Early onset or syndromic epilepsy
Gene: PLAA
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
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
Comment when marking as ready: Sufficient cases for disease association, >3 cases with seizuresCreated: 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.
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
Source Wessex and West Midlands GLH was added to PLAA.
Source NHS GMS was added to PLAA.
Zornitza Stark: Seizures are part of the pheno
Gene: plaa has been classified as Green List (High Evidence).
Phenotypes for gene: PLAA were changed from to Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies 617527; Lethal Infantile Epileptic Encephalopathy
Publications for gene: PLAA were set to
Mode of inheritance for gene: PLAA was changed from to BIALLELIC, autosomal or pseudoautosomal
Gene: plaa has been classified as Green List (High Evidence).
Expert Review Amber was added to PLAA. Panel: Genetic Epilepsy Syndromes
PLAA was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services
PLAA was created by Sarah Leigh