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Intellectual disability

Gene: PRR12

Green List (high evidence)

PRR12 (proline rich 12)
EnsemblGeneIds (GRCh38): ENSG00000126464
EnsemblGeneIds (GRCh37): ENSG00000126464
OMIM: 616633, Gene2Phenotype
PRR12 is in 3 panels

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: Gene status was changed to Green due to a expert review by Konstantinos Varvagiannis on Leduc et al. 2018 who reports on 3 unrelated individuals with de novo pathogenic variants in PRR12. (PMID: 29556724). All individuals have ID. PRR12 is not currently in OMIM and is listed as probable in Gene2Phen.
Created: 29 May 2019, 1:23 p.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

PMID: 29556724 (Leduc et al. 2018) reports on 3 unrelated individuals with de novo pathogenic variants in PRR12. The common phenotype consisted of DD/ID (3/3), iris anomalies (colobomas in 2/3 with stellate iris patern in all) as well as additional vision problems and behavioral anomalies.

3 different loss-of-function variants are reported. These variants affected the longer transcript (Ensembl ENST00000418929.6 or NM_020719 - short : ENST00000615927.1) with a single one affecting both.

PRR12 appears to be intolerant to loss-of-function muatations (pLI of 1). Some LoF variants exist in ExAC/gnomAD although the majority appear to be low-quality variants.

As commented by the authors 2 individuals with de novo variants exist in Decipher (1 in-frame deletion and a missense SNV - both variants appear in fig.2 of the article) [a few more DDD study participants in the denovo-db all from PMID: 28135719 : http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=PRR12].

Alternative explanations for the phenotype (eg. CHARGE syndrome, etc) were ruled out in many individuals in the article.

Functional studies have not been performed. //

PMID: 26163108 (Córdova-Fletes al. 2015) is a previous report cited by Leduc et al. One individual with balanced translocation [t(10;19)] with disruption of PRR12 is described. This individual presented with ID and behavioral anomalies (without details on eventual coloboma or other iris anomalies).

The translocation was balanced and led to fusion of PRR12 with LMIZ1. The breakpoint was located within intron 11 (PRR12 is a 14-exon gene) with fusion of PRR12 exon 11 with ZMIZ1 exon 8 upon RT-PCR. Both PRR12/ZMIZ1 products were predicted to be truncated due to frameshift and introduction of premature stop codon.

[Surprisingly qPCR and Western blot in patient LCLs were suggestive of increased PRR12 expression compared to controls suggesting either a compensation mechanism or longer half-life/accumulation of the aberrant PRR12].

Expression of wt PRR12 was highest during embryonic development in mouse/rat brain cells suggesting a role in early CNS development. The transcript studied (corresponding to the longest human transcript) was exclusively located in the nucleus compared to a shorter one located primary in the nucleus but also outside suggesting that PRR12 might be involved in regulation of transcription.

In line with this several genes linked to neurodevelopmental processes/neuronal communication appeared be dysregulated in lymphoblastoid cell lines (LCLs) from the translocation patient.

A role for ZMIZ1 is similarly discussed.

Edit [12-Jan-2019]: Note that ZMIZ1 is also proposed to be an ID gene in a recent study by Carapito et al. (doi.org/10.1016/j.ajhg.2018.12.007). //

PRR12 is included in gene panels for ID offered by diagnostic laboratories. //

As a result, this gene can be considered for inclusion in this panel as green (or amber).
Created: 5 Dec 2018, 12:25 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Global developmental delay; Intellectual disability; Abnormality of the iris; Abnormality of vision; Behavioral abnormality

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Green
  • Expert Review Green
  • Expert Review
Phenotypes
  • Global developmental delay, Intellectual disability, Abnormality of the iris, Abnormality of vision, Behavioral abnormality
  • Abnormality of the iris
  • Behavioral abnormality
  • Intellectual disability
  • Global developmental delay
  • Abnormality of vision
OMIM
616633
Clinvar variants
Variants in PRR12
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

25 Jul 2019, Gel status: 3

Set mode of inheritance

Catherine Snow (Genomics England)

Mode of inheritance for gene PRR12 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

25 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to PRR12. Source Expert Review was added to PRR12. Added phenotypes Global developmental delay, Intellectual disability, Abnormality of the iris, Abnormality of vision, Behavioral abnormality for gene: PRR12 Publications for gene PRR12 were changed from 29556724; 26163108 to 28135719; 26163108; 29556724 Rating Changed from No List (delete) to Green List (high evidence)

5 Dec 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: PRR12 was added gene: PRR12 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PRR12 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRR12 were set to 29556724; 26163108 Phenotypes for gene: PRR12 were set to Global developmental delay; Intellectual disability; Abnormality of the iris; Abnormality of vision; Behavioral abnormality Penetrance for gene: PRR12 were set to unknown Review for gene: PRR12 was set to GREEN gene: PRR12 was marked as current diagnostic