Childhood onset hereditary spastic paraplegia

Gene: FICD

I don't know

The review of this gene is inconsistent.

The FICD gene has been reviewed in the Neonatal diabetes panel review and has been regarded as an amber gene based on 3 cases being reported in one publication (PMID: 36704923) but all with the same variant and 2 families share a common haplotype. Some functional data. This is not dissimilar from the information provided in the initial review of this gene within the Childhood onset hereditary spastic paraplegia gene panel.

The variant within the neonatal diabetes-related publication is located at codon 371 vs codon 374 associated with the severe motor neuron disease (PMID: 36136088). Both codons code for an Arg residue and both are associated with the active site of the FICD; however, the reported clinical features in the two cohorts show significant variation. This gene should be considered as an AMBER-list variant until further evidence is available to detail the clinical presentation of individual with biallelic loss of function variants in the FICD gene.

Created: 18 Sep 2025, 11:17 a.m. | Last Modified: 18 Sep 2025, 11:17 a.m.

Panel Version: 8.10

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 36136088
• 36704923

Green List (high evidence)

This gene was reassessed in light of the amber review by John Taylor, highlighting that two distinct phenotypes linked to similar variants located in the catalytic motif of FICD have been assessed differently.

FICD was rated amber on Neonatal diabetes (293) in context of infantile diabetes and neurodevelopmental delay associated with a single variant p.Arg371Ser, in three consanguineous families, two of which shared a common haplotype (PMID: 36704923).

A separate association with severe motor neuron disease (rated green on this panel) is based on four unrelated families from different ethnic backgrounds, who all harbour the p.Arg374His variant, which was homozygous in all but one case where the variant was present in a compound heterozygous state with a frameshift variant, p.Gly370GlufsTer53. One patient from this cohort also had diabetes mellitus. Haplotype analysis did indicate that there is a shared haplotype in all patients with the p.Arg374His variant, strongly suggesting a founder effect (PMID: 36136088).

Recently, an additional four individuals from two families were reported (PMID: 40062579) with variants affecting the Arg374 residue, who presented with complicated HSP and diabetes mellitus, merging these two previously distinct presentations.
The report describes one Serbian family, comprising 2 sibs with cHSP (age of onset: 5 and 6) and diabetes mellitus (age of diagnosis: 25 and 27). The sibs had the recurrent homozygous variant p.Arg374His - however, the haplotype identified in the previous report was not found in this family, suggesting that this is an independent event.
The second was a consanguineous family from Saudi Arabia with 2 sibs affected by progressive HSP and diabetes (one prediabetic) - age of onset unclear but paediatric. This family harboured a novel homozygous variant, p.Arg374Cys. No cognitive deficits were reported in either family.

The coexistence of motor neuron disease and diabetes suggests a broader range of neurological and metabolic effects of FICD dysfunction which does warrant further investigation. It is possible that these presentations may be more related than initially thought - individuals diagnosed with infancy-onset diabetes mellitus may develop spasticity later in life, and vice versa.

Overall the recent report does lend additional support for inclusion of FICD on this panel. This gene will also be added to the Monogenic diabetes (472) panel to cover the diabetes phenotype with later onset than the initial report which was reviewed on the Neonatal diabetes (293) panel.

Created: 13 Oct 2025, 3:58 p.m. | Last Modified: 13 Oct 2025, 3:58 p.m.

Panel Version: 8.16

The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:34 p.m. | Last Modified: 24 Feb 2025, 5:34 p.m.

Panel Version: 7.6

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 92, autosomal recessive, OMIM:620911

Publications

• 36704923
• 36136088
• 40062579

Green List (high evidence)

Comment on list classification: There is sufficient evidence available (four unrelated families and functional work) for the association of this gene with green rating on the next GMS update.

Created: 23 Oct 2024, 3:53 p.m. | Last Modified: 23 Oct 2024, 3:53 p.m.

Panel Version: 6.9

PMID:36136088 reported three unrelated families with recurrent homozygous missense variant in FICD gene (p.Arg374His) and the patients presented with a a neurodegenerative disease of upper and lower motor neurons. A patient from one further family was identified with compound heterozygous variants in FICD gene (p.Arg374His and p.Gly370GlufsTer53).

All these patients had onset of symptoms in childhood with progressive course. Their clinical manifestations included severe lower limb spasticity and mild upper limb spasticity. In addition, nerve conduction test showed motor neuropathy.

Fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP.

This gene has been associated with relevant phenotypes in OMIM (MIM #620911).
Sources: Literature

Created: 23 Oct 2024, 3:50 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 92, autosomal recessive, OMIM:620911

Publications

• 36136088