; Mode of pathogenicity: ; Publications: 28323226, 26138117, 27108999, 26153217; Phenotypes: Macrocephaly, dysmorphic facies, and psychomotor retardation, OMIM:617011; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v4.35 DPH1 Esther Kinning reviewed gene: DPH1: Rating: GREEN; Mode of pathogenicity: ; Publications: 32732226, 30877278, 29362492, 25558065; Phenotypes: Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v4.35 DDX6 Natalie Bibb reviewed gene: DDX6: Rating: RED; Mode of pathogenicity: ; Publications: 31422817; Phenotypes: Intellectual developmental disorder with impaired language and dysmorphic facies, OMIM:618653; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v4.35 CTDP1 Stephanie Allen reviewed gene: CTDP1: Rating: AMBER; Mode of pathogenicity: ; Publications: 20301787, 14517542, 24690360, 29174527, 25529582; Phenotypes: Congenital cataracts, facial dysmorphism, and neuropathy, OMIM:604168; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v4.34 ZMIZ1 Achchuthan Shanmugasundram gene: ZMIZ1 was added
gene: ZMIZ1 was added to Fetal anomalies. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: ZMIZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZMIZ1 were set to 30639322; 31879022
Phenotypes for gene: ZMIZ1 were set to Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies, OMIM:618659
Fetal anomalies v4.34 TUBGCP2 Achchuthan Shanmugasundram gene: TUBGCP2 was added
gene: TUBGCP2 was added to Fetal anomalies. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, OMIM:618737
Fetal anomalies v4.34 TRRAP Achchuthan Shanmugasundram gene: TRRAP was added
gene: TRRAP was added to Fetal anomalies. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: TRRAP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRRAP were set to 30827496
Phenotypes for gene: TRRAP were set to multiple congenital anomalies; Developmental delay with or without dysmorphic facies and autism, OMIM:618454
Fetal anomalies v4.34 RHOA Achchuthan Shanmugasundram gene: RHOA was added
gene: RHOA was added to Fetal anomalies. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: RHOA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RHOA were set to Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, somatic mosaic, OMIM:618727
Fetal anomalies v4.34 RAP1B Achchuthan Shanmugasundram gene: RAP1B was added
gene: RAP1B was added to Fetal anomalies. Sources: NHS GMS,Expert Review Red
Mode of inheritance for gene: RAP1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAP1B were set to 26280580; 32627184
Phenotypes for gene: RAP1B were set to Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies, OMIM:620654
Fetal anomalies v4.34 PPP2R3C Achchuthan Shanmugasundram gene: PPP2R3C was added
gene: PPP2R3C was added to Fetal anomalies. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: PPP2R3C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPP2R3C were set to 30893644; 34714774; 34750818
Phenotypes for gene: PPP2R3C were set to Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy, OMIM:618419
Fetal anomalies v4.34 PHF21A Achchuthan Shanmugasundram Source NHS GMS was added to PHF21A.
Mode of inheritance for gene PHF21A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, OMIM:618725 for gene: PHF21A
Publications for gene: PHF21A were updated from to 31649809; 30487643; 22770980
Fetal anomalies v4.34 KAT5 Achchuthan Shanmugasundram gene: KAT5 was added
gene: KAT5 was added to Fetal anomalies. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: KAT5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KAT5 were set to 32822602
Phenotypes for gene: KAT5 were set to Neurodevelopmental disorder wtih dysmorphic facies, sleep disturbance, and brain abnormalities, OMIM:619103
Fetal anomalies v4.34 INTS1 Achchuthan Shanmugasundram gene: INTS1 was added
gene: INTS1 was added to Fetal anomalies. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: INTS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INTS1 were set to 28542170; 31428919; 30622326
Phenotypes for gene: INTS1 were set to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, OMIM:61857
Fetal anomalies v4.34 HERC1 Achchuthan Shanmugasundram gene: HERC1 was added
gene: HERC1 was added to Fetal anomalies. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: HERC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HERC1 were set to 28323226; 26138117; 27108999; 26153217
Phenotypes for gene: HERC1 were set to Macrocephaly, dysmorphic facies, and psychomotor retardation, OMIM:617011
Fetal anomalies v4.34 FRA10AC1 Achchuthan Shanmugasundram gene: FRA10AC1 was added
gene: FRA10AC1 was added to Fetal anomalies. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: FRA10AC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FRA10AC1 were set to 34694367
Phenotypes for gene: FRA10AC1 were set to Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, OMIM:620113
Fetal anomalies v4.34 DDX6 Achchuthan Shanmugasundram Source NHS GMS was added to DDX6.
Source Expert Review Red was added to DDX6.
Mode of inheritance for gene DDX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Intellectual developmental disorder with impaired language and dysmorphic facies, OMIM:618653 for gene: DDX6
Publications for gene: DDX6 were updated from to 31422817
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Fetal anomalies v4.15 KCNK9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are several unrelated cases reported with KCNK9 variants and Birk-Barel syndrome (MIM #612292). Clinical presentations include motor and speech delay, impaired intellectual development, early feeding difficulties, muscular hypotonia, behavioral abnormalities and dysmorphic features.

In addition, this gene has also been associated with phenotypes on the DD panel of Gene2Phenotype resource with 'limited' rating.

As reviewed by Sarah Graham, a foetus has also been reported with KCNK9 variant and with phenotypes consistent with this disorder.

Hence, this gene can be promoted to green rating in the next GMS update.
Fetal anomalies v4.12 GNB2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Sarah Graham, monoallelic GNB2 variants are associated with a neurodevelopmental disorder with features including dysmorphic facial features, cardiac and renal abnormalities.

