Intellectual disabilityGene: PRR12 Green List (high evidence)
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.
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
Global developmental delay; Intellectual disability; Abnormality of the iris; Abnormality of vision; Behavioral abnormality
Variants in this GENE are reported as part of current diagnostic practice
Mode of inheritance for gene PRR12 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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)
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
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).
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).
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.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
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 [email protected]
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.