BabyScreen+ newborn screening
Gene: PCSK9 Green List (high evidence)Green List (high evidence)
Rated as 'strong actionability' in paediatric patients by ClinGen.
The clinical features of HoFH are characterized by extensive xanthomas, premature and progressive cardiovascular disease (CVD), and total cholesterol >500 mg/dL.
HoFH commonly presents as physical manifestations in infancy and early childhood, consisting primarily of fleshy cutaneous and tendinous xanthomata, most marked in the Achilles tendon. Clinical CVD events begin as early as the first decade of life, but usually manifest by the second decade, consisting primarily of coronary ostial stenoses and occlusions, aortic valve thickening with stenosis and/or regurgitation, and extensive atherosclerosis of the aortic root. Untreated, most individuals with HoFH develop severe CAD and aortic stenosis before age 20 and die before age 30. Children as young as 4 years of age have suffered sudden death due to acute MI. The rate of either death or coronary bypass surgery by the teenage years is high.
The initial treatment for individuals with FH, irrespective of their calculated cardiovascular risk, should be a high intensity statin. Statin therapy is recommended to be initiated by 8-12 years of age; however, HoFH patients under the age of 8-10 years with high-risk family history, high-risk conditions, or multiple risk factors might be considered for medication initiation at a younger age. Target serum LDL-C concentrations have not been established for children, but in adults, the goal should be a reduction of at least 50% in LDL-C concentration from baseline. Statin treatment is lifelong.
Ezetimibe, as a monotherapy or in combination with statin therapy, is recommended as an option for treating HoFH in patients in whom initial statin therapy is contraindicated or not tolerated or when LDL-C levels are not controlled by statins alone.
LDL-C apheresis should be offered for treatment of HoFH with initiation based on response to lipid-lowering therapy (LLT), the presence of CHD, and child weight (>15kg). For children, treatment can be performed as early as technically feasible (before age 5 and at least by age 8).
Dietary modifications may be started after 2 years of age and should be under the supervision of a dietician or nutritionist for children and young adults.Created: 29 Dec 2022, 10:04 p.m. | Last Modified: 29 Dec 2022, 10:04 p.m.
Panel Version: 0.1750
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Hypercholesterolemia, familial, 3, MIM# 603776
Added phenotypes Hypercholesterolaemia, familial, 3, MIM# 603776 for gene: PCSK9
Gene: pcsk9 has been classified as Green List (High Evidence).
Phenotypes for gene: PCSK9 were changed from Hypercholesterolemia to Hypercholesterolaemia, familial, 3, MIM# 603776
Gene: pcsk9 has been classified as Green List (High Evidence).
Tag for review tag was added to gene: PCSK9. Tag treatable tag was added to gene: PCSK9. Tag metabolic tag was added to gene: PCSK9.
gene: PCSK9 was added gene: PCSK9 was added to gNBS. Sources: Expert Review Amber,BabySeq Category B gene Mode of inheritance for gene: PCSK9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: PCSK9 were set to Hypercholesterolemia
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.