Intellectual disability - microarray and sequencing
Gene: PRKAR1B
The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.Created: 11 Oct 2023, 9:34 a.m. | Last Modified: 11 Oct 2023, 9:34 a.m.
Panel Version: 5.286
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.Created: 3 May 2023, 5:45 p.m. | Last Modified: 3 May 2023, 5:45 p.m.
Panel Version: 5.98
Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.Created: 3 May 2023, 5:45 p.m. | Last Modified: 3 May 2023, 5:45 p.m.
Panel Version: 5.98
Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.Created: 3 May 2023, 5:44 p.m. | Last Modified: 3 May 2023, 5:44 p.m.
Panel Version: 5.98
Comment on list classification: There is sufficient evidence for this gene to be promoted to GREEN rating at the next GMS update.Created: 3 May 2023, 5:44 p.m. | Last Modified: 3 May 2023, 5:44 p.m.
Panel Version: 5.97
As reviewed by Zornitza Stark (Australian Genomics) and Konstantinos Varvagiannis, there are six unrelated individuals carrying heterozygous missense PRKAR1B variants. Three variants are reported in total and four patients carried the same variant p.Arg335Trp. All six patients presented with global developmental delay, autism spectrum disorder and apraxia/dyspraxia.
This gene has been associated with relevant phenotypes in OMIM (MIM #619680) and Gene2Phenotype (with 'moderate' rating in the DD panel).Created: 3 May 2023, 5:36 p.m. | Last Modified: 3 May 2023, 5:36 p.m.
Panel Version: 5.93
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
Publications
Manuscript now published PMID 33833410:
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: 3 Feb 2022, 9:48 p.m. | Last Modified: 3 Feb 2022, 9:48 p.m.
Panel Version: 3.1496
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Marbach-Schaaf neurodevelopmental syndrome MIM#619680
Publications
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
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: LiteratureCreated: 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
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
Tag watchlist was removed from gene: PRKAR1B. Tag Q2_23_promote_green was removed from gene: PRKAR1B.
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)
Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Gene: prkar1b has been classified as Amber List (Moderate Evidence).
Publications for gene: PRKAR1B were set to 25414040; 33833410
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
Publications for gene: PRKAR1B were set to 25414040; 33833410
Publications for gene: PRKAR1B were set to 25414040; 33833410
Tag Q2_23_promote_green tag was added to gene: PRKAR1B.
Phenotypes for gene: PRKAR1B were changed from Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680 to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
Phenotypes for gene: PRKAR1B were changed from Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680 to Marbach-Schaaf neurodevelopmental syndrome, OMIM:619680
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
Publications for gene: PRKAR1B were set to 25414040; 33833410
Publications for gene: PRKAR1B were set to 25414040; 33833410
Publications for gene: PRKAR1B were set to 25414040; 33833410
Publications for gene: PRKAR1B were set to 25414040; 33833410
Publications for gene: PRKAR1B were set to 25414040; 33833410
Publications for gene: PRKAR1B were set to https://doi.org/10.1101/2020.09.10.20190314; 25414040
Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for gene: PRKAR1B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Tag watchlist tag was added to gene: PRKAR1B.
Gene: prkar1b has been classified as Amber List (Moderate Evidence).
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