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Intellectual disability

Gene: FBXL3

Green List (high evidence)

FBXL3 (F-box and leucine rich repeat protein 3)
EnsemblGeneIds (GRCh38): ENSG00000005812
EnsemblGeneIds (GRCh37): ENSG00000005812
OMIM: 605653, Gene2Phenotype
FBXL3 is in 1 panel

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: FBXL3 was added to the ID panel and rated Green by Konstantinos Varvagiannis. based on PMID:30481285 (Ansar et al. 2019)

All members displayed Global Developmental delay. FBXL3 is in OMIM although not in G2P.

Three families:
Family from Pakistan - Large consanguineous family, all 5 affected individuals were homozygous for a frameshift variant. Parents were heterozygous.
A family (2 sibs) parents were first cousins from Lebanon were homozygous for a nonsense variant.
A third patient from Italy (born to distantly related parents) from Italy had a missense variant [NM_012158.2:c.1072T>C or p.(Cys358Arg)] in the homozygous state, both parents hetrozygous.

The missense variant Cys358Arg concerns the same codon as a similar - previously studied - variant (Cys358Ser) which has reported to affect the mouse circadian rhythm PMID: 29259298. Disturbance of circadian rhythm was observed in the patient with the Cys358Arg variant.

The authors (PMID: 30481285) 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).

There are sufficient cases of ID/DD from unrelated families to warrant a Green rating.
Created: 20 May 2019, 4:06 p.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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
Created: 28 Nov 2018, 7:16 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual disability; Short stature

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert Review
Phenotypes
  • Short stature
  • Intellectual developmental disorder with short stature, facial anomalies, and speech defects, 606220
  • Intellectual disability
OMIM
605653
Clinvar variants
Variants in FBXL3
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

25 Jul 2019, Gel status: 3

Added New Source, Set Phenotypes, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to FBXL3. Added phenotypes Intellectual developmental disorder with short stature, facial anomalies, and speech defects, 606220 for gene: FBXL3 Rating Changed from No List (delete) to Green List (high evidence)

28 Nov 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

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