Hereditary spastic paraplegia

Gene: KDM5C

Comment on list classification: Upgraded from Amber to Green as there are now sufficient unrelated cases (>3) of spastic paraplegia with variants in this gene (updated references in publications list). KDM5C is also already Green on the GMS-equivalent HSP panels.

Created: 19 Aug 2021, 11:41 a.m. | Last Modified: 19 Aug 2021, 11:41 a.m.

Panel Version: 1.240

I don't know

Gene to be reviewed again after the GMS Neurology specialist test group have reviewed and agreed rating of gene on the Hereditary spastic paraplegia - childhood onset panel on May 2019

Created: 3 May 2019, 8:35 a.m.

Added 'watchlist' tag.

Created: 8 Jan 2019, 3:15 p.m.

Comment on list classification: Updated rating from Red to Amber. Gene added to panel and rated Red by Chris Buxton (Bristol NHS). MIM:300534 is characterized by ID, progressive spastic paraplegia, short stature, microcephaly, and dysmorphic facial appearance. Chris Buxton reports 2 families from the literature (PMIDs10982473; 15586325; 26919706) with KDM5C variants and spastic paraplegia symptoms. Therefore Amber awaiting further cases.

Created: 8 Jan 2019, 3:15 p.m.

PMID:26919706 investigated a family of 3 boys with ID and among them identified two different variants in KDM5C: Two affected boys have c.633delG and the other has c.631delC. The boys presented with severe DD, progressive spasticity (predominantly in the lower limbs), epilepsy and subclinical hypothyroidism. The mother has two different frameshift mutations: a heterozygous germline mutation, c.631delC, and a low-prevalence somatic mutation, c.633delG.

Created: 8 Jan 2019, 3:13 p.m.

PMID:15586325 (Jensen 2005) identifed a L731F variant in 4 members of a family with X-linked complicated spastic paraplegia previously described by Claes et al (2000, PMID:10982473).

Created: 8 Jan 2019, 3:13 p.m.

Comment on list classification: This gene is awaiting curator evaluation and rating.

Created: 19 Dec 2018, 2:12 p.m.

Red List (low evidence)

Claes (2000, 10982473) reported candidate HSP locus Xp21.1-Xq21.3. Jensen (2005, 15586325) identified as JARID1C(syn)/KDM5C gene: c.2191C>T Leu731Phe. 4 males in same pedigree: two generations present with severe MR, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasia. Additional features are aggressive behavior and strabismus;

Fujita (2016, 26919706). Two different fs deletion variants. maternal reversion mechanims? Progressive spasticity component to phenotype.

Currently diagnostic on Sheffield's HSP panel
Sources: Literature

Created: 27 Nov 2018, 1:34 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Intellectual disability; developmental delay; progressive spasticity; epilepsy; hypothyroidism

Publications

• 10982473
• 15586325
• 26919706