Monogenic diabetes

Gene: FICD

Green List (high evidence)

Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - at least 6 families with diabetes mellitus and biallelic variants at the Arg371 or Arg374 residue of this gene (PMID: 36704923; 36136088; 40062579)

Created: 13 Oct 2025, 4:20 p.m. | Last Modified: 13 Oct 2025, 4:20 p.m.

Panel Version: 3.5

- PMID: 36704923 (2022) - infantile diabetes and neurodevelopmental delay associated with a single variant p.Arg371Ser, in three consanguineous families, two of which shared a common haplotype

- PMID: 36136088 (2022) - four unrelated families from different ethnic backgrounds, all harboured the same 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. Haplotype analysis did indicate that there is a shared haplotype in all patients with the p.Arg374His variant, strongly suggesting a founder effect. Affected individuals presented with severe motor neuron disease and one patient from this cohort also had diabetes mellitus.

- PMID: 40062579 (2025) - an additional four individuals from two families 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.
Sources: Literature

Created: 13 Oct 2025, 4:16 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 92, autosomal recessive, OMIM:620911; diabetes mellitus, MONDO:0005015; Neonatal insulin-dependent diabetes mellitus, HP:0000857

Publications

• 36704923
• 36136088
• 40062579