Genetic Epilepsy
Gene: DAB1 Red List (low evidence)Red List (low evidence)
WES trio analysis identified compound heterozygous DAB1 canonical splice variants in a child with epilepsy (onset 6 years), developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities. RT-PCR confirms that the first variant (c.307-2A>T) causes a in-frame deletion of 3 amino acids. The second variant (c.67+1G>T) is reported to causes an in-frame deletion of exon 4 (first coding exon) and loss of the ATG initiation site.
New LoF mechanism suggested. Repeat expansion in this gene is known to be associated with disease.
Sources: Expert listCreated: 18 Oct 2021, 9:22 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
epilepsy; developmental delay; cerebellar ataxia; structural brain abnormalities; oral motor difficulty
Publications
Red List (low evidence)
Single individual reported with compound heterozygous variants in this gene: canonical splice variants in a child with epilepsy (onset 6 years), developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities. RT-PCR confirms that the first variant (c.307-2A>T) causes a in-frame deletion of 3 amino acids. The second variant (c.67+1G>T) is reported to causes an in-frame deletion of exon 4 (first coding exon) and loss of the ATG initiation site.
Note repeat expansions in this gene have an established association with disease.Created: 4 Oct 2021, 6:13 p.m. | Last Modified: 4 Oct 2021, 6:13 p.m.
Panel Version: 0.9312
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Ataxia; Intellectual disability
Publications
Green List (high evidence)
Comment on list classification: Note: the pentanucleotide repeat is the only cause of ataxia for this gene, which is not detected by current WES/WGS technologies.Created: 18 Apr 2020, 5:20 p.m. | Last Modified: 18 Apr 2020, 5:20 p.m.
Panel Version: 0.48
In 35 affected individuals from 3 large, multigenerational kindreds from southern Portugal with ataxia had expansion of a heterozygous 5-bp ATTTC(n) insertion in the 5-prime UTR intron 3 of the DAB1 gene.
Sources: Expert listCreated: 18 Apr 2020, 5:19 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Spinocerebellar ataxia 37 MIM#615945
Publications
Mode of pathogenicity
Other
Source Victorian Clinical Genetics Services was removed from DAB1. Phenotypes for gene: DAB1 were changed from epilepsy; developmental delay; cerebellar ataxia; structural brain abnormalities; oral motor difficulty to Neurodevelopmental disorder, MONDO:0700092, DAB1-related
Gene: dab1 has been classified as Red List (Low Evidence).
Gene: dab1 has been classified as Red List (Low Evidence).
gene: DAB1 was added gene: DAB1 was added to Genetic Epilepsy. Sources: Expert list Mode of inheritance for gene: DAB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DAB1 were set to PMID: 33928188 Phenotypes for gene: DAB1 were set to epilepsy; developmental delay; cerebellar ataxia; structural brain abnormalities; oral motor difficulty Review for gene: DAB1 was set to RED
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 panelapp@genomicsengland.co.uk
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.