Childhood onset hereditary spastic paraplegia

Gene: FBXO31

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: 8.45

Comment on list classification: There are more than 3 unrelated cases reported in literature with a recurrent de novo heterozygous 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, this gene can be promoted to Green at the next GMS update, with MOI set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted.

Created: 13 Mar 2026, 12:58 p.m. | Last Modified: 13 Apr 2026, 4:27 p.m.

Panel Version: 8.44

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, 12:55 p.m. | Last Modified: 13 Apr 2026, 4:26 p.m.

Panel Version: 8.44

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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

Publications

• 24623383
• 32989326
• 33675180
• 35019165
• 41640354
• 41640354