Childhood onset hereditary spastic paraplegia

Gene: PI4KA

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, 2:55 p.m. | Last Modified: 1 Feb 2023, 3:02 p.m.

Panel Version: 3.9

Green List (high evidence)

This paper supports the idea that mutations in this gene can cause a relatively pure spastic paraplegia (PMID: 34415322 PMCID: PMC8557332 DOI: 10.1093/brain/awab124), which I think would justify inclusion of the gene on the HSP panel.

Created: 22 Dec 2021, 1:47 p.m. | Last Modified: 22 Dec 2021, 1:47 p.m.

Panel Version: 2.121

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
spastic paraplegia; leukodystrophy; white matter abnromality; seizures; intellectual disability

Publications

• PMID: 34415322

I don't know

After consulting with the Genomics England Clinical Team it was decided that this gene should be added to the Hereditary spastic paraplegia - childhood onset panel with an Amber rating.

Helen Brittain:
"I think the spasticity is likely to be secondary to the CNS findings and therefore might opt for amber at this stage, as it is perhaps unlikely to be clearly relevant to the more typical cohort with isolated spasticity that will be targeted by that panel."

Created: 25 Oct 2021, 10:22 a.m. | Last Modified: 25 Oct 2021, 10:22 a.m.

Panel Version: 2.87

This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.

Created: 1 Sep 2021, 1:47 p.m. | Last Modified: 25 Oct 2021, 10:16 a.m.

Panel Version: 2.87

Publications

• 25855803
• 34415322
• 34415310