This gene has been associated with phenotypes in OMIM (MIM #619503) and DD panel of Gene2Phenotype resource (with 'Definitive' rating, previously known as 'confirmed').

A foetus was also reported with phenotypes consistent with this gene.

Hence, this gene can be promoted to green rating in the next GMS update.
Fetal anomalies v4.11 GNB2 Achchuthan Shanmugasundram Phenotypes for gene: GNB2 were changed from to Neurodevelopmental disorder with hypotonia and dysmorphic facies, OMIM:619503
Fetal anomalies v4.9 GNB2 Achchuthan Shanmugasundram reviewed gene: GNB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31698099, 34183358, 36658419; Phenotypes: Neurodevelopmental disorder with hypotonia and dysmorphic facies, OMIM:619503; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v4.3 GNB2 Sarah Graham gene: GNB2 was added
gene: GNB2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GNB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNB2 were set to 36658419
Mode of pathogenicity for gene: GNB2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: GNB2 was set to GREEN
Added comment: Gene associated with autosomal dominant neurodevelopmental disorder; features include dysmorphic facial features, cardiac and renal abnormalities (OMIM #619503). Recurrent de novo pathogenic missense variant p.(Lys89Glu) (https://www.ncbi.nlm.nih.gov/clinvar/variation/1217306/) reported in a fetus with phenotype consistent with this gene: cardiac abnormalities (hypoplastic left heart and hypoplastic aortic arch, double outlet right ventricle, great arteries located side-by-side, ventricular septal defect, persistent left superior vena cava connecting to coronary sinus), renal agenesis, mildly dysmorphic facies (Byrne 2023 PMID: 36658419).
Sources: Literature
Fetal anomalies v3.157 PLD1 Arina Puzriakova changed review comment from: Comment on list classification: This Green gene was signed off in Nov 2022 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.; to: Comment on list classification: This Green gene was signed off in Mar 2023 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.
Fetal anomalies v3.157 PLD1 Arina Puzriakova Added comment: Comment on list classification: This Green gene was signed off in Nov 2022 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.
Fetal anomalies v3.156 PLD1 Arina Puzriakova commented on gene: PLD1: Copied review from Paediatric or syndromic cardiomyopathy (749) v3.43 panel:

Jesse Hayesmoore (Oxford Regional Genetics Laboratory)
Red List (low evidence)

"On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease (not cardiomyopathy) have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines."
Created: 31 Jan 2024, 12:04 p.m. | Last Modified: 31 Jan 2024, 12:17 p.m
Fetal anomalies v3.109 ESAM Julia Baptista gene: ESAM was added
gene: ESAM was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to PMID: 36996813
Phenotypes for gene: ESAM were set to intracranial hemorrhage; cerebral anomalies
Review for gene: ESAM was set to GREEN
Added comment: Four fetuses from three unrelated families (different LOF biallelic variants) with fetal intracranial hemorrhage. Fetal brain tissue from one of the affected individuals at 31 weeks' gestational age showed lack of ESAM staining in the capillary endothelial cells, thus confirming loss of ESAM. Another individual had an abnormal prenatal ultrasound and the pregnancy was terminated at 32 weeks' gestation, but no DNA was available to test for the familial variant.
Neurodevelopmental disorder with cerebral calcifications, hydrocephalus, focal white matter lesions, retina anomalies and dysmorphic features.
Sources: Literature
Fetal anomalies v3.73 MYL9 Arina Puzriakova commented on gene: MYL9: Third family reported by Billon et al. 2020 (PMID: 32621347) with the same homozygous exon 4 deletion of MYL9 as the one detected by Moreno et al. 2018 (PMID: 29453416) in an unrelated case. Family includes three sibs affected with megacystis, intestinal malrotation, small and thin colon, as well as some dysmorphic features. Fetopathological examination confirmed the diagnosis of MMIHS.
Fetal anomalies v2.12 CHAMP1 Achchuthan Shanmugasundram Phenotypes for gene: CHAMP1 were changed from INTELLECTUAL DISABILITY to Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features, OMIM:616579
Fetal anomalies v2.8 KIF21A Hannah Robinson gene: KIF21A was added
gene: KIF21A was added to Fetal anomalies. Sources: Literature,NHS GMS
Mode of inheritance for gene: KIF21A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF21A were set to 34740919
Phenotypes for gene: KIF21A were set to Arthrogryposis; fetal akinesia
Penetrance for gene: KIF21A were set to unknown
Review for gene: KIF21A was set to GREEN
gene: KIF21A was marked as current diagnostic
Added comment: Falb et al 2023 (PMID: 34740919) describe two unrelated families in which biallelic loss of function variants segregated with a severe form of fetal akinesia characterised by arthrogryposis multiplex, pulmonary hypoplasia and variable facial dysmorphisms.

Exeter Genomics Laboratory has identified an unrelated third case homozygous for a nonsense variant in KIF21A. The patient had an antenatal diagnosis of talipes, arthrogryposis, polyhydramnios and lack of fetal movements. At birth, all joints displayed fixed flexion deformities, no primitive reflexes, poor muscle bulk and care was re-oriented shortly after birth.

