Hereditary spastic paraplegia - childhood onset

Gene: KDM5C

Green List (high evidence)

KDM5C (lysine demethylase 5C)
EnsemblGeneIds (GRCh38): ENSG00000126012
EnsemblGeneIds (GRCh37): ENSG00000126012
OMIM: 314690, Gene2Phenotype
KDM5C is in 9 panels

4 reviews

Nick Beauchamp (Sheffield Diagnostic Genetics Service)

Green List (high evidence)

Spastic diplegia present in majority of cases. Childhood onset. Additional patient with likely de novo nonsense mutation identified using Sheffield panel.
Created: 10 May 2019, 7:49 a.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)

Publications

Variants in this GENE are reported as part of current diagnostic practice

Louise Daugherty (Genomics England Curator)

I don't know

Amber gene with Green GLH rating, Gene discussed in view of discrepant rating(s) from GLH(s). Green rating agreed at the GMS Neurology Specialist Test Group Webex on 17th May 2019.
Created: 21 May 2019, 4:50 p.m.
Rating and review submitted on behalf of James Polke (Neurogenetics Laboratory,Institute of Neurology, London), on behalf of London North GLH for GMS Neurology specialist test group.
Created: 9 May 2019, 4:54 p.m.
Amber rating on Hereditary spastic paraplegia panel 1.198

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.
Rebecca Foulger (Genomics England curator), 8 Jan 2019

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.
Rebecca Foulger (Genomics England curator), 8 Jan 2019

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).
Rebecca Foulger (Genomics England curator), 8 Jan 2019

Comment on list classification: This gene is awaiting curator evaluation and rating.
Sarah Leigh (Genomics England Curator), 19 Dec 2018

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
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018 Red rating submitted
Created: 2 May 2019, 4:09 p.m.

James Polke (Neurogenetics Laboratory, Institute of Neurology, London)

Green List (high evidence)

2 families from literature-progressive spastic paraplegia included in clinical feature. In sheffields HSP panel
Created: 28 Apr 2019, 4:16 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
Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; Intellectual disability; developmental delay; progressive spasticity; epilepsy; hypothyroidism

Rebecca Foulger (Genomics England curator)

Comment on list classification: Updated rating from Red to Amber following review on the Hereditary spastic paraplegia panel.
Created: 8 Jan 2019, 3:17 p.m.

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Literature
Phenotypes
  • Intellectual disability
  • developmental delay
  • epilepsy
  • progressive spasticity
  • Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534
  • hypothyroidism
OMIM
314690
Clinvar variants
Variants in KDM5C
Penetrance
None
Publications
Panels with this gene

History Filter Activity

21 May 2019, Gel status: 3

Added New Source, Status Update

Louise Daugherty (Genomics England Curator)

Source Expert Review Green was added to KDM5C. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

13 May 2019, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: KDM5C were set to 10982473; 26919706; 15586325

13 May 2019, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source Yorkshire and North East GLH was added to KDM5C.

2 May 2019, Gel status: 2

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: kdm5c has been classified as Amber List (Moderate Evidence).

28 Apr 2019, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: kdm5c has been classified as Green List (High Evidence).

28 Apr 2019, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source NHS GMS was added to KDM5C.

28 Apr 2019, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source London North GLH was added to KDM5C.

3 Apr 2019, Gel status: 2

Set Phenotypes, Set publications

Louise Daugherty (Genomics England Curator)

Added phenotypes Intellectual disability; developmental delay; epilepsy; progressive spasticity; Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; hypothyroidism for gene: KDM5C Publications for gene KDM5C were changed from 26919706; 15586325; 10982473 to 10982473; 26919706; 15586325

28 Jan 2019, Gel status: 2

Panel promoted to version 1.0

Louise Daugherty (Genomics England Curator)

Rebecca Foulger: Comment on list classification

8 Jan 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: kdm5c has been classified as Amber List (Moderate Evidence).

8 Jan 2019, Gel status: 1

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: KDM5C were changed from Intellectual disability; progressive spasticity; epilepsy; hypothyroidism; developmental delay to Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; Intellectual disability; progressive spasticity; epilepsy; hypothyroidism; developmental delay

19 Dec 2018, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Sarah Leigh (Genomics England Curator)

gene: KDM5C was added gene: KDM5C was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Red,Literature Mode of inheritance for gene: KDM5C was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: KDM5C were set to 26919706; 15586325; 10982473 Phenotypes for gene: KDM5C were set to Intellectual disability; progressive spasticity; epilepsy; hypothyroidism; developmental delay