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Fetal anomalies v6.74 SLC35A3 Arina Puzriakova Phenotypes for gene: SLC35A3 were changed from Arthrogryposis, mental retardation, and seizures, OMIM:615553 to Arthrogryposis, impaired intellectual development, and seizures, OMIM:615553
Fetal anomalies v5.15 PIGY Sarah Graham reviewed gene: PIGY: Rating: AMBER; Mode of pathogenicity: ; Publications: 26293662, 38790248; Phenotypes: Hyperphosphatasia with impaired intellectual development syndrome 6, MIM#616809; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v5.15 NARS Samantha Doyle reviewed gene: NARS: Rating: RED; Mode of pathogenicity: ; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, MIM#619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, MIM#619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v5.15 GNAI1 Natalie Canham reviewed gene: GNAI1: Rating: RED; Mode of pathogenicity: ; Publications: 34685729, 34819662, 39083633, 38441201, 33473207; Phenotypes: Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, MIM#619854; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v5.13 PIGY Achchuthan Shanmugasundram Source NHS GMS was added to PIGY.
Added phenotypes Hyperphosphatasia with impaired intellectual development syndrome 6, OMIM:616809 for gene: PIGY
Publications for gene: PIGY were updated from to 26293662; 38790248
Fetal anomalies v5.13 NARS Achchuthan Shanmugasundram gene: NARS was added
gene: NARS was added to Fetal anomalies. Sources: NHS GMS,Expert Review Red
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225; 32788587
Phenotypes for gene: NARS were set to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092
Fetal anomalies v4.180 DEAF1 Achchuthan Shanmugasundram Phenotypes for gene: DEAF1 were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT 24; Vulto-van Silfout-de Vries syndrome, OMIM:615828; Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures, OMIM:617171; Autism, intellectual disability, basal ganglia dysfunction and epilepsy to Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures, OMIM:617171; Vulto-van Silfout-de Vries syndrome, OMIM:615828
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 v4.84 PPP3CA Achchuthan Shanmugasundram Phenotypes for gene: PPP3CA were changed from Severe Neurodevelopmental Disease with Seizures; Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, OMIM:618265 to Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, OMIM:618265
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 v4.35 PPP3CA Anna de Burca reviewed gene: PPP3CA: Rating: GREEN; Mode of pathogenicity: ; Publications: 28942967, 33082562, 29432562; Phenotypes: Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, OMIM:618265; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v4.35 NFIB Stephanie Allen reviewed gene: NFIB: Rating: GREEN; Mode of pathogenicity: ; Publications: 30388402, 32902921, 33130023; Phenotypes: Macrocephaly, acquired, with impaired intellectual development, OMIM:618286; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v4.35 DEAF1 Natalie Canham reviewed gene: DEAF1: Rating: RED; Mode of pathogenicity: ; Publications: 28940898, 30923367, 26048982, 24726472, 26834045; Phenotypes: Vulto-van Silfout-de Vries syndrome, OMIM:615828, Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures, OMIM:617171; 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 v4.34 PPP3CA Achchuthan Shanmugasundram Source NHS GMS was added to PPP3CA.
Mode of inheritance for gene PPP3CA was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, OMIM:618265 for gene: PPP3CA
Publications for gene: PPP3CA were updated from to 28942967; 33082562; 29432562
Fetal anomalies v4.34 NFIB Achchuthan Shanmugasundram gene: NFIB was added
gene: NFIB was added to Fetal anomalies. Sources: Expert Review Amber,NHS GMS
Mode of inheritance for gene: NFIB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NFIB were set to 30388402; 32902921; 33130023
Phenotypes for gene: NFIB were set to Macrocephaly, acquired, with impaired intellectual development, OMIM:618286
Fetal anomalies v4.34 DEAF1 Achchuthan Shanmugasundram Source NHS GMS was added to DEAF1.
Mode of inheritance for gene DEAF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Vulto-van Silfout-de Vries syndrome, OMIM:615828; Neurodevelopmental disorder with hypotonia, impaired expressive language, and with or without seizures, OMIM:617171 for gene: DEAF1
Publications for gene: DEAF1 were updated from to 28940898; 30923367; 26048982; 24726472; 26834045
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 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 v1.988 KDM5C Arina Puzriakova Added comment: Comment on mode of inheritance: A subset of female carriers have been shown to have impaired intellectual development and/or developmental delay (PMIDs: 10982473; 16538222; 18697827; 19826449; 21575681; 32279304) showing that females can be symptomatic.

