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Intellectual disability
Gene: FBXO31

FBXO31 (F-box protein 31)
EnsemblGeneIds (GRCh38): ENSG00000103264
EnsemblGeneIds (GRCh37): ENSG00000103264
OMIM: 609102, Gene2Phenotype
FBXO31 is in 3 panels

4 reviews

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on phenotypes: OMIM phenotype checked 13th Apr 2026.
Created: 13 Apr 2026, 4:36 p.m. | Last Modified: 13 Apr 2026, 4:36 p.m.

Panel Version: 9.378

Comment on mode of inheritance: There are more than 3 unrelated cases reported in literature with a recurrent heterozygous de novo missense variant FBXO31 p.Asp334Asn, presenting with childhood-onset spasticity, dystonia, ID, with or without cerebral abnormalities on MRI. There are 2 recessive pedigrees reported, where individuals presented solely with intellectual disability and dysmorphic features. Hence, there is not enough evidence for the recessive association to be included, and the MOI should be changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.
Created: 13 Apr 2026, 4:32 p.m. | Last Modified: 13 Apr 2026, 4:33 p.m.

Panel Version: 9.376

Monoallelic cases:

PMID: 32989326 Jin et al., 2020
Report of 2 unrelated patients with the same de novo FBXO31 mutation 16:87367889:C:T, p.Asp334Asn. Disease onset was under age two years.
F218-003 - Female, European, presented with spastic diplegia, as well as Esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus.
F699-003 - Male, European, presented with spastic paraplegia, as well as Ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation.

PMID: 33675180 Dzinovic et al., 2021
Report of a 9yo boy of Slovakian descent, with a de novo FBXO31 variant c.1000G>A (p.Asp334Asn) - trio WES. He presented with complex, non‐progressive movement‐disorder syndrome dominated by spasticity and dystonia. Brain MRI showed bilateral occipital and parietal white‐matter volume reduction, irregular white‐matter dysmyelination. Intellectual disability estimated at Moderate severity (no IQ assessment; loss of speech at the age of 1.5 years, receptive language disorder)
FBXO31 p.Asp334Asn is not reported in gnomAD v4.1.0. Revel prediction is Uncertain (0.46).

PMID: 41858232 Galaz-Montoya et al., 2026
4 additional probands reported, all with the de novo FBXO31 p.Asp334Asn heterozygous variant. Core phenotypes: "cerebral palsy" i.e. mix of spasticity, dystonia, and hypotonia; ID/GDD, and speech impairment. Age of onset: at birth or very early childhood. Brain MRI showed hypoplastic corpus callosum (3/4), ventriculomegaly (2/4), and white matter abnormalitites (2/4). Authors propose the monoallelic disorder could be called "Kruer syndrome".

PMID: 41640354 Schierbaum et al., 2026
13yo patient with with spastic diplegia, ID, and abnormal brain MRI findings: "ears of the lynx", thin corpus callosum, and periventricular white matter changes. Trio WGS showed that he had a de novo FBXO31 NM_024735.5, c.1000G>A, p.(Asp334Asn) variant.

BIALLELIC CASES:
PMID: 24623383 Mir et al., 2014
Consanguineous Pakistani pedigree, FBXO31 p.(Cys283Asnfs*81) segregated with intellectual disability in a recessive manner. Method: autozygosity mapping, WES, Sanger seq.

PMID: 35019165 Moudi et al., 2022
Iranian consanguineous pedigree, 2 sibs with a homozygous FBXO31 c.1532G>A, p.Arg511Gln variant (7 alleles in gnomAD v4.1.1, no homozygotes). Heterozygous family members not affected. Phenotype: moderate ID, developmental delay, dysmorphic facial features.

FBXO31 is putatively linked to AR ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979 in OMIM (accessed 13th Apr 2026).
Created: 13 Mar 2026, 12:49 p.m. | Last Modified: 13 Apr 2026, 4:26 p.m.

