Adult onset hereditary spastic paraplegia

Gene: HSPD1

I don't know

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains Amber.

Created: 1 Feb 2023, 4:14 p.m. | Last Modified: 1 Feb 2023, 4:14 p.m.

Panel Version: 2.7

Comment on list classification: The evidence for this gene-disease association is borderline as only 2 families have been reported to date with HSPD1-related AD adult-onset SPG which may be associated with variable penetrance. However, this phenotype is likely best represented by the R60 panel which may justify its inclusion to minimise risk of missing diagnoses - this will be flagged for GMS discussion to determine the most appropriate classification given the current evidence.

Created: 13 Apr 2022, 3:42 p.m. | Last Modified: 13 Apr 2022, 3:42 p.m.

Panel Version: 1.101

Monoallelic variants have been associated with adult-onset HSP (SPG13, MIM# 605280) and are pertinent to this adult panel. To date, only two pathogenic heterozygous missense variants in the HSPD1 gene have been identified: p.V72I in seven affected adults from a French family (PMIDs: 10677329, 11898127) and p.Q461E in a 58-year-old Danish woman (PMID: 17420924). In both families, the disease was transmitted as a late-onset autosomal-dominant trait, with variable penetrance. Differences in penetrance correlated with functional tests using E. coli complementation assays which showed that the p.V72I variant completely abolished, whereas the p.Q461E variant only mildly compromised bacterial growth.

Created: 13 Apr 2022, 3:33 p.m. | Last Modified: 13 Apr 2022, 3:33 p.m.

Panel Version: 1.99

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Spastic paraplegia 13, autosomal dominant, OMIM:605280

Publications

• 10677329
• 11898127
• 17420924

I don't know

Adult onset. One clear family but also not fully penetrant. Another individual with two unaffected brothers with mutation.

Created: 10 May 2019, 11:58 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 11898127

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

I don't know

Review and rating submitted byJames Polke (Neurogenetics Laboratory,Institute of Neurology, London), unless specified in the review comment, on behalf of London North GLH for GMS Neurology specialist test group.

Created: 9 May 2019, 4:50 p.m.

I don't know

Pseudogene confounds variant calling. Publications- 1) 2 affected memebers from same family SPG, 2) 1 pt identified in a screen of 23 unrelated danish, affected pt's 2 brothers had the same mutation but no manifestations of SPG, FHX suggests mother may have been affected ?reduce penetrance. pt 3)linkage studies, followed by candidate gene analysis, of a large Israeli Bedouin family with autosomal recessive hypomyelinating leukodystrophy HLD4.

Created: 25 Apr 2019, 1:22 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Spastic paraplegia 13, autosomal dominant or pseudoautosomal, NOT imprinted, 605280; Leukodystrophy, hypomyelinating, 4, autosomal recessive, 612233