Mendeliome
Gene: DIAPH1 Green List (high evidence)Green List (high evidence)
OMIM:
Deafness, autosomal dominant 1, with or without thrombocytopenia (AD)
Seizures, cortical blindness, microcephaly syndrome (AR) - Microcephaly (up to -10 SD)
Microcephaly:
PMID: 24781755 (2015) - five individuals from a consanguineous family with severe microcephaly >2SD below the mean for age with homozygous nonsense variant in DIAPH1
PMID: 26463574 (2016) - two different homozygous LOF variants identified in two unrelated consanguineous families. The affected individuals were diagnosed with postnatal microcephaly (>2SD), early-onset epilepsy, severe vision impairment, and pulmonary symptoms including bronchiectasis and recurrent respiratory infections.
Summary (microcephaly) - Three unrelated consanguineous families with homozygous LOF variants
Deafness:
PMID: 24781755 (2016) - Two unrelated pedigrees with a heterozygous truncating (confirmed) variant in 4 and 3 individuals in each family with macrothrombocytopenia and sensorineural hearing loss. Gain of function is the suspected mechanism.
PMID: 27707755 (2016) - Heterozygous nonsense variant in two families with hearing loss.
PMID: 27808407 (2017) - Two families with different heterozygous truncating variants with ADNSHL. An association with thrombocytopenia was also identified.
PMID: 28003573 (2017) - Novel missense variant in a patient with ADNSHL.
PMID: 28815995 (2017) - Heterozygous nonsense variant in a family with progressive hearing loss and macrothrombocytopenia
Summary (deafness): at least eight families with AD deafness and in some cases macrothrombocytopeniaCreated: 2 Sep 2020, 4:15 p.m. | Last Modified: 2 Sep 2020, 4:15 p.m.
Panel Version: 0.4114
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Deafness; thrombocytopenia; Seizures; cortical blindness; microcephaly
Publications
Publications for gene DIAPH1 were changed from 27808407; 28003573; 28815995; 26912466; 24781755; 26463574; 33662367; 36212620; 39076976; 39120629 to 27808407; 28003573; 28815995; 26912466; 24781755; 26463574; 33662367; 36212620; 39076976; 39120629
Publications for gene DIAPH1 were changed from 27808407; 28003573; 28815995; 26912466; 24781755; 26463574 to 27808407; 28003573; 28815995; 26912466; 24781755; 26463574
Publications for gene DIAPH1 were changed from 27808407; 28003573; 28815995; 26463574; 26912466; 24781755 to 27808407; 28003573; 28815995; 26463574; 26912466; 24781755
Publications for gene DIAPH1 were changed from 27808407; 28003573; 28815995; 26463574; 24781755 to 27808407; 28003573; 28815995; 26463574; 24781755
Phenotypes for gene: DIAPH1 were changed from DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, MONDO:0044635 to DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, MONDO:0044635; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, MONDO:0014714 Publications for gene DIAPH1 were changed from 24781755; 24781755; 27808407; 28003573; 28815995; 26463574 to 24781755; 24781755; 27808407; 28003573; 28815995; 26463574
Source Victorian Clinical Genetics Services was removed from DIAPH1. Source Literature was added to DIAPH1. Phenotypes for gene: DIAPH1 were changed from Deafness; thrombocytopenia 124900; Seizures; cortical blindness; microcephaly 616632 to DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, MONDO:0044635
Gene: diaph1 has been classified as Green List (High Evidence).
Phenotypes for gene: DIAPH1 were changed from to Deafness; thrombocytopenia 124900; Seizures; cortical blindness; microcephaly 616632
Publications for gene: DIAPH1 were set to
Mode of inheritance for gene: DIAPH1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
gene: DIAPH1 was added gene: DIAPH1 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: DIAPH1 was set to Unknown
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.