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Intellectual disability - microarray and sequencing v5.300 PRKAR1B Arina Puzriakova Phenotypes for gene: PRKAR1B were changed from Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
Intellectual disability - microarray and sequencing v5.299 PRKAR1B Arina Puzriakova Tag watchlist was removed from gene: PRKAR1B.
Tag Q2_23_promote_green was removed from gene: PRKAR1B.
Intellectual disability - microarray and sequencing v5.286 PRKAR1B Arina Puzriakova reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.286 PRKAR1B Arina Puzriakova Source NHS GMS was added to PRKAR1B.
Source Expert Review Green was added to PRKAR1B.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Intellectual disability - microarray and sequencing v5.98 PRKAR1B Achchuthan Shanmugasundram Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.98 PRKAR1B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.
Intellectual disability - microarray and sequencing v5.98 PRKAR1B Achchuthan Shanmugasundram Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.98 PRKAR1B Achchuthan Shanmugasundram Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.98 PRKAR1B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.
Intellectual disability - microarray and sequencing v5.98 PRKAR1B Achchuthan Shanmugasundram Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.98 PRKAR1B Achchuthan Shanmugasundram Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.98 PRKAR1B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.
Intellectual disability - microarray and sequencing v5.98 PRKAR1B Achchuthan Shanmugasundram Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.97 PRKAR1B Achchuthan Shanmugasundram Deleted their comment
Intellectual disability - microarray and sequencing v5.97 PRKAR1B Achchuthan Shanmugasundram Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.97 PRKAR1B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.
Intellectual disability - microarray and sequencing v5.97 PRKAR1B Achchuthan Shanmugasundram Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.97 PRKAR1B Achchuthan Shanmugasundram Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v5.97 PRKAR1B Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.
Intellectual disability - microarray and sequencing v5.97 PRKAR1B Achchuthan Shanmugasundram Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v5.96 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability - microarray and sequencing v5.96 PRKAR1B Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1B were changed from Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680 to Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure
Intellectual disability - microarray and sequencing v5.96 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability - microarray and sequencing v5.96 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability - microarray and sequencing v5.97 PRKAR1B Achchuthan Shanmugasundram Tag Q2_23_promote_green tag was added to gene: PRKAR1B.
Intellectual disability - microarray and sequencing v5.97 PRKAR1B Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1B were changed from Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680 to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
Intellectual disability - microarray and sequencing v5.96 PRKAR1B Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1B were changed from Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680 to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
Intellectual disability - microarray and sequencing v5.96 PRKAR1B Achchuthan Shanmugasundram Phenotypes for gene: PRKAR1B were changed from Global developmental delay; Intellectual disability; Autism; Attention deficit hyperactivity disorder; Aggressive behavior; Abnormality of movement; Upslanted palpebral fissure to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
Intellectual disability - microarray and sequencing v5.95 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability - microarray and sequencing v5.95 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability - microarray and sequencing v5.96 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability - microarray and sequencing v5.95 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability - microarray and sequencing v5.95 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to 25414040; 33833410
Intellectual disability - microarray and sequencing v5.95 PRKAR1B Achchuthan Shanmugasundram Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
Intellectual disability - microarray and sequencing v5.94 PRKAR1B Achchuthan Shanmugasundram Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.94 PRKAR1B Achchuthan Shanmugasundram Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.94 PRKAR1B Achchuthan Shanmugasundram Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.94 PRKAR1B Achchuthan Shanmugasundram Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.94 PRKAR1B Achchuthan Shanmugasundram Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v5.93 PRKAR1B Achchuthan Shanmugasundram reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33833410; Phenotypes: Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.1496 PRKAR1B Zornitza Stark reviewed gene: PRKAR1B: Rating: GREEN; Mode of pathogenicity: None; Publications: 33833410; Phenotypes: Marbach-Schaaf neurodevelopmental syndrome MIM#619680; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability - microarray and sequencing v3.525 PRKAR1B Ivone Leong Tag watchlist tag was added to gene: PRKAR1B.
Intellectual disability - microarray and sequencing v3.525 PRKAR1B Ivone Leong Classified gene: PRKAR1B as Amber List (moderate evidence)
Intellectual disability - microarray and sequencing v3.525 PRKAR1B Ivone Leong Added comment: Comment on list classification: New gene added by Konstantinos Varvagiannis. Based on the provided evidence this gene has been given an Amber rating.
Intellectual disability - microarray and sequencing v3.525 PRKAR1B Ivone Leong Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Intellectual disability - microarray and sequencing v3.500 PRKAR1B Konstantinos Varvagiannis 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
Added comment: 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