Retinal disorders

Gene: PRDM13

Reviewing the evidence for this gene being green:

Two conditions are considered here: autosomal dominant progressive bifocal chorioretinal atrophy (PBCRA) and North Carolina macular dystrophy (NCMD). Both affect the macula from birth but PBCRA shows disease progression with retinal dysfunction, while NCMD is a stationary disorder with restricted retinal involvement but variable expressivity. The majority of reports relate to NCMD.

Over the 4 studies listed in detail below, 1 variant from 2 unrelated familes in the upstream region of MRDM13 were associated with PBCRA, and 4 different variants in the upstream region of MRDM13 were associated with a NCMD phenotype. Additionally 3+ tandem duplications (123 kb, 69 kb and 98 kb) which include MRDM13 and its upstream region (plus the CCNC gene in 2 cases) were identified in families with NCMD. The mechanism of action is proposed as increase in expression levels of MRDM13.

In the current WGS pipeline variants in the upstream region wouldn't be prioritised as not protein altering but could potentially be prioritised through known pathogenic variant prioritisation if they are in ClinVar/CVA as pathogenic/likely pathogenic.

Further reports of duplication of PRDM13 and the DNase 1 hypersensitivity site in families with NCMD - PMID: 39959174 (Mexican family) , PMID: 34427740 (Chinese family, CCNC also in the duplication)

PMID:30710461 Silva et al 2019 - WGS of 2 families with autosomal dominant progressive bifocal chorioretinal atrophy (PBCRA and 1 family with a related developmental macular dystrophy.
All those with PBCRA (6 affected individuals) have a SNV chr6:100046804T>C) located 7.8 kb upstream of PRDM13. Haplotype analysis suggest this variant arose independently in the two families. In the 3rd family a de-novo variant was found at chr6:100046783A>C which is 21 bp from the other variant. The mother in this family (de-novo variant) had a clinical presentation similar to NCMD but the affected child had a more severe macular atrophy and findings more typical of PBCRA. Suggests altered spatiotemporal expression of PRDM13 in the phenotypically distinct but related conditions.

PMID: 28973654 Manes et al 2017 2 families with NCMD with 2 large tandem duplications spanning the entire CCNC and PRDM13 genes and their potential DNase 1 hypersensitivity site. The families appear to been unrelated with only 1 microsatelite marker in common. A 98 kb tandem duplication was identified in both families. In fruit flies overexpression of the PRDM13 orthologue led to a strong pheontype of photoreceptor degeneration, but knockdown of the CCNC or PDRM13 orthologues, and overexpression of CCNC did not lead to any eye defects.

PMID: 27777503 Browne et al 2016 - in a 4 generation family with NCMD genomic analsysi was performed on 4 affected and 2 unaffected family members. A 69 kb tandem duplication that contains an entire intact PRDM13 gene copy, a partial CCNC gene copy, and a copy of the DNase I hypersensitive site located between the 5′ ends of both genes. The authors propose that it is more likely that expression levels of PRDM13 are more likely to be impacted than CCNC (being a partial duplication).

PMID: 26507665 Small et al 2016 Targeted sequencing of the critical region on chr6 (MCDR1) linked to NCMD in 3 families and RT-PCR analysis of gene expression in human retinal cells in 141 members of 12 families with NCMD and 261 unrelated control individuals.
12 families with clinical features of NCMD were studied. But 6 share a common haplotype on chr6. 5 exhibit a different haplotype marker on chr 6. The 12th family has been linked to a locus on chr 5. Families A-F -variant (V1) chr6:100040906G>T in all affected members , families G-I (V2) chr6:100040987G>C, family J (V3)chr6:100041040 C>T, Family K (V4) chr6:100020205-100143306,123101 bp tandem duplication. Variants V1 to V3 are upstream of PRDM13 (a retinal transcription factor) in a DNase 1 hypersensitivity site. Variant V4 is a tandem duplication of the PRDM13 gene including the upstream region. Collectively, V1 to V4 were present in 91 of 91 affected members of these 11 families, absent from 38 of 38 unaffected members, and absent from 261 unrelated control individuals (522 chromosomes)

Using iPSCs they showed that as cells progress from a pluripotent stem cell state to mature retinal neurons, PRDM13 transcript is downregulated. CCNC (on the other side of the variants) is consistently expressed across all developmental time points.

Created: 29 Jul 2026, 5:12 p.m. | Last Modified: 29 Jul 2026, 5:12 p.m.

Panel Version: 9.10

Green List (high evidence)

Variants in a DNase hypersensitivity region upstream of PRDM13 and duplications of the gene cause the condition. May not be tractable by all NGS assays. The mechanism of disease is reported to be gain-of-function.

Created: 13 Oct 2020, 7:52 a.m. | Last Modified: 13 Oct 2020, 7:52 a.m.

Panel Version: 2.20

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Macular dystrophy, North Carolina type MIM#136550

Publications

• 29258872
• 28973654
• 26507665
• 30710461

Mode of pathogenicity
Other

I don't know

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 8 Mar 2022, 10:06 a.m. | Last Modified: 8 Mar 2022, 10:06 a.m.

Panel Version: 2.243

This gene is associated with a relevant phenotype in Gene2Phenotype but not in OMIM. There is enough evidence to support a gene-disease assocation. This gene should be rated Green at the next review.

Created: 27 Jan 2021, 10:49 a.m. | Last Modified: 27 Jan 2021, 10:49 a.m.

Panel Version: 2.137

Submitted on behalf of the GMS Eye specialist group. These genes are also from RetNet. There is currently not enough evidence to rate these genes Green, therefore they have been given an Amber rating.

Created: 27 Dec 2019, 9:10 a.m. | Last Modified: 27 Dec 2019, 9:10 a.m.

Panel Version: 2.5