Taken together, three unrelated cases including segregation evidence in the published families provides sufficient evidence for the gene-disease association.
Sources: Literature, NHS GMS
Fetal anomalies v1.966 SETD2 Arina Puzriakova Phenotypes for gene: SETD2 were changed from SETD2-associated Overgrowth Syndrome to microcephaly; profound intellectual disability; congenital anomalies; dysmorphic facial features
Fetal anomalies v1.964 SETD2 Rhiannon Mellis reviewed gene: SETD2: 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: PMID: 32710489, 33255631; Phenotypes: microcephaly, profound intellectual disability, congenital anomalies, dysmorphic facial features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.900 MRPS16 Rhiannon Mellis gene: MRPS16 was added
gene: MRPS16 was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: MRPS16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS16 were set to PMID: 28749478
Phenotypes for gene: MRPS16 were set to Combined oxidative phosphorylation deficiency 2
Review for gene: MRPS16 was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Amber on mitochondrial/inborn errors of metabolism etc. Not Green on any panel. One previous case reported with "agenesis of the corpus callosum, dysmorphism, and fatal neonatal lactic acidosis. The patient was small at birth, with dysmorphic facies, low-set ears, nonpitting edema of the limbs, brachydactyly, and redundant skin over the neck. She died of intractable metabolic acidosis at age 3 days." PMID:15505824 (2004).

One further fetal case reported by Shamseldin et al. 2018 (PMID: 28749478) with hydrops, very short long bones, and partial ACC
Sources: Expert Review, Literature
Fetal anomalies v1.900 CACNA1S Rhiannon Mellis gene: CACNA1S was added
gene: CACNA1S was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: CACNA1S was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA1S were set to PMID: 33060286; 28012042
Phenotypes for gene: CACNA1S were set to Congenital myopathy; arthrogryposis
Review for gene: CACNA1S was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Previously only monoallelic variants reported associated with malignant hyperthermia and periodic paralysis but more recently biallelic variants have been associated with congenital myopathy. In Ravenscroft et al 2020 (PMID: 33060286) the reported biallelic variants were VUS but strong suspicion of causality: the proband had polyhydramnios, scalp oedema, bilateral wrist contractures, bilateral talipes and reduced fetal movements, ToP at 26/40. Mild facial dysmorphic features were noted on autopsy, including low anterior hairline, mild hypertelorism and moderate retrognathia. A previous pregnancy was affected with polyhydramnios and reduced fetal movements, delivered at 32/40 due to placental abruption and died at 10 days. On photos the baby had ptosis and broad nasal tip. The biallelic variants segregated within the family (parents and the 2 unaffected sibs all het). No cell lines available for functional studies.
Another study (PMID: 28012042) reports 7 families with congenital myopathy and CACNA1S mutations (both recessive and dominant), of whom 3 had cases with antenatal onset (reduced fetal movements).
Sources: Expert Review, Literature
Fetal anomalies v1.900 FTO Rhiannon Mellis gene: FTO was added
gene: FTO was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: FTO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FTO were set to PMID: 31130284; 19559399; 26378117
Phenotypes for gene: FTO were set to Growth retardation, developmental delay, facial dysmorphism
Review for gene: FTO was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Details of review:
Not Green on any panels (only 2 families reported to date). On OMIM: Growth retardation, developmental delay, facial dysmorphism. One fetal case reported by Monies et al 2019 (PMID: 31130284) with Dandy-Walker malformation, IUGR, and polyhydramnios. This fits with the phenotype reported in one consanguineous family with 9 affected individuals reported by Boissel 2009 PMID: 19559399. The other reported case is PMID: 26378117 - a homozygous missense variant in FTO was identified in a 21-month old girl who presented with growth retardation, failure to thrive, severely delayed development, Dysmorphic facial features, decreased brain parenchyma, delayed myelination, and a thin corpus callosum.
Sources: Expert Review, Literature
Fetal anomalies v1.900 LOX Rhiannon Mellis gene: LOX was added
gene: LOX was added to Fetal anomalies. Sources: Expert Review,Literature
Mode of inheritance for gene: LOX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LOX were set to PMID: 31742715
Phenotypes for gene: LOX were set to Aortopathy
Review for gene: LOX was set to AMBER
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: May be fetally relevant but currently limited evidence, support adding to the Fetal anomalies panel as Amber gene.

Currently rated Green on the following other PanelApp panel(s): familial thoracic aortic aneurysm

Details of review:
Reported as a novel genotype-phenotype association in Aggarwal et al 2020 (PMID: 31742715), in a fetus with homozygous missense variants. Heterozygous variants in this gene are known to cause thoracic aortic aneurysm. The fetus presented with unexplained IUD and on post-mortem had: Excessive skin folds, emphysematous bullae on lung surface, Facial dysmorphism, distal joint contractures, internal haemorrhages. Histopathology and special stains confirmed degradation of collagen and elastin in the aorta, pleura and skin. If we are going to add to panel suggest putting MOI as biallelic only (and accept that this would be an incidental finding for carrier parents that would lead to them needing monitoring for aortic aneurysm)
Sources: Expert Review, Literature
Fetal anomalies v1.880 MED13L Rhiannon Mellis reviewed gene: MED13L: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33142350, PMID: 32058062; Phenotypes: Intellectual disability, dysmorphic features, congenital heart malformations, talipes; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.851 RAC3 Arina Puzriakova Phenotypes for gene: RAC3 were changed from Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability to Neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, OMIM:618577
Fetal anomalies v1.836 MSMO1 Arina Puzriakova Tag for-review was removed from gene: MSMO1.
Fetal anomalies v1.836 MSMO1 Arina Puzriakova commented on gene: MSMO1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Fetal anomalies v1.835 MSMO1 Arina Puzriakova Source Expert Review Green was added to MSMO1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v1.749 CDK8 Rhiannon Mellis gene: CDK8 was added
gene: CDK8 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: CDK8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDK8 were set to PMID: 31742715; 30905399
Phenotypes for gene: CDK8 were set to Syndromic developmental disorder with hypotonia and behavioural abnormalities
Review for gene: CDK8 was set to GREEN
Added comment: This gene and phenotype were reviewed during a meeting on 21st October 2021 between representatives of the North Thames and Central & South R21 testing GLHs.

