Adult onset neurodegenerative disorder

Gene: VRK1

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, 4:47 p.m. | Last Modified: 10 Oct 2023, 4:47 p.m.

Panel Version: 4.37

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on list classification: There is sufficient evidence (five unrelated cases) for this gene to be promoted to GREEN at the next major update.

Created: 30 May 2023, 6:30 p.m. | Last Modified: 30 May 2023, 6:30 p.m.

Panel Version: 4.26

As reviewed by Zornitza Stark, there are two cases each with spinal muscular atrophy and distal hereditary motor neuropathy, while one case was reported with amyotrophic lateral sclerosis.

Created: 30 May 2023, 6:29 p.m. | Last Modified: 30 May 2023, 6:29 p.m.

Panel Version: 4.23

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Pontocerebellar hypoplasia type 1A, OMIM:607596; spinal muscular atrophy, MONDO:0001516; distal hereditary motor neuropathy, MONDO:0018894; familial amyotrophic lateral sclerosis, MONDO:0005144

Publications

• 26583493
• 31837156
• 34169149

I don't know

PMID 34169149: expanding spectrum of neurologic disorders associated with VRK1. Two Hispanic individuals, one homozygous (R321C: VUS and LP/P in ClinVar) and one cHet (R321C+V236M, latter P and more recently VUS in ClinVar), with slowly progressive weakness and a clinical syndrome consistent with adult-onset spinal muscular atrophy WITHOUT pontocerebellar atrophy.

No hom in gnomAD and both have been reported in cHet individuals with other features: R321C in association with adult-onset amyotrophic lateral sclerosis and V236M with rapidly progressive sensorimotor polyneuropathy and microcephaly.

Authors suggest PMID 26583493 and 31837156 have similar reports. PMID 26583493 reports a 32yo Hispanic individual, cHet H119R+R321C, with early-onset amyotrophic lateral sclerosis, 5 years progressive weakness. PMID 31837156 reports two patients with adult-onset length-dependent motor neuropathy from unrelated consanguineous families of Moroccan Jewish descent, both hom for R387H.

Created: 7 Aug 2021, 6:41 a.m. | Last Modified: 7 Aug 2021, 6:41 a.m.

Panel Version: 2.179

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia

Publications

• 34169149
• 26583493
• 31837156

Red List (low evidence)

Pontocerebellar hypoplasia (PCH) refers to a group of severe neurodegenerative disorders affecting growth and function of the brainstem and cerebellum, resulting in little or no development. Red

Created: 2 Sep 2019, 4:06 p.m. | Last Modified: 2 Sep 2019, 4:06 p.m.

Panel Version: 1.99

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Pontocerebellar hypoplasia 1A (#607596)

Red List (low evidence)

Onset prenatally or at birth; Confused picture of phenotypes associated with small number of patients. No clear association with adult onset neurodegeneration

Created: 23 Jul 2019, 3:35 p.m. | Last Modified: 23 Jul 2019, 3:35 p.m.

Panel Version: 1.72

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Pontocerebellar hypoplasia type 1A; 607596; Amyotrophic lateral sclerosis

Publications

• 26583493

Red List (low evidence)

As discussed with the GMS Neurology Specialist Test Group webex call 11th September 2019: The Specialist Test Group all agreed that there is only enough evidence to rate this gene Red

Created: 20 Sep 2019, 4:19 p.m. | Last Modified: 20 Sep 2019, 4:19 p.m.

Panel Version: 1.106

Review and rating from Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group. All the green and amber, except for the genes with triplet repeats, were reviewed.

Created: 2 Sep 2019, 4:46 p.m. | Last Modified: 2 Sep 2019, 4:46 p.m.

Panel Version: 1.101

Review and rating submitted by Nick Beauchamp (Sheffield Diagnostic genetics Service), on behalf of Yorkshire and North East GLH for GMS Neurology specialist test group.

Created: 23 Jul 2019, 3:51 p.m. | Last Modified: 23 Jul 2019, 3:51 p.m.

Panel Version: 1.74

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

Created: 23 Apr 2019, 5:35 p.m.

Red List (low evidence)