Intellectual disability syndromic and non-syndromic
Gene: PRKAR1B

PRKAR1B (protein kinase cAMP-dependent type I regulatory subunit beta)
EnsemblGeneIds (GRCh38): ENSG00000188191
EnsemblGeneIds (GRCh37): ENSG00000188191
OMIM: 176911, Gene2Phenotype
PRKAR1B is in 2 panels

2 reviews

Paul De Fazio (Victorian Clinical Genetics Services)

Green List (high evidence)

6 individuals reported with neurodevelopmental disorders, 5 confirmed de novo. 4 carried the same variant p.(Arg335Trp).

Phenotypes include global developmental delay, autism spectrum disorder, apraxia/dyspraxia. 3 patients, all with the p.(Arg335Trp) variant, also had reduced pain sensitivity and congenital hypotonia.
Created: 7 Jan 2022, 3:57 a.m. | Last Modified: 7 Jan 2022, 3:57 a.m.

Panel Version: 0.4418

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

Phenotypes
Marbach-Schaaf neurodevelopmental syndrome MIM#619680

Publications

33833410

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

Created: 7 Jan 2022, 3:57 a.m.
Last Modified: 7 Jan 2022, 3:57 a.m.
Panel version: 0.4418

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, 3:14 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

https://doi.org/10.1101/2020.09.10.20190314
25414040

Created: 1 Nov 2020, 3:14 p.m.

Panel version: 0.3128

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Green

Phenotypes

Marbach-Schaaf neurodevelopmental syndrome MIM#619680
Global developmental delay
Intellectual disability
Autism
Attention deficit hyperactivity disorder
Aggressive behavior
Abnormality of movement
Upslanted palpebral fissure

OMIM

176911

Clinvar variants

Variants in PRKAR1B

Penetrance

unknown

Publications

Panels with this gene