Clinical review and curation was performed by Lyn Chitty, Alison Male, Rowenna Roberts, Rhiannon Mellis (North Thames GLH) and Stephanie Allen, Denise Williams and Esther Kinning (Central & South GLH).

Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Already rated Green on the following other PanelApp panel(s): Intellectual disability; Severe paediatric disorders

Details of review:
Aggarwal et al 2020 report a heterozygous nonsense variant in a fetus with ventriculomegaly and Ebstein anomaly resulting in IUFD. Post-mortem found additionally congenital diaphragmatic hernia, common atrium and facial dysmorphism. This nonsense variant is at the same position as a hotspot for missense variants reported in a paediatric cohort (Calpena et al 2019, PMID: 30905399) with overlapping but milder phenotype: half of the 12 children in that cohort had cardiac defects, most had dysmorphic features - hence Aggarwal et al propose that this is a more severe (prenatal) presentation of the same multiple malformation syndrome, caused here by a nonsense rather than missense mutation.
Sources: Literature, Expert Review
Fetal anomalies v1.728 SCUBE3 Sarah Leigh Phenotypes for gene: SCUBE3 were changed from Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184 to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184; short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 MONDO:0030953
Fetal anomalies v1.727 SCUBE3 Sarah Leigh gene: SCUBE3 was added
gene: SCUBE3 was added to Fetal anomalies. Sources: Expert Review Amber,Other
Q2_21_rating tags were added to gene: SCUBE3.
Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCUBE3 were set to 33308444
Phenotypes for gene: SCUBE3 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies OMIM:619184
Penetrance for gene: SCUBE3 were set to unknown
Fetal anomalies v1.720 WLS Zornitza Stark gene: WLS was added
gene: WLS was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WLS were set to 34587386
Phenotypes for gene: WLS were set to structural congenital anomalies
Review for gene: WLS was set to GREEN
Added comment: - Homozygous variants in 10 affected persons from 5 unrelated families.
- Affected individuals had multiorgan defects, including microcephaly, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects.
- The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis.
Sources: Literature
Fetal anomalies v1.693 ASPH Ivone Leong Added comment: Comment on phenotypes: Previously:
FACIAL DYSMORPHISM, LENS DISLOCATION, ANTERIOR SEGMENT ABNORMALITIES, AND SPONTANEOUS FILTERING BLEBS
Fetal anomalies v1.693 ASPH Ivone Leong Phenotypes for gene: ASPH were changed from FACIAL DYSMORPHISM, LENS DISLOCATION, ANTERIOR SEGMENT ABNORMALITIES, AND SPONTANEOUS FILTERING BLEBS to Traboulsi syndrome, OMIM:601552
Fetal anomalies v1.692 MYOD1 Ivone Leong gene: MYOD1 was added
gene: MYOD1 was added to Fetal anomalies. Sources: Expert Review Amber,Literature
Q3_21_rating tags were added to gene: MYOD1.
Mode of inheritance for gene: MYOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYOD1 were set to 26733463; 30403323; 31260566
Phenotypes for gene: MYOD1 were set to Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies, OMIM:618975
Fetal anomalies v1.685 TMEM94 Ivone Leong Phenotypes for gene: TMEM94 were changed from Intellectual developmental disorder with cardiac defects and dysmorphic facies to Intellectual developmental disorder with cardiac defects and dysmorphic facies, OMIM:618316
Fetal anomalies v1.670 SPTBN5 Arina Puzriakova gene: SPTBN5 was added
gene: SPTBN5 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SPTBN5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN5 were set to 32732226
Phenotypes for gene: SPTBN5 were set to Multicystic kidney; Oligohydramnios
Review for gene: SPTBN5 was set to RED
Added comment: Novel candidate gene identified in a fetus with multicystic kidney and oligohydramnios detected by fetal ultrasound. Autopsy showed multiple congenital abnormalities including hygroma coli, spina bifida, polycystic kidneys, facial dysmorphism, common mesenterin, rachischisis, sacral vertebral agenesis. Compound heterozygous variants including a truncating variant were found by exome sequencing.
Sources: Literature
Fetal anomalies v1.663 DPH1 Arina Puzriakova gene: DPH1 was added
gene: DPH1 was added to Fetal anomalies. Sources: Literature
Q2_21_rating tags were added to gene: DPH1.
Mode of inheritance for gene: DPH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPH1 were set to 25558065; 29362492; 30877278; 32732226
Phenotypes for gene: DPH1 were set to Developmental delay with short stature, dysmorphic facial features, and sparse hair, OMIM:616901
Review for gene: DPH1 was set to GREEN
Added comment: Biallelic variants in this gene cause a neurodevelopmental disorder characterised by ID/DD, short stature, dysmorphic features, craniofacial and ectodermal anomalies. Several reports note antenatal anomalies and multiple congenital abnormalities that may conceivably be detected prenatally.

