Early onset or syndromic epilepsy

Gene: PLAA

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AR neurodegenerative disorder with progressive microcephaly, spasticity and brain abnormalities, seizures are a variable feature of this disorder. Falik Zaccai et al,2017 - large consang Israeli family and a similarly aff patient from an unrelated consang family from the same geographical region - 3/7 had seizures - all had the same hom missense variant and haplotype analysis confirmed a common ancestral haplotype. Functional studies done. Hall et al, 2017 - 10 patients from 4 consang families of Pakistani or Saudi origin - 8/10 developed seizures 3 families had a hom missense variant and the other had a hom fs variant.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with progressive microcephaly spasticity and brain anomalies, 617527

Publications

• 28007986
• 28413018

Comment when marking as ready: Sufficient cases for disease association, >3 cases with seizures

Created: 22 Nov 2018, 2:01 p.m.

Comment on list classification: 3 variants found in 5 families (but two families likely to have common ancestral haplotype). Seizures reported in all families.

Created: 22 Nov 2018, 1:55 p.m.

PLAA is associated with Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies in OMIM and Lethal Infantile Epileptic Encephalopathy in Gene2Phenotype (probable).

Falik Zaccai et al. (2017)(PMID: 28007986) report 2 consanguineous families from Israel. In both, patients have a p.Leu752Phe homozygous variant that segregates with the family. Haplotype analysis (supported a common ancestral haplotype in Families A and B. Functional studies using patient fibroblasts indicate a loss of function effect for the variant. Some affected individuals in both families show seizures.

Hall et al. (2017)(PMID: 28413018) report 4 unrelated families. In 3 (all originally from Pakistan) a homozygous p.Gly23Val change was found, in the other family (Middle Eastern) a p.Leu24Profs*55 change. In all 4 families individuals presented with seizures. Functional studies show that PLAA is essential for neural function.

Summary, 3 variants found with functional evidence that the are deleterious. >3 cases of seizures.

Created: 22 Nov 2018, 1:46 p.m.

Green List (high evidence)

Seizures are part of the phenotype in this neurodevelopment disorder.

Created: 19 Aug 2018, 11:15 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, MIM#617527

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