Therefore, the MOI should be updated from 'X-linked.. biallelic in females' to 'X-linked.. monoallelic in females may cause disease' at the next GMS panel update. This also reflects the current MOI on all other relevant panels.
Fetal anomalies v1.882 MED13L Arina Puzriakova Phenotypes for gene: MED13L were changed from INTELLECTUAL DISABILITY to Impaired intellectual development and distinctive facial features with or without cardiac defects, OMIM:616789
Fetal anomalies v1.860 GNAI1 Arina Puzriakova Phenotypes for gene: GNAI1 were changed from GNAI1 syndrome to Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, OMIM:619854
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 v1.380 DPM3 Arina Puzriakova Phenotypes for gene: DPM3 were changed from CONGENITAL DISORDER OF GLYCOSYLATION TYPE 1O to ?Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15, 618992; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, 612937
Fetal anomalies v1.229 CHRNA3 Rhiannon Mellis gene: CHRNA3 was added
gene: CHRNA3 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: CHRNA3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CHRNA3 were set to Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT, 191800
Review for gene: CHRNA3 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 v1.215 DPM3 Rhiannon Mellis reviewed gene: DPM3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 15, 618992, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, 612937; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.185 TRMT10A Rhiannon Mellis gene: TRMT10A was added
gene: TRMT10A was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TRMT10A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TRMT10A were set to Microcephaly, short stature, and impaired glucose metabolism 1
Review for gene: TRMT10A 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 (Severe microcephaly). 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.
Sources: Literature
Fetal anomalies v1.119 FKBP8 Eleanor Williams gene: FKBP8 was added
gene: FKBP8 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FKBP8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FKBP8 were set to 32969478
Phenotypes for gene: FKBP8 were set to spina bifida HP:0002414
Review for gene: FKBP8 was set to AMBER
Added comment: Not associated with a phenotype in OMIM.

PMID: 32969478 - Tian et al 2020 - performed Sanger sequencing of FKBP8 on DNA samples from 472 spina bifida (SB) affected fetuses and 565 unaffected controls. 5 different rare heterozygous variants (MAF ≤ 0.001) were identified among the SB patients, while no deleterious rare variants were identified in the controls. 4 of the variants are missense, the other is a stop-gain. 2 cases were in white-Hispanic patients while the other 3 were non-white Hispanic. Functional studies showed that p.Glu140* affected FKBP8 localization to the mitochondria and impaired its interaction with BCL2 ultimately leading to an increase in cellular apoptosis. p.Ser3Leu, p.Lys315Asn and p.Ala292Ser variants decreased FKBP8 protein level. Gene expression was studied in mouse Fkbp8-/- embryos and found to be abnormal. Previous mouse models have shown neural tube defects.

Sufficient cases to rate green, but only the FKBP8 gene looked at so perhaps some caution required while further evidence is gathered.
Sources: Literature
Fetal anomalies v1.94 TOGARAM1 Arina Puzriakova gene: TOGARAM1 was added
gene: TOGARAM1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: TOGARAM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOGARAM1 were set to 32747439
Phenotypes for gene: TOGARAM1 were set to Cleft of the lip and palate; Microphthalmia; Cerebral dysgenesis; Hydrocephalus
Added comment: PMID: 32747439 (2020) - Novel gene-disease association. In two sibling fetuses with a malformation disorder characterised by microcephaly, severe cleft lip and palate, microphthalmia, and brain anomalies, WES revealed compound heterozygous variants ([c.1102C>T, p.Arg368Trp] and [c.3619C>T, p.Arg1207*]) in the TOGARAM1 gene.

Functional analysis of the missense variant in a C. elegans model showed impaired lipophilic dye uptake, with shorter and altered cilia in sensory neurons. In vitro analysis revealed faster microtubule polymerisation compared to wild-type, suggesting aberrant tubulin binding.
Sources: Literature
Fetal anomalies v0.304 IARS Rebecca Foulger Phenotypes for gene: IARS were changed from Growth Retardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and Infantile Hepatopathy to Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, 617093
Fetal anomalies v0.149 AIRE Rebecca Foulger Source Expert Review Red was added to AIRE.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Fetal anomalies v0.148 AIRE Rebecca Foulger edited their review of gene: AIRE: 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 not fetally-relevant. Additional notes from clinical review: Disease confidence in DD-G2P is 'both DD and IF'. Would not present fetally. Action taken: Demoted AIRE gene rating from Amber to Red.; Changed rating: RED
Fetal anomalies v0.110 AIRE Rebecca Foulger commented on gene: AIRE: Changed rating to Amber to reflect DDG2P Disease confidence of 'DD and IF' for AUTOIMMUNE POLYENDOCRINOPATHY SYNDROME TYPE 1.
Fetal anomalies v0.109 AIRE Rebecca Foulger Source Expert Review Amber was added to AIRE.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Fetal anomalies v0.7 AIRE Rebecca Foulger reviewed gene: AIRE: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v0.1 PGAP1 Rebecca Foulger gene: PGAP1 was added
gene: PGAP1 was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber
Mode of inheritance for gene: PGAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PGAP1 were set to Intellectual disability, encephalopathy, impaired GPI-anchor maturation
Fetal anomalies v0.1 AIRE Rebecca Foulger gene: AIRE was added
gene: AIRE was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: AIRE was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: AIRE were set to AUTOIMMUNE POLYENDOCRINOPATHY SYNDROME TYPE 1