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Intellectual disability

Gene: PRKAR1B

Amber List (moderate evidence)

PRKAR1B (protein kinase cAMP-dependent type I regulatory subunit beta)
EnsemblGeneIds (GRCh38): ENSG00000188191
EnsemblGeneIds (GRCh37): ENSG00000188191
OMIM: 176911, Gene2Phenotype
PRKAR1B is in 1 panel

2 reviews

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the provided evidence this gene has been given an Amber rating.
Created: 12 Nov 2020, 3:14 p.m. | Last Modified: 12 Nov 2020, 3:14 p.m.
Panel Version: 3.525

Konstantinos Varvagiannis (Other)

I don't know

Please consider inclusion of this gene with amber rating pending publication of the preprint and/or additional evidence.

Marbach et al. (2020 - medRxiv : https://doi.org/10.1101/2020.09.10.20190314 - last author : C. Schaaf) report 6 unrelated individuals with heterozygous missense PRKAR1B variants.

All presented formal ASD diagnosis (6/6), global developmental delay (6/6) and intellectual disability (all - formal evaluations were lacking though). Additional features included neurologic anomalies (movement disorders : dyspraxia, apraxia, clumsiness in all, with tremor/dystonia or involuntary movements as single occurrences). Three displayed high pain tolerance. Regression in speech was a feature in two. Additional behavior anomalies included ADHD (4-5/6) or aggression (3/6). There was no consistent pattern of malformations, physical anomalies or facial features (with the exception of uplsanted palpebral fissures reported in 4).

3 different missense variants were identified (NM_00116470:c.1003C>T - p.Arg335Trp, c.586G>A - p.Glu196Lys, c.500_501delAAinsTT - p.Gln167Leu) with Arg355Trp being a recurrent one within this cohort (4/6 subjects). A possible splicing effect may apply for the MNV. All variants are absent from gnomAD and the SNVs had CADD scores > 24.

In all cases were parental samples were available (5/6), the variant had occurred as a de novo event.

Protein kinase A (PKA) is a tetrameric holoenzyme formed by the association of 2 catalytic (C) subunits with a regulatory (R) subunit dimer. Activation of PKA is achieved through binding of 2 cAMP molecules to each R-subunit, and unleashing(/dissociation) of C-subunits to engage substrates. PRKACA/B genes encode the Cα- and Cβ-subunits while the 4 functionally non-redundant regulatory subunits are encoded by PRKAR1A/1B/2A/2B genes. As the authors comment, the RIβ subunit is primarily expressed in brain with higher expression in cortex and hypothalamus.

The functional consequences of the variants at cellular level were not studied.

Previous studies have demonstrated that downregulation of RIβ in murine hippocampal cultures, reduced phosphorylation of CREB, a transcription factor involved in long-term memory formation. The authors speculate that a similar effect on cAMP/PKA/CREB cascade may mediate the cognitive effects in humans. RIβ deficient mice also display diminished nociceptive pain, similar to the human phenotype. [Several refs provided].

The authors cite the study by Kaplanis et al (2020 - PMID: 33057194), where in a large sample of 31,058 trio exomes of children with developmental disorders, PRKAR1B was among the genes with significant enrichment for de novo missense variants. [The gene has a pLI score of 0.18 in gnomAD / o/e = 0.26 - so pLoF variants may not be deleterious].

Please note that a specific PRKAR1B variant (NM_002735.2:c.149T>G - p.Leu50Arg) has been previous reported to segregate with a late-onset neurodegenerative disorder characterized by dementia and/or parkinsonism within a large pedigree with 12 affected individuals [Wong et al 2014 - PMID: 25414040].
Sources: Literature
Created: 1 Nov 2020, 3:17 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • Autism
  • Attention deficit hyperactivity disorder
  • Aggressive behavior
  • Abnormality of movement
  • Upslanted palpebral fissure
Tags
watchlist
OMIM
176911
Clinvar variants
Variants in PRKAR1B
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

12 Nov 2020, Gel status: 2

Added Tag

Ivone Leong (Genomics England Curator)

Tag watchlist tag was added to gene: PRKAR1B.

12 Nov 2020, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: prkar1b has been classified as Amber List (Moderate Evidence).

1 Nov 2020, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: PRKAR1B was added gene: PRKAR1B was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: PRKAR1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040 Phenotypes for gene: PRKAR1B were set to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure Penetrance for gene: PRKAR1B were set to unknown Review for gene: PRKAR1B was set to AMBER