Fetal ultrasound phenotypes reported in literature include IUGR, polyhydramnios, craniostenosis, cardiac abnormalities, brain anomalies, and polydactyly (PMID: 25558065; 29362492; 30877278; 32732226)
Sources: Literature
Fetal anomalies v1.641 EBF3 Sarah Leigh Added comment: Comment on phenotypes: Intellectual Disability, Ataxia, and Facial Dysmorphism
Fetal anomalies v1.641 EBF3 Sarah Leigh Phenotypes for gene: EBF3 were changed from Intellectual Disability, Ataxia, and Facial Dysmorphism to Hypotonia, ataxia, and delayed development syndrome OMIM:617330; hypotonia, ataxia, and delayed development syndrome MONDO:0015021
Fetal anomalies v1.625 OTUD5 Arina Puzriakova gene: OTUD5 was added
gene: OTUD5 was added to Fetal anomalies. Sources: Expert Review
Q2_21_rating tags were added to gene: OTUD5.
Mode of inheritance for gene: OTUD5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: OTUD5 were set to 33131077; 33523931
Phenotypes for gene: OTUD5 were set to Multiple congenital anomalies-neurodevelopmental syndrome, X-linked, OMIM:301056
Review for gene: OTUD5 was set to GREEN
Added comment: OTUD5 is associated with a relevant phenotype in OMIM but not yet in Gene2Phenotype.

- PMID: 33131077 (2021) - 13 male patients from a single family with three generations affected. Patients presented prenatally or during the neonatal period with IUGR, ventriculomegaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and severe neurodevelopmental delay. The disease is typically fatal during infancy, mainly due to sepsis (pneumonias). Female carriers are asymptomatic. WGS in four individuals identified a unique candidate variant in the OTUD5 gene (NM_017602.3:c.598G > A, p.Glu200Lys). The variant cosegregated with the disease in 10 tested individuals.

- PMID: 33523931 (2021) - Another 10 individuals from 7 families reported. Key features include poor growth, global developmental delay with impaired intellectual development, and variable abnormalities of the cardiac, skeletal, and genitourinary systems. Most affected individuals also have hypotonia and dysmorphic craniofacial features. Brain imaging typically shows enlarged ventricles and thin corpus callosum; some have microcephaly, whereas others have hydrocephalus. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade.
Sources: Expert Review
Fetal anomalies v1.280 MYO18B Arina Puzriakova Phenotypes for gene: MYO18B were changed from Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism to Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism, OMIM:616549; Klippel-Feil anomaly-myopathy-facial dysmorphism syndrome, MONDO:0014689
Fetal anomalies v1.262 MSMO1 Arina Puzriakova Publications for gene: MSMO1 were set to
Fetal anomalies v1.261 MSMO1 Arina Puzriakova Phenotypes for gene: MSMO1 were changed from Microcephaly, congenital cataract, and psoriasiform dermatitis to Microcephaly, congenital cataract, and psoriasiform dermatitis, OMIM:616834; Microcephaly-congenital cataract-psoriasiform dermatitis syndrome, MONDO:0014793
Fetal anomalies v1.260 MSMO1 Arina Puzriakova Classified gene: MSMO1 as Amber List (moderate evidence)
Fetal anomalies v1.260 MSMO1 Arina Puzriakova Gene: msmo1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.259 MSMO1 Arina Puzriakova Tag for-review tag was added to gene: MSMO1.
Fetal anomalies v1.228 CTU2 Rhiannon Mellis gene: CTU2 was added
gene: CTU2 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CTU2 were set to Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, 618142
Review for gene: CTU2 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Green on related panel(s): CAKUT
Sources: Expert list
Fetal anomalies v1.214 MSMO1 Rhiannon Mellis gene: MSMO1 was added
gene: MSMO1 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: MSMO1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MSMO1 were set to Microcephaly, congenital cataract, and psoriasiform dermatitis
Review for gene: MSMO1 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Green on related panel(s): Severe microcephaly
Sources: Expert list
Fetal anomalies v1.214 MYO18B Rhiannon Mellis gene: MYO18B was added
gene: MYO18B was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: MYO18B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MYO18B were set to Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism
Review for gene: MYO18B was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Green on related panel(s): Neuromuscular disorders
Sources: Expert list
Fetal anomalies v1.115 MN1 Rhiannon Mellis gene: MN1 was added
gene: MN1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MN1 were set to 31834374; 31839203; 15870292
Phenotypes for gene: MN1 were set to CEBALID syndrome, 618774
Mode of pathogenicity for gene: MN1 was set to Other
Review for gene: MN1 was set to GREEN
Added comment: Copied from MN1 review on Cortical malformations panel:

Associated with phenotype in OMIM, and a probable gene for MN1 C-terminal truncation syndrome in G2P.

Over 20 unrelated probands reported with heterozygous MN1 truncating variants, associated with a distinct phenotype which includes DD, craniofacial abnormalities, hearing loss, and structural abnormalities in the brain (e.g. polymicrogyria, dysmorphic corpus callosum and anomalies of the cerebellum - rhombencephalosynapsis).

Most variants cluster in the C-terminal, and all were predicted to escape NMD. Authors postulated that the resulting truncated protein may have a dominant-negative or gain-of-function effect. Also phenotypically supportive knockout mouse model.
Sources: Literature
Fetal anomalies v1.73 TMEM94 Rhiannon Mellis gene: TMEM94 was added
gene: TMEM94 was added to Fetal anomalies. Sources: Literature,Expert Review
Mode of inheritance for gene: TMEM94 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM94 were set to PMID: 30526868
Phenotypes for gene: TMEM94 were set to Intellectual developmental disorder with cardiac defects and dysmorphic facies
Review for gene: TMEM94 was set to GREEN
Added comment: Literature reports 10 patients from 6 unrelated families, and a mouse model PMID: 30526868

