Mendeliome
Gene: PRDM16 Green List (high evidence)Green List (high evidence)
Lit review for LoF variants (focusing on unique reports). Note the gene is LoF constrained in gnomAD.
Summary:
DCM: 2 (1 de novo)
LVNC: 7 (3 de novo)
DCM with LVNC: 1 (1 de novo)
NCCM: 4 (1 de novo)
Unknown CM: 1
- PMID 29367541: p.S350fs*48 (de novo) in a paediatric DCM case with mild features of LVNC. WES testing
- PMID 29447731: p.(Asn19Ilefs*114), c.676+1G>A (de novo), p.(Arg950*) found in a noncompaction cardiomyopathy cohort. Panel testing.
- PMID 30847666: c.37+1G>A in an unknown cardiomyopathy patient and c.676+1G>A in a noncompaction cardiomyopathy patient. Panel testing.
- PMID 33082984: p.Ser189Valfs*22 in an LVNC patient (unknown inheritance). Exome and mitochondrial genome testing. Note they classified the variant as a VUS (but 'highly suspicious') due to the uncertain gene-disease association for PRDM16.
- PMID 32183154: p.Ser723fs in an LVNC patient. LVNC/CHD cohort. Panel testing.
- PMID 33500567: p.Thr938GlnfsX34 in an LVNC patient from the LMM cohort (additional variants reported in the study but they were all from previously published data).
- PMID 34540771: p.R525Pfs*79 (de novo), p.K702* (de novo), and Q543* (unknown) in LVNC patients, panel testing.
- PMID 34350506: Female patient with de novo p.S255* variant. 8mo onset, of paediatric DCM, arrhymthia noted as "premature ventricular contractions". Panel testing.
- PMID 34935411: p.R525Pfs*79 (unknown inheritance) in a paediatric DCM patient. No family history. No ventricular arrhythmia. Appears distinct from Schultze-Berndt 2021 (different authors, insitute, phenotype). Panel testing.Created: 21 Oct 2022, 4:36 a.m. | Last Modified: 21 Oct 2022, 4:36 a.m.
Panel Version: 1.418
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Cardiomyopathy, dilated, 1LL MIM#615373; Left ventricular noncompaction 8 MIM#615373
Publications
Variants in this GENE are reported as part of current diagnostic practice
I don't know
Assessed as LIMITED by ClinGen for DCM. However, note two additional cases and a mouse model since.
The first publication that associated PRDM16 with DCM was published in 2013 (Arndt et al, PMID: 23768516). The Arndt et al study included analysis of 131 heart biopsies from simplex cases of DCM, from which 4 missense variants (p.Glu271Lys, p.Pro291Leu, p.Lue887Pro and p.Val1101Met) in 5 unrelated individuals were identified. An additional 12 year old patient with mild to moderate LV dysfunction and LV dilatation in addition to features of LV non-compaction carried a truncating variant (p.Lys702X). Another study (Long et al, 2017, PMID: 29367541), reported a 4 month old DCM patient carrying a de novo predicted truncating variant, c.1047dupC (p.S350fsX48). Fetal presentation with a de novo LoF variant reported in PMID 31965688, and a further de novo missense in PMID 29367541.
Cardiac localization studies showing that PRDM16 is expressed in LV myocardium in human and mouse hearts. Further, PRDM16 knockdown zebrafish and transgenic zebrafish for the c.2104A>T (p.Lys702X) variant demonstrated bradycardia and significantly reduced cardiac output, however, cardiac output was restored in morphant embryos with increased doses of wild-type human PRDM16 (Ardnt et al, 2013, PMID: 23768516).
PMID 34915728 describes a mouse model with LV-specific dilation and dysfunction, as well as biventricular noncompaction.Created: 19 Apr 2022, 1:03 a.m. | Last Modified: 19 Apr 2022, 1:03 a.m.
Panel Version: 0.13043
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Cardiomyopathy, dilated, 1LL MIM#615373; Left ventricular noncompaction 8 MIM#615373
Publications
Publications for gene: PRDM16 were set to 23768516; 29367541; 34915728; 31965688; 29367541
Gene: prdm16 has been classified as Green List (High Evidence).
Gene: prdm16 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: PRDM16 were changed from to Cardiomyopathy, dilated, 1LL MIM#615373; Left ventricular noncompaction 8 MIM#615373
Publications for gene: PRDM16 were set to
Mode of inheritance for gene: PRDM16 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: prdm16 has been classified as Amber List (Moderate Evidence).
gene: PRDM16 was added gene: PRDM16 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: PRDM16 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.