BabyScreen+ newborn screening
Gene: LAMP2 Amber List (moderate evidence)Green List (high evidence)
X-linked dominant genetic disorder characterized by cardiomyopathy, skeletal myopathy, and neurocognitive deficits
Most men and many women with LAMP2 gene mutations will develop cardiac disease that includes hypertrophic cardiomyopathy and/or dilated cardiomyopathy, cardiac pre-excitation syndrome, and a propensity for arrhythmias. The prognosis is directly related to the severity of the cardiac disease, and many patients will die from sudden cardiac death. Males are typically more severely affected than females.
Early onset cardiomyoapthy and neurodevelopmental phenotype - reproductive utility to prevent multiple affected pregnancies. High-penetrance cardiomyopathy with high risk of arrhythmia and or transplant. Neurodevelopmental issues allow preparation and early childhood intervention.
- Ages of onset in Cohort studies and personal experience M 0.25–45 F2–58
- The family known to RCH/MMC is neonatal onset cardiomyopathy, symptomatic, potentially we should publish more formally, was presented at HGSA
International natural history study ongoing.
Expect therapy in next few years. Trials ongoing in Europe and US with therapy for CM and improvement in ND outcomes.
Rocket Pharmaceuticals Adeno-associated- vector-501 (RP-A501) (AAV9.LAMP2B), an investigational gene therapy product for DD and the first potential gene therapy for monogenic heart failure.Created: 15 Feb 2023, 4:27 a.m. | Last Modified: 15 Feb 2023, 4:27 a.m.
Panel Version: 0.1865
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Childhood onset cardiomyopathy (Severe); Neuordevelopmental phenotype
I don't know
Treatment is currently symptomatic.
On watch list with regards to specific treatment/clinical trials.Created: 29 Mar 2023, 2 a.m. | Last Modified: 29 Mar 2023, 2 a.m.
Panel Version: 0.2140
For review: age of onset is typically adolescence.Created: 26 Sep 2022, 9:42 a.m. | Last Modified: 26 Sep 2022, 9:42 a.m.
Panel Version: 0.211
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Danon disease, MIM# 300257
Green List (high evidence)
Gene-disease association: well established
Onset:Childhood (average age 12y males and 19y females
Treatment: cardiomyopathy treatment, ? transplantCreated: 26 Sep 2022, 3:47 a.m. | Last Modified: 26 Sep 2022, 3:47 a.m.
Panel Version: 0.199
Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes
Danon disease - cardiomyopathy, retinal disease, cognitive dysfunction
Added phenotypes Danon disease, MIM# 300257 for gene: LAMP2
Gene: lamp2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: LAMP2 were changed from Danon disease, MIM# 300257 to Danon disease, MIM# 300257
Gene: lamp2 has been classified as Green List (High Evidence).
Tag for review was removed from gene: LAMP2.
Tag cardiac tag was added to gene: LAMP2.
Gene: lamp2 has been classified as Red List (Low Evidence).
Phenotypes for gene: LAMP2 were changed from Danon disease to Danon disease, MIM# 300257
Mode of inheritance for gene: LAMP2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Gene: lamp2 has been classified as Red List (Low Evidence).
Tag for review tag was added to gene: LAMP2.
gene: LAMP2 was added gene: LAMP2 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: LAMP2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: LAMP2 were set to Danon disease
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.