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Childhood onset hereditary spastic paraplegia v8.4 NOTCH3 Achchuthan Shanmugasundram changed review comment from: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families.

Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. 19 of these patients from 11 different families were reported with spasticity.

Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. Spasticity and ataxia were reported in three and four patients respectively.

Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.; to: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families.

Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia.

19 of these patients from 11 different families were reported with spasticity. Mean age at the onset of symptoms was 28 months, ranging from congenital to 17 years old.

Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. Spasticity and ataxia were reported in three and four patients respectively.

Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.
Childhood onset hereditary spastic paraplegia v8.4 NOTCH3 Achchuthan Shanmugasundram Classified gene: NOTCH3 as Amber List (moderate evidence)
Childhood onset hereditary spastic paraplegia v8.4 NOTCH3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Lauren Turton, there is sufficient evidence available for the association of biallelic LoF variants from NOTCH3 gene with childhood-onset spastic paraplegia. Hence, this gene can be promoted to green rating in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.4 NOTCH3 Achchuthan Shanmugasundram Gene: notch3 has been classified as Amber List (Moderate Evidence).
Childhood onset hereditary spastic paraplegia v8.3 NOTCH3 Achchuthan Shanmugasundram Phenotypes for gene: NOTCH3 were changed from Spasticity, stroke, periatrial white matter volume loss to neurodevelopmental disorder, MONDO:0700092
Childhood onset hereditary spastic paraplegia v8.2 NOTCH3 Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: NOTCH3.
Tag Q3_25_NHS_review tag was added to gene: NOTCH3.
Childhood onset hereditary spastic paraplegia v8.2 NOTCH3 Achchuthan Shanmugasundram reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: None; Publications: 39191170; Phenotypes: neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v8.1 NOTCH3 Lauren Turton gene: NOTCH3 was added
gene: NOTCH3 was added to Childhood onset hereditary spastic paraplegia. Sources: NHS GMS
Mode of inheritance for gene: NOTCH3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NOTCH3 were set to 39191170
Phenotypes for gene: NOTCH3 were set to Spasticity, stroke, periatrial white matter volume loss
Review for gene: NOTCH3 was set to GREEN
Added comment: Twenty-five patients from 17 unrelated families harbouring homozygous or compound heterozygous variants in NOTCH3. Among them 18 carried LoF variants.
Patients had a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Mean age at the onset of symptoms was 28 months, ranging from congenital to 17 years old.
Showed that patients with the biallelic LoF variants had a different phenotype to that seen in CADASIL.
Sources: NHS GMS