Ataxia and cerebellar anomalies - narrow panel

Gene: COQ4

Green List (high evidence)

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

Created: 11 Oct 2023, 10:01 a.m. | Last Modified: 11 Oct 2023, 10:01 a.m.

Panel Version: 4.37

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on classification of this gene: The rating for this gene should be GREEN, as this gene has been implicated in ataxia, as identified from biallelic variants from at least nine unrelated individuals/ families (from six different studies), and supported by results from both in vitro and in vivo functional studies.

Two siblings harbouring homozygous variant c.230C > T (p.Thr77Ile) were identified with childhood-onset spinocerebellar ataxia with stroke-like episodes. Similarly, childhood-onset ataxia was also reported from two siblings from Turkey with homozygous missense variants c.164G>T (p.Gly55Val) and one patient from Iranian ancestry with homozygous variant c.437T>G (p.Phe146Cys). The more severely affected of the siblings from Turkey was treated with high dose of CoQ10 for one month, which resulted in significant improvement in neurological signs and symptoms.

In another report, one patient harbouring c.577C>T (p.Pro193Ser) & c.718C>T (p.Arg240Cys) variants were associated with progressive spasticity, while another patient harbouring c.284G>A (p.Gly95Asp) & c.305G>A (p.Arg102His) variants were associated with a neurodevelopmental disorder. Both patients presented motor impairment and ataxia.

Six patients from four families with bi-allelic variants were reported with adult-Onset ataxia-spasticity spectrum phenotype and this was milder than previously reported. Three patients (c.305G>A & c.473G>A, c.434G>A & c.437T>G, c.376G>A & c.473G>A) were identified with hereditary spastic paraparesis, two patients (c.202+4A>C & c.202+4A>C) with cerebellar ataxia and one patient (c.305G>A & c.473G>A) with milder signs of both.

COQ4 was not associated with either childhood-onset ataxia or with adult-onset ataxia-spasticity spectrum disease in OMIM or Gene2Phenotype. However, functional studies performed in patient-derived fibroblasts, yeasts and zebrafish larvae confirms the role of COQ4 in brain development. The coq4 F0 CRISPR zebrafish line particularly showed motor defects and cell reduction in a specific area of the hindbrain, a region reminiscent of the human cerebellum.

Created: 10 Dec 2022, 8:58 a.m. | Last Modified: 10 Dec 2022, 8:58 a.m.

Panel Version: 3.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Coenzyme Q10 deficiency, primary, 7, OMIM:616276

Publications

• 30225196
• 30847826
• 33215859
• 33704555
• 36047608

Green List (high evidence)

The phenotype of COQ4 deficiency is very broad. In the three publications, at 6 individuals from 4 families are reported as having childhood onset ataxia.
Sources: Literature

Created: 1 Dec 2021, 11:53 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Childhood onset ataxia

Publications

• PMID: 30225196
• 33704555
• 30847826