Intellectual disability - microarray and sequencing
Gene: PLAA Green List (high evidence)Comment when marking as ready: Appropriate phenotype, sufficient casesCreated: 13 Nov 2017, 4:10 p.m.
Comment on list classification: Updated rating from Amber to Green: Although not yet curated in DD-G2P, 3 cases in different populations from 2 different papers (PMID:28007986 and PMID:28413018) support causation of an ID phenotype (2 families plus 1 individual).Created: 17 Aug 2017, 12:38 p.m.
In 7 infants from 3 consanguineous Pakistani families with a lethal form of NDMSBA, Hall et al. (2017, PMID:28413018) identified a homozygous missense mutation in the PLAA gene (G23V). Haplotype analysis indicated a common founder rather than a recurrent mutation. Hall et al., also report a Saudi Arabian patient with NDMSBA and homozygosity for a 1-bp duplication in the PLAA gene resulting in a frameshift and premature termination. All 4 patients had profound developmental delay and seizures.Created: 17 Aug 2017, 12:34 p.m.
In 7 patients from 2 consanguineous Israeli families with neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (NDMSBA, MIM:617527), Falik Zaccai et al. (2017, PMID:28007986) identified a homozygous missense mutation in the PLAA gene (L752F). The variant was found in a heterozygous state in 3 of 92 residents from the local village. Haplotype analysis indicated a common ancestral haplotype in the 2 families. All patients had severe mental and language developmental delay.Created: 17 Aug 2017, 12:33 p.m.
Comment on phenotypes: Phenotypes of MIM:617527 include global developmental delay, mental retardation and progressive microcephaly (recorded in both PMID:28007986 and PMID:28413018).Created: 17 Aug 2017, 12:27 p.m.
Green List (high evidence)
This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_manual . Main mutation mechanism : Missense and Loss of functionCreated: 27 Jul 2017, 8:02 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Publications
Green List (high evidence)
Promoted to Green from Amber more than three unrelated cases. This is a neurodevelopmental disorder characterized by infantile onset of progressive microcephaly, spasticity and severe global developmental delay resulting in profound mental retardation and severely impaired or absent motor function. More variable features include seizures and optic atrophy.Created: 29 Nov 2017, 2:10 p.m.
Comment on list classification: This gene is from an expert list and needs further assessment by the Genomics England curation team to access inclusion and pertinence to this panel.Created: 28 Jul 2017, 3:15 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, 617527; NDMSBA; Epileptic Encephalopathy
Publications
Source Victorian Clinical Genetics Services was added to PLAA.
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Publications for gene PLAA was set to ['28413018', '28007986']
This gene has been classified as Green List (High Evidence).
Publications for PLAA were set to 28007986; 28413018
Phenotypes for PLAA were set to Epileptic Encephalopathy; Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, 617527
This gene has been classified as Amber List (Moderate Evidence).
PLAA was added to Intellectual disabilitypanel. Sources: BRIDGE study SPEED NEURO Tier1 Gene
PLAA was created by BRIDGE
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.