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Cerebral Palsy v1.367 REPS2 Mark Cleghorn gene: REPS2 was added
gene: REPS2 was added to Cerebral Palsy. Sources: Other
Mode of inheritance for gene: REPS2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: REPS2 were set to complex neurodevelopmental disorder MONDO:0100038; Cerebral palsy HP:0100021
Penetrance for gene: REPS2 were set to unknown
Review for gene: REPS2 was set to AMBER
Added comment: REPS2
Hao Hu, Guangzhou Women and Children’s MC
ESHG talk 1/6/24, unpublished

Proposed X-linked cerebral palsy + NDD gene

4 unrelated males with predicted deleterious hemizygous REPS2 variants, 2 PTC, 2 missense. 2 de novo, 2 maternally inherited
Phenotypes: 2 w CP + moderate ID/ASD, 2 w NDD NOS
Variants described:
c.1050_1052delGAA;p.K351del
c.1040T>C; p.I347T
c.962C>G; p.S321C
c.1736delA; p.N579Tfs*17

In vitro assay of above 4 variants suggest reduced REPS2 protein stability
Zebrafish model: REPS2 expressed in neuronal cells, REPS2 knock down have reduced motor activity and abN neuronal morphology
Mouse model hemizygous w one of above variants (not specified): reduced performance in cognitive tasks, abnormal neuronal migration pattern on post mortem examination
Mechanism may relate to dopamine signalling?
Sources: Other
Cerebral Palsy v1.367 KIAA1109 Clare van Eyk gene: KIAA1109 was added
gene: KIAA1109 was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: KIAA1109 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA1109 were set to PMID: 39213953
Phenotypes for gene: KIAA1109 were set to Alkuraya-Kucinskas syndrome, MIM#617822
Review for gene: KIAA1109 was set to RED
Added comment: Single individual with compound heterozygous variants (1 nonsense, 1 missense) reported in a monocentric cohort study (PMID: 39213953). Clinically West syndrome with evolution to Lennox-Gastaut, severe DD, ID, vision problems, microcephaly, feeding difficulties, spasticity, corpus callosum hypoplasia, cerebral atrophy, heterotopia.
Sources: Literature
Cerebral Palsy v1.356 DHPS Clare van Eyk gene: DHPS was added
gene: DHPS was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: DHPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHPS were set to PMID: 30661771; 38843839
Phenotypes for gene: DHPS were set to Neurodevelopmental disorder with seizures and speech and walking impairment (NEDSSWI), MIM#618480
Review for gene: DHPS was set to AMBER
Added comment: NEDSSWI is an autosomal recessive disorder with onset in infancy. In the first case series of 5 patients from 4 families, pregnancy complications including pregnancy-induced hypertension, preeclampsia, oligohydramnios, low blood pressure and premature birth were reported (PMID: 30661771). Patients show global developmental delay and hypotonia, hypertonia, spasticity, or poor coordination. 2 individuals have been reported with a cerebral palsy diagnosis (PMID: 30661771;38843839).
Sources: Literature
Cerebral Palsy v1.315 EBP Clare van Eyk gene: EBP was added
gene: EBP was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: EBP was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: EBP were set to PMID: 38693247
Phenotypes for gene: EBP were set to MEND syndrome, MIM#300960
Review for gene: EBP was set to RED
Added comment: 1 individual reported with hemizygous likely pathogenic missense variant in large-scale exome sequencing study (PMID: 38693247). Detailed clinical information not supplied. MEND syndrome is associated with severe neurological involvement (e.g. intellectual disability, delayed psychomotor development, seizures, hydrocephalus, cerebellar/corpus callosum hypoplasia, Dandy-Walker malformation, hypotonia).
Sources: Literature
Cerebral Palsy v0.48 ALK Zornitza Stark Marked gene: ALK as ready
Cerebral Palsy v0.48 ALK Zornitza Stark Gene: alk has been classified as Amber List (Moderate Evidence).
Cerebral Palsy v0.48 ALK Zornitza Stark Classified gene: ALK as Amber List (moderate evidence)
Cerebral Palsy v0.48 ALK Zornitza Stark Gene: alk has been classified as Amber List (Moderate Evidence).
Cerebral Palsy v0.43 ALK Dean Phelan gene: ALK was added
gene: ALK was added to Cerebral Palsy. Sources: Literature
Mode of inheritance for gene: ALK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALK were set to PMID: 32989326
Phenotypes for gene: ALK were set to Spastic-dystonic diplegia
Review for gene: ALK was set to AMBER
Added comment: PMID: 32989326 - Large cohort study of cerebral palsy cases identified two de novo variants in two patients with spastic diplegia with mild tremor, scattered subcortical hyperintensities and an atrial septal defect; and spastic-dystonic diplegia, white matter abnormalities and epilepsy, respectively, with no evidence of neuroblastoma in either patient.
Sources: Literature