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Intellectual disability - microarray and sequencing v2.558 FBXL3 Konstantinos Varvagiannis gene: FBXL3 was added
gene: FBXL3 was added to Intellectual disability. Sources: Literature,Expert Review
Mode of inheritance for gene: FBXL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXL3 were set to 30481285
Phenotypes for gene: FBXL3 were set to Intellectual disability; Short stature
Penetrance for gene: FBXL3 were set to Complete
Review for gene: FBXL3 was set to GREEN
Added comment: Ansar et al. (PMID: 30481285) report on 8 individuals from 3 consanguineous families, all homozygous for FBXL3 variants.

The phenotype consisted of mild to severe intellectual disability (8/8), short stature (8/8) with a few common facial features.

In the first family - from Pakistan - all affected individuals were homozygous for a frameshift variant. The 2 sibs from the second family (from Lebanon) were homozygous for a nonsense variant. A further patient, born to distantly related parents from Italy, was found to harbor a missense variant [NM_012158.2:c.1072T>C or p.(Cys358Arg)] in the homozygous state.

FBXL3 is part of an ubiquitin ligase complex that binds the central clock protein cryptochromes (CRY1/2) mediating their degradation. Cys358Arg concerns the same codon as a similar - previously studied - variant (Cys358Ser) reported to affect the mouse circadian rhythm. Disturbance of circadian rhythm was observed in the patient with the Cys358Arg variant.

As previously demonstrated for mutations of the same codon and in line with a pathogenic role for this variant, in silico studies predict impaired interaction of FBXL3 with CRY2. It is proposed that the nonsense and frameshift variants lead to a similar effect due to severe truncation of the protein (upstream of leucine-rich domains important for this interaction).

The authors note that other F-box proteins are implicated in intellectual disability (as in the case of FBXO11 and FBXL4, both rated green in this panel).

As a result, FBXL3 can be considered for inclusion in this panel as green (or amber).
Sources: Literature, Expert Review
Intellectual disability - microarray and sequencing v2.508 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability - microarray and sequencing v2.508 FBXO11 Helen Brittain Added comment: Comment on list classification: Appropriate phenotype, sufficient number of cases.
Intellectual disability - microarray and sequencing v2.508 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Appropriate phenotype, sufficient number of cases.
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Appropriate phenotype, sufficient number of cases.
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Appropriate phenotype, sufficient cases
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Appropriate phenotype, sufficient cases
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Sufficient cases with appropriate phenotype
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Classified gene: FBXO11 as Green List (high evidence)
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Added comment: Comment on list classification: Sufficient cases with appropriate phenotype
Intellectual disability - microarray and sequencing v2.507 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Green List (High Evidence).
Intellectual disability - microarray and sequencing v2.506 FBXO11 Helen Brittain Marked gene: FBXO11 as ready
Intellectual disability - microarray and sequencing v2.506 FBXO11 Helen Brittain Added comment: Comment when marking as ready: Appropriate phenotype and sufficient cases
Intellectual disability - microarray and sequencing v2.506 FBXO11 Helen Brittain Gene: fbxo11 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v2.452 FBXO11 Sarah Leigh Phenotypes for gene: FBXO11 were changed from Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089 to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
Intellectual disability - microarray and sequencing v2.451 FBXO11 Sarah Leigh Phenotypes for gene: FBXO11 were changed from Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089 to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
Intellectual disability - microarray and sequencing v2.450 FBXO11 Sarah Leigh Phenotypes for gene: FBXO11 were changed from Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089 to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
Intellectual disability - microarray and sequencing v2.449 FBXO11 Sarah Leigh Phenotypes for gene: FBXO11 were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures to Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities 618089
Intellectual disability - microarray and sequencing v2.448 FBXO11 Sarah Leigh Classified gene: FBXO11 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v2.448 FBXO11 Sarah Leigh Gene: fbxo11 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v2.448 FBXO11 Sarah Leigh Classified gene: FBXO11 as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v2.448 FBXO11 Sarah Leigh Gene: fbxo11 has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing FBXO11 Konstantinos Varvagiannis Added gene to panel