Panel Version: 9.376

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
neurodevelopmental disorder, MONDO:0700092; ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979

Publications

Created: 13 Mar 2026, 12:49 p.m.
Last Modified: 13 Apr 2026, 4:33 p.m.
Panel version: 9.376

Sarah Leigh (Genomics England Curator)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 14 Mar 2022, 2:22 p.m. | Last Modified: 14 Mar 2022, 2:22 p.m.

Panel Version: 3.1519

Created: 14 Mar 2022, 2:22 p.m.
Last Modified: 14 Mar 2022, 2:22 p.m.
Panel version: 3.1519

Ivone Leong (Genomics England Curator)

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Created: 30 Jun 2021, 3:17 p.m. | Last Modified: 30 Jun 2021, 3:17 p.m.

Panel Version: 3.1150

Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). There is not enough evidence to support a gene-disease association so this gene has been given an Amber rating.
Created: 4 Dec 2020, 2:50 p.m. | Last Modified: 4 Dec 2020, 2:50 p.m.

Panel Version: 3.585

Created: 4 Dec 2020, 2:50 p.m.
Last Modified: 4 Dec 2020, 2:50 p.m.
Panel version: 3.1150

Zornitza Stark (Australian Genomics)

Green List (high evidence)

PMIDs 33675180; 32989326: three unrelated individuals with de novo missense variant, (p.Asp334Asn) and spastic-dystonic CP, including ID.

AR ID: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.
Created: 10 May 2021, 10:40 a.m. | Last Modified: 10 May 2021, 10:40 a.m.

Panel Version: 3.1069

Bi-allelic variants: Single consanguineous family reported with homozygous truncating variant, limited functional evidence.

Mono-allelic variants: 2 unrelated probands reported as part of a 'cerebral palsy' cohort harbouring the same de novo missense variant (p.Asp334Asn). The variant affects the cyclin D interaction site, leading to an apparent gain of function of cyclin D degradation, supported by Western blots from patient fibroblasts which showed decreased cyclin D expression.

Patient phenotypes: Spastic diplegia, with esotropia, ID, dysarthria, mixed receptive/expressive language disorder, ADHD, cleft palate, intestinal malrotation and midgut volvulus (patient 1); Spastic paraplegia with ventricular dilation and thin corpus callosum, ID, attention deficit, anxiety, language impairments, strabismus, severe constipation (patient 2).
Sources: Literature
Created: 4 Nov 2020, 2:41 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Mental retardation, autosomal recessive 45, MIM#615979; Intellectual disability, spasticity, autosomal dominant

Publications

Created: 4 Nov 2020, 2:41 a.m.

Panel version: 3.1069

Details

Mode of Inheritance

BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Sources

Expert Review Green

Phenotypes

?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979

Tags

Q2_26_MOI

OMIM

609102

Clinvar variants

Variants in FBXO31

Penetrance

None

Publications

Panels with this gene

History Filter Activity

13 Apr 2026, Gel status: 3

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: FBXO31 were changed from ?Mental retardation, autosomal recessive 45, OMIM:615979; Intellectual disability, autosomal dominant to ?Intellectual developmental disorder, autosomal recessive 45, OMIM:615979

13 Apr 2026, Gel status: 3

Set publications

Ida Ertmanska (Genomics England Curator)

Publications for gene: FBXO31 were set to 24623383; 32989326; 33675180

13 Apr 2026, Gel status: 3

Added Tag

Ida Ertmanska (Genomics England Curator)

Tag Q2_26_MOI tag was added to gene: FBXO31.

13 Mar 2026, Gel status: 3

Removed Tag

Ida Ertmanska (Genomics England Curator)

Tag Q1_26_MOI was removed from gene: FBXO31.

13 Mar 2026, Gel status: 3

Added Tag

Ida Ertmanska (Genomics England Curator)

Tag Q1_26_MOI tag was added to gene: FBXO31.

14 Mar 2022, Gel status: 3