Childhood onset hereditary spastic paraplegia

Gene: TECPR2

Green List (high evidence)

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: 10 Oct 2023, 5:14 p.m. | Last Modified: 10 Oct 2023, 5:19 p.m.

Panel Version: 4.20

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Neuser et al. (2021) report 17 unrelated cases with a biallelic pathogenic variants in TECPR2. The study also includes 11 previously reported patients. The core manifestations in these individuals are global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea. Peripheral neuropathy was present in two-thirds of all individuals. The majority of the pathogenic variants identified are truncating variants; however, missense variants were also found, predominantly located in the N-terminal and C-terminal regions. The TECPR2 gene is implicated in the autophagy pathway, which is critical to the development and function of the central nervous system. Loss of function variants in several genes of the autophagy pathway lead to both neurodevelopmental and neurodegenerative diseases. In summary, this gene should be promoted to GREEN in this panel, with autosomal recessive mode of inheritance.

Created: 20 Jan 2023, 11:23 a.m. | Last Modified: 20 Jan 2023, 11:24 a.m.

Panel Version: 3.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay, OMIM:615031

Publications

• 33847017

Green List (high evidence)

SPG49 is an autosomal recessive complicated form of spastic paraplegia. PMID 23176824 reported 4 Jewish Bukharian individuals homozygous for same founder variant and delayed psychomotor development, intellectual disability, and onset of spastic paraplegia in the first decade. Affected individuals also had dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, some of which were fatal. Three additional patients from unrelated non-Bukharian families reported in PMID 26542466, harboring two novel variants (c.1319delT, c.C566T) in this gene. In addition to intellectual disability and evolving spasticity, autonomic-sensory neuropathy accompanied by chronic respiratory disease and paroxysmal autonomic events were prominent

Created: 20 Sep 2020, 7:15 a.m. | Last Modified: 20 Sep 2020, 7:15 a.m.

Panel Version: 2.15

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 49, autosomal recessive, 615031; Autonomic-sensory neuropathy

Publications

• 23176824
• 26542466

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

I don't know

Childhood onset, one or two families reported. Suggested in Heimer et al 2016 PMID 26542466 not a form of HSP.

Created: 10 May 2019, 10:25 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 23176824
• 26542466

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

I don't know

Red gene with Green and Amber GLH rating, Gene discussed in view of discrepant rating(s) from GLH(s). Amber 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.

Red rating on Hereditary spastic paraplegia panel 1.198

Oz-Levi (2012, 23176824 ), ?founder fs deletion in Jewish Bukharian families with HSP-related phenotype. Some functional studies supporting an association. Zhu (2015, 25590979), different homozygous fs deletion. Pt had overlapping manifestations with SPG49. No functional studies. Currently included in Sheffield's HSP panel
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018. Submitted Amber rating.

PMID:26542466 (2016) report 3 additional patients from unrelated non-Bukharian families, harboring two novel variants (c.1319delT, c.C566T) in TECPR2, suggesting that variants are not restricted to Bukharian origin.
Rebecca Foulger (Genomics England curator), 31 Oct 2017

Comment when marking as ready: limited evidence founder Jewish mutation
emma baple (Genomics England Curator), 10 May 2016

Created: 2 May 2019, 4:52 p.m.

Green List (high evidence)

delayed motor development, spastic paraparesis, gastroesophageal reflux, and recurrent apneic episodes. affected members of 3 Jewish Bukharian families with autosomal recessive spastic paraplegia-49. In sheffield HSP panel

Created: 28 Apr 2019, 4:16 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 49, autosomal recessive, 615031