Mendeliome
Gene: CFAP54 Green List (high evidence)Green List (high evidence)
PMID:39362668 reported four unrelated patients aged between 2 and 25 years old, three of whom were compound heterozygous and one homozygous for pathogenic variants in CFAP54. All reported chronic respiratory symptoms and all three patients for whom data was available had bronchiectasis. Two patients reported neonatal chest symptoms, one did not and data was missing for the other patient. No data were available on fertility status. In keeping with other C1d mutations they all had situs solitus and normal EM and HSVMA in those where data were available, but studies of in vitro ciliary transport performed in two subjects found that this was impaired in both.
As there are six unrelated families reported with ciliary dyskinesia (MIM #621125), this gene can now be promoted to green rating.Created: 1 Apr 2025, 7:40 p.m. | Last Modified: 1 Apr 2025, 7:40 p.m.
Panel Version: 1.2400
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Ciliary dyskinesia, primary, 54, OMIM:621125
Publications
I don't know
PMID 37725231: three probands from two families with PCD, supportive mouse models x2.Created: 14 Mar 2025, 4:18 a.m. | Last Modified: 14 Mar 2025, 4:18 a.m.
Panel Version: 1.2369
PMID 36593121: Three men identified with bi-allelic variants and multiple morphologic abnormalities of the flagella or non-obstructive azoospermia.
PMID: 26224312: Homozygous mice have PCD characterized by hydrocephalus, male infertility (spermatogenesis defects in flagella maturation), and mucus accumulation. Brain analysis showed mild dilatation of the lateral ventricles. Tracheal cilia beat frequency was significantly reduced. The gene was highest expressed in the testis and lungs
Sources: LiteratureCreated: 12 Mar 2025, 8:13 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Spermatogenic failure 98, MIM# 621124; HCiliary dyskinesia, primary, 54, MIM# 621125
Publications
Phenotypes for gene: CFAP54 were changed from Spermatogenic failure 98, MIM# 621124; Hydrocephalus, male infertility, mucus accumulation to Ciliary dyskinesia, primary, 54, MIM:621125; Spermatogenic failure 98, MIM# 621124; Hydrocephalus, male infertility, mucus accumulation
Publications for gene: CFAP54 were set to 26224312; 36593121
Gene: cfap54 has been classified as Green List (High Evidence).
Gene: cfap54 has been classified as Amber List (Moderate Evidence).
Gene: cfap54 has been classified as Red List (Low Evidence).
gene: CFAP54 was added gene: CFAP54 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CFAP54 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CFAP54 were set to 26224312; 36593121 Phenotypes for gene: CFAP54 were set to Spermatogenic failure 98, MIM# 621124; Hydrocephalus, male infertility, mucus accumulation Review for gene: CFAP54 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.