Reviewed with Prof Lyn Chitty for fetally relevant phenotype (Yes - Congenital heart malformations including: Atrial septal defect; Ventricular septal defect; Pulmonary hypoplasia; Pulmonary atresia; Tetralogy of Fallot; Double outlet right ventricle
Sources: Literature, Expert Review
Fetal anomalies v1.73 NUP88 Julia Baptista gene: NUP88 was added
gene: NUP88 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: NUP88 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP88 were set to PMID: 30543681
Phenotypes for gene: NUP88 were set to fetal akinesia
Review for gene: NUP88 was set to RED
Added comment: Bonnin et al reported biallelic variants in two unrelated families.
A homozygous missense variant was identified in family A and the co-segregation data was supportive (tested 4 unaffected and 2 of the 4 affected fetuses). Compound heterozygous in-frame and nonsense variants were identified in the proband in family B (co-segregation studies in 2 unaffected sibs). The clinical features included fetal akinesia and arthrogryposis multiplex congenita. Polyhydramnios, muscle atrophy and dysmorphic features were also described.
Sources: Literature
Fetal anomalies v1.73 ITGA8 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber awaiting GLH review. Additional phenotypes were reported in the fetuses and sibling (who died perinatally) from PMID:24439109 (clubbed feet, facial dysmorphism, pulmonary hypoplasia, bilateral cryptorchidism) although renal agenesis is the primary phenotype and only 2 families from one paper.
Fetal anomalies v1.49 ALG9 Rebecca Foulger changed review comment from: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants. In addition to summarising the 3 patients from Tham et al (PMID:25966638) who died in utero
, they report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had a homozygous variant in ALG9: p.Tyr287Cys.; to: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants. In addition to summarising the 3 patients from Tham et al (PMID:25966638) who died in utero, they report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had a homozygous variant in ALG9: p.Tyr287Cys.
Fetal anomalies v1.49 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants. In addition to summarising the 3 patients from Tham et al (PMID:25966638) who died in utero
, they report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had a homozygous variant in ALG9: p.Tyr287Cys.
Fetal anomalies v1.41 SMG9 Rebecca Foulger commented on gene: SMG9: PMID:31390136. Lecoquierre et al., 2019 performed exome sequencing in a patient with syndromic DD and diverse malformations including cleft lip and palate, facial dysmorphia, brain abnormalities, herat defect, growth retardation and severe infections. She carried a homozygous SMG9 variant, p.(Gln393*). Her unaffected parents were both heterozygous. Phenotypes were first noted in-utero: polyhydamnios, lateral cleft lip and palate, and IUGR noted on ultrasound.
Fetal anomalies v1.41 SMG9 Rebecca Foulger commented on gene: SMG9: PMID:27018474. Shaheen et al, 2016 report 2 consanguineous families with different homozygous LOF variants in SMG9 and and a similar set of congenital anomalies including craniofacial dysmorphism, and major brain and heart malformations.
Fetal anomalies v1.35 CNOT3 Rebecca Foulger Phenotypes for gene: CNOT3 were changed from CNOT3 syndrome; Intellectual developmental disorder with speech delay, 618672 autism, and dysmorphic facies to CNOT3 syndrome; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, 618672
Fetal anomalies v1.34 CNOT3 Rebecca Foulger Phenotypes for gene: CNOT3 were changed from CNOT3 syndrome to CNOT3 syndrome; Intellectual developmental disorder with speech delay, 618672 autism, and dysmorphic facies
Fetal anomalies v1.22 POLE Rebecca Foulger Phenotypes for gene: POLE were changed from IUGR; severe growth failure of prenatal onset to IUGR; severe growth failure of prenatal onset; FILS syndrome, 615139; facial dysmorphism, immunodeficiency, livedo, and short stature (FILS)
Fetal anomalies v0.311 MRPS22 Rebecca Foulger edited their review of gene: MRPS22: Added comment: This gene was re-reviewed in a consistency check by Anna de Burca (Genomics England Clinical Team). Outcome of review: Yates et al study (PMID:28425981) pulled out a pathogenic variant in MRPS22 in a deceased fetal case with Hydrops, CNS malformations and cardiomyopathy picked up on U/S scan. Additional info from OMIM: A boy with oxidative phosphorylation defect in PMID:21189481 who had microcephaly, dysmorphic features etc at birth. 3 siblings in PMID:17873122. Therefore if include Yates et al, there are 3 cases. ; Changed rating: GREEN; Changed publications: 17873122, 21189481
Fetal anomalies v0.311 TCF20 Rebecca Foulger edited their review of gene: TCF20: Added comment: As agreed with Anna de Burca (Genomics England Clinical team): Keep TCF20 as Amber: the structural phenotypes are variable (and largely mild). All individuals have ID/DD but the accompanying dysmorphic features are inconsistent, and the authors suggest additional genes may be responsible/modifying- some of the patients had variants in additional genes (or the phenotypes might be very very rare).; Changed publications: 30739909, 30819258
Fetal anomalies v0.311 MAN1B1 Rebecca Foulger commented on gene: MAN1B1: This gene was reviewed by Anna de Burca (Genomics England Clinical Team) under the category of storage disorders. Outcome of review: Rate as Amber- mild dysmorphic phenotype.
Fetal anomalies v0.250 TRAF7 Rebecca Foulger Phenotypes for gene: TRAF7 were changed from Developmental Delay, Congenital Anomalies, and Dysmorphic Features to Developmental Delay, Congenital Anomalies, and Dysmorphic Features; Cardiac, facial, and digital anomalies with developmental delay, 618164
