Intellectual disability - microarray and sequencing
Gene: CCDC47 Green List (high evidence)Comment on list classification: New gene added by external expert and reviewed by curation team: appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.Created: 21 Feb 2019, 3:07 p.m.
Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (Morimoto el al., 2018)Created: 21 Feb 2019, 3:04 p.m.
Comment on phenotypes: Added OMIM phenotype and MIMidCreated: 21 Feb 2019, 3:02 p.m.
Green List (high evidence)
Morimoto el al. (PMID: 30401460) report on 4 individuals from 4 unrelated families with biallelic LoF variants in CCDC47. The phenotype consisted of abnormal (woolly) hair, liver dysfunction, common facial features as well as DD/ID.
The patients were found to harbor the variants in compound heterozygous or more commonly in homozygous state (due to consanguinity and/or common ancestry). 4 loss-of-function variants are reported in total (using NM_020198.2 as a reference):
- c.811C>T or p.(Arg271*) [consanguineous family of Turkish origin]
- c.1145delT or p.(Leu382Argfs*2) [probably a founder mutation in Amish]
- c.1165delT or p.(Ser389Leufs*25)
- c.1189C>T or p.(Arg397*)
Decreased mRNA levels in fibroblasts/lymphoblastoid cells were shown as well as absence of the protein upon Western blot using antibodies recognizing the N and C terminus (thus suggesting NMD).
Localization of CCDC47 in the ER was demonstrated with perturbed Ca+2 homeostasis and signalling in the ER.
Ccdc47-knockout mice present features similar to the human phenotypes eg. growth, neurological as well as heart anomalies. In mice embryonic/neonatal lethality was noted in some cases which might be associated with recurrent miscarriages reported in 3 patient families.
CCDC47 is not associated with any phenotype in G2P or OMIM.
As a result, this gene can be considered for inclusion in this panel as green (or amber).
Sources: LiteratureCreated: 12 Dec 2018, 10 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Woolly hair; Abnormality of the liver; Global developmental delay; Intellectual disability
Publications
Tag gene-checked tag was added to gene: CCDC47.
Gene: ccdc47 has been classified as Green List (High Evidence).
Phenotypes for gene: CCDC47 were changed from Woolly hair; Abnormality of the liver; Global developmental delay; Intellectual disability to Woolly hair; Abnormality of the liver; Global developmental delay; Intellectual disability; Trichohepatoneurodevelopmental syndrome, 618268
gene: CCDC47 was added gene: CCDC47 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CCDC47 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CCDC47 were set to 30401460 Phenotypes for gene: CCDC47 were set to Woolly hair; Abnormality of the liver; Global developmental delay; Intellectual disability Penetrance for gene: CCDC47 were set to Complete Review for gene: CCDC47 was set to GREEN
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.