Hereditary neuropathy or pain disorder

Gene: FA2H

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:02 p.m. | Last Modified: 24 Feb 2025, 5:02 p.m.

Panel Version: 6.148

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Comment on list classification: Promoting with amber with a recommendation for green rating as there are now 4 cases with peripheral neuropathy and variants in this gene reported.

Created: 26 Oct 2024, 9:45 p.m. | Last Modified: 26 Oct 2024, 9:45 p.m.

Panel Version: 5.98

Associated with Spastic paraplegia 35, autosomal recessive in OMIM (OMIM:612319)

Peripheral neuropathy reported in 4 cases - 1 from PubMed:22146942 and 3 from PubMed:31135052

PubMed:22146942 - Pierson et al 2012 - describe a 10-year-old male, from a non-consanguineous family, with progressive spastic paraplegia, dystonia, ataxia, and cognitive decline associated with a sural axonal neuropathy. The patient has a paternally derived missense mutation and an overlapping novel maternally derived ~28-kb genomic deletion in FA2H.

PubMed:31135052 - Rattay et al 2019 - studied 19 cases from 16 families with biallelic FA2H mutations resulting in hereditary spastic paraplegia (HSP) type SPG35. Variants in FA2H were identified by Sanger sequencing, a next generation sequencing (NGS)-based HSP gene panel and whole exome sequencing. Truncating variants and missense variants were identified. Gait problems started almost invariably in early childhood at a median age of 4 years. Lower limb predominant spastic tetraparesis accompanied by truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits were present in ∼90% of cases. Peripheral neuropathy was present in 27% (3/11) of cases.

Created: 26 Oct 2024, 9:43 p.m. | Last Modified: 26 Oct 2024, 9:43 p.m.

Panel Version: 5.97

Phenotypes
Spastic paraplegia 35, autosomal recessive, OMIM:612319; hereditary spastic paraplegia 35, MONDO:0012866

Publications

• 22146942
• 31135052

I don't know

Review and rating uploaded from file (Curation_Template_GMS_Neuro_AR_20190521.xlsx) submitted by Alex Rossor (UCL Institute of Neurology) on behalf of London North GLH for GMS Neurology specialist test group.

Created: 11 Jun 2019, 1:40 p.m.

Green List (high evidence)

peripheral neuropathy now reportedin 3 additional patients

Created: 19 Oct 2024, 10:34 p.m. | Last Modified: 19 Oct 2024, 10:34 p.m.

Panel Version: 5.19

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
SPG35, Childhood onset spasticity, cognitive decline and leukodystrophy. Mild sensory axonal neuropathy on NCS. Epilepsy, dysphagia, dysarthria and dystonia also observed.

Publications

• 22146942:31135052