Fetal anomalies v0.244 HNRNPK Rebecca Foulger commented on gene: HNRNPK: Au-Kline syndrome is a multiple malformation syndrome associated with intellectual disability. Patients have facial dysmorphic features and frequently have skeletal and connective tissue anomalies, craniosynostosis, congenital heart malformations, and renal anomalies (PMID:29904177). Structural phenotypes reported in the literature include talipes and partial agenesis of corpus callosum. Au et al., 2018 (PMID:29904177) report prenatal presentation with 5 patients showing increased nuchal translucency and 5 patients had hydronephrosis.
Fetal anomalies v0.225 CTDP1 Rebecca Foulger edited their review of gene: CTDP1: Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March and April 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Phenotype is fetally-relevant but limited evidence: include on the Fetal anomalies panel as an Amber gene. Additional notes from clinical review: Although CTDP1 has a 'confirmed' Disease confidence rating in DD-G2P for CONGENITAL CATARACTS FACIAL DYSMORPHISM AND NEUROPATHY SYNDROME, the disorder is prevalent in Bulagarian Gypsy populations, and is limited to a founder variant.; Changed publications: 14517542, 29174527, 20301787, 24690360
Fetal anomalies v0.224 SMO Rebecca Foulger commented on gene: SMO: Added 'somatic' tag alonside the 'mosaicism' tag following clinical review of SMO (April 26th 2019 with Lyn Chitty, Anna de Burca, Richard Scott and Rhiannon Mellis.
Fetal anomalies v0.224 SMO Rebecca Foulger Tag somatic tag was added to gene: SMO.
Fetal anomalies v0.222 SMO Rebecca Foulger edited their review of gene: SMO: Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March and April 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Confirmed that phenotype is fetally-relevant: include on the Fetal anomalies panel as a Green gene. Additional notes from clinical review: Somatic mosaic.; Changed rating: GREEN
Fetal anomalies v0.166 TMEM165 Rebecca Foulger edited their review of gene: TMEM165: Added comment: This gene and phenotype were discussed during review of borderline cases in April 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Confirmed that phenotype is fetally-relevant: keep on the Fetal anomalies panel as Green. Additional notes from clinical review: OMIM phenotypes include growth retardation, and most had short stature. Other features included dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia.; Changed rating: GREEN
Fetal anomalies v0.161 SMOC1 Rebecca Foulger edited their review of gene: SMOC1: Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Confirmed that phenotype is fetally-relevant: keep on the Fetal anomalies panel as a Green gene.; Changed rating: GREEN
Fetal anomalies v0.153 QRICH1 Rebecca Foulger edited their review of gene: QRICH1: Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Confirmed that phenotype is fetally-relevant: keep on the Fetal anomalies panel as a Green gene. Additional notes from clinical review: Only 5 cases reported so far so phenotype is not that well-characterised yet. Some dysmorphic features may be detectable prenatally- one case had IUGR, and another had severe microcephaly.; Changed rating: GREEN
Fetal anomalies v0.134 CREBBP Rebecca Foulger edited their review of gene: CREBBP: Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Confirmed that phenotype is fetally-relevant: keep on the Fetal anomalies panel as Green. Additional notes from clinical review: Several dysmorphic features.; Changed rating: GREEN
Fetal anomalies v0.134 CDKL5 Rebecca Foulger edited their review of gene: CDKL5: Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Confirmed that phenotype is fetally-relevant: keep on the Fetal anomalies panel as Green. Additional notes from clinical review: Phenotype includes progressive microcephaly (which may or may not be detectable in a fetus) plus subtle dysmorphic features and small feet.; Changed rating: GREEN
Fetal anomalies v0.115 TRAF7 Rebecca Foulger gene: TRAF7 was added
gene: TRAF7 was added to Fetal anomalies. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: TRAF7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRAF7 were set to 29961569
Phenotypes for gene: TRAF7 were set to Developmental Delay, Congenital Anomalies, and Dysmorphic Features
Mode of pathogenicity for gene: TRAF7 was set to Other - please provide details in the comments
Fetal anomalies v0.9 SMOC2 Rebecca Foulger reviewed gene: SMOC2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v0.9 SMOC1 Rebecca Foulger reviewed gene: SMOC1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v0.9 SMO Rebecca Foulger commented on gene: SMO: DDG2P rating in original PAGE list: Confirmed for Curry-Jones Syndrome
Fetal anomalies v0.9 RPS23 Rebecca Foulger commented on gene: RPS23: DDG2P rating in original PAGE list: Probable for Microcephaly, hearing loss, and dysmorphic features
Fetal anomalies v0.9 MTOR Rebecca Foulger commented on gene: MTOR: DDG2P rating in original PAGE list: Confirmed for Smith-Kingsmore syndrome
Fetal anomalies v0.8 SUFU Rebecca Foulger Phenotypes for gene: SUFU were changed from Medulloblastoma, desmoplastic 155255; Joubert Syndrome with Cranio-facial and Skeletal Defects; Basal cell nevus syndrome 109400 to Joubert Syndrome with Cranio-facial and Skeletal Defects; Basal cell nevus syndrome 109400
Fetal anomalies v0.3 SMO Rebecca Foulger Tag mosaicism tag was added to gene: SMO.
Fetal anomalies v0.3 SMO Rebecca Foulger commented on gene: SMO: Mosaicism tag added based on original PAGE file which records Mosaic MOI for Curry-Jones Syndrome.
Fetal anomalies v0.3 SMO Rebecca Foulger reviewed gene: SMO: Rating: AMBER; Mode of pathogenicity: Other - please provide details in the comments; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v0.1 TMCO1 Rebecca Foulger gene: TMCO1 was added
gene: TMCO1 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: TMCO1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TMCO1 were set to CRANIOFACIAL DYSMORPHISM, SKELETAL ANOMALIES, AND MENTAL RETARDATION SYNDROME
