Childhood onset hereditary spastic paraplegia
Gene: KDM5C
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
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 submittedCreated: 2 May 2019, 4:09 p.m.
2 families from literature-progressive spastic paraplegia included in clinical feature. In sheffields HSP panelCreated: 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
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.
Phenotypes for gene: KDM5C were changed from Intellectual disability; developmental delay; epilepsy; progressive spasticity; Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; hypothyroidism to Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type, OMIM:300534
Publications for gene: KDM5C were set to 10982473; 26919706; 15586325; 18697827
Source Expert Review Green was added to KDM5C. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Publications for gene: KDM5C were set to 10982473; 26919706; 15586325
Source Yorkshire and North East GLH was added to KDM5C.
Gene: kdm5c has been classified as Amber List (Moderate Evidence).
Gene: kdm5c has been classified as Green List (High Evidence).
Source NHS GMS was added to KDM5C.
Source London North GLH was added to KDM5C.
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
Rebecca Foulger: Comment on list classification
Gene: kdm5c has been classified as Amber List (Moderate Evidence).
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
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