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Mendeliome

Gene: PRDM16

Green List (high evidence)

PRDM16 (PR/SET domain 16)
EnsemblGeneIds (GRCh38): ENSG00000142611
EnsemblGeneIds (GRCh37): ENSG00000142611
OMIM: 605557, Gene2Phenotype
PRDM16 is in 6 panels

2 reviews

Paul De Fazio (Victorian Clinical Genetics Services)

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

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Victorian Clinical Genetics Services
Phenotypes
  • Cardiomyopathy, dilated, 1LL MIM#615373
  • Left ventricular noncompaction 8 MIM#615373
OMIM
605557
Clinvar variants
Variants in PRDM16
Penetrance
None
Publications
Panels with this gene

History Filter Activity

21 Oct 2022, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: PRDM16 were set to 23768516; 29367541; 34915728; 31965688; 29367541

21 Oct 2022, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: prdm16 has been classified as Green List (High Evidence).

19 Apr 2022, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: prdm16 has been classified as Amber List (Moderate Evidence).

19 Apr 2022, Gel status: 2

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: PRDM16 were changed from to Cardiomyopathy, dilated, 1LL MIM#615373; Left ventricular noncompaction 8 MIM#615373

19 Apr 2022, Gel status: 2

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: PRDM16 were set to

19 Apr 2022, Gel status: 2

Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of inheritance for gene: PRDM16 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

19 Apr 2022, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: prdm16 has been classified as Amber List (Moderate Evidence).

17 Nov 2019, Gel status: 3

Created, Added New Source, Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

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