Fetal anomalies v0.1 TBX15 Rebecca Foulger gene: TBX15 was added
gene: TBX15 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: TBX15 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TBX15 were set to Craniofacial Dysmorphism, Hypoplasia of Scapula and Pelvis, and Short Stature; Cousin Syndrome
Fetal anomalies v0.1 TBCE Rebecca Foulger Added phenotypes HYPOPARATHYROIDISM-RETARDATION-DYSMORPHISM SYNDROME for gene: TBCE
Fetal anomalies v0.1 TAF1 Rebecca Foulger gene: TAF1 was added
gene: TAF1 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: TAF1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: TAF1 were set to Dysmorphic Features, Intellectual Disability, and Neurological Manifestations
Fetal anomalies v0.1 SZT2 Rebecca Foulger gene: SZT2 was added
gene: SZT2 was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber
Mode of inheritance for gene: SZT2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SZT2 were set to INFANTILE ENCEPHALOPATHY WITH EPILEPSY AND DYSMORPHIC CORPUS CALLOSUM
Fetal anomalies v0.1 SUFU Rebecca Foulger Added phenotypes Medulloblastoma, desmoplastic 155255 for gene: SUFU
Fetal anomalies v0.1 STAR Rebecca Foulger gene: STAR was added
gene: STAR was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: STAR was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STAR were set to CHOLESTEROL DESMOLASE-DEFICIENT CONGENITAL ADRENAL HYPERPLASIA
Fetal anomalies v0.1 SMOC2 Rebecca Foulger gene: SMOC2 was added
gene: SMOC2 was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber
Mode of inheritance for gene: SMOC2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SMOC2 were set to DENTIN DYSPLASIA, TYPE I, WITH MICRODONTIA AND MISSHAPEN TEETH
Fetal anomalies v0.1 SMOC1 Rebecca Foulger gene: SMOC1 was added
gene: SMOC1 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: SMOC1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SMOC1 were set to OPHTHALMOACROMELIC SYNDROME
Fetal anomalies v0.1 SMO Rebecca Foulger gene: SMO was added
gene: SMO was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: SMO was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SMO were set to Curry-Jones Syndrome
Fetal anomalies v0.1 RPS23 Rebecca Foulger gene: RPS23 was added
gene: RPS23 was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber
Mode of inheritance for gene: RPS23 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: RPS23 were set to Microcephaly, hearing loss, and dysmorphic features
Fetal anomalies v0.1 POC1A Rebecca Foulger gene: POC1A was added
gene: POC1A was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: POC1A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: POC1A were set to SHORT STATURE, ONYCHODYSPLASIA, FACIAL DYSMORPHISM, AND HYPOTRICHOSIS SYNDROME
Fetal anomalies v0.1 PHIP Rebecca Foulger gene: PHIP was added
gene: PHIP was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: PHIP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PHIP were set to Developmental delay, ID, obesity and dysmorphic features
Fetal anomalies v0.1 OTUD6B Rebecca Foulger gene: OTUD6B was added
gene: OTUD6B was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber
Mode of inheritance for gene: OTUD6B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: OTUD6B were set to Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features
Fetal anomalies v0.1 MTOR Rebecca Foulger gene: MTOR was added
gene: MTOR was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: MTOR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MTOR were set to Smith-Kingsmore syndrome
Fetal anomalies v0.1 INPPL1 Rebecca Foulger gene: INPPL1 was added
gene: INPPL1 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: INPPL1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: INPPL1 were set to OPSISMODYSPLASIA
Fetal anomalies v0.1 EBF3 Rebecca Foulger gene: EBF3 was added
gene: EBF3 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: EBF3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: EBF3 were set to Intellectual Disability, Ataxia, and Facial Dysmorphism
Fetal anomalies v0.1 DHCR24 Rebecca Foulger gene: DHCR24 was added
gene: DHCR24 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: DHCR24 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DHCR24 were set to DESMOSTEROLOSIS
Fetal anomalies v0.1 CTDP1 Rebecca Foulger gene: CTDP1 was added
gene: CTDP1 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: CTDP1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CTDP1 were set to CONGENITAL CATARACTS FACIAL DYSMORPHISM AND NEUROPATHY SYNDROME
Fetal anomalies v0.1 BPTF Rebecca Foulger gene: BPTF was added
gene: BPTF was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber
Mode of inheritance for gene: BPTF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: BPTF were set to Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features
Fetal anomalies v0.1 B3GAT3 Rebecca Foulger gene: B3GAT3 was added
gene: B3GAT3 was added to Fetal anomalies. Sources: Expert Review Green,PAGE Additional Gene List
Mode of inheritance for gene: B3GAT3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: B3GAT3 were set to Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects 245600
Fetal anomalies v0.1 ASXL2 Rebecca Foulger gene: ASXL2 was added
gene: ASXL2 was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber
Mode of inheritance for gene: ASXL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ASXL2 were set to Developmental delay, macrocephaly, and dysmorphic features
Fetal anomalies v0.1 ASPH Rebecca Foulger gene: ASPH was added
gene: ASPH was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber
Mode of inheritance for gene: ASPH was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ASPH were set to FACIAL DYSMORPHISM, LENS DISLOCATION, ANTERIOR SEGMENT ABNORMALITIES, AND SPONTANEOUS FILTERING BLEBS