PIK3R1

Inheritance Pattern: AR

Disease ID:MONDO:0014083

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:1060136

Submitter: ClinGen

*PIK3R1* was first reported in relation to autosomal dominant SHORT syndrome in 2013 (PMIDs: 23810382, 23810379, 23810378) and with immunodeficiency 36 in 2014 (PMID: 25133428). Subsequent publications report patients presenting with overlapping features of both conditions, supporting the lumping of these entities into a single disease spectrum referred to as *PIK3R1*-related immunodeficiency and SHORT syndrome (PMIDs: 27076228, 28302518). SHORT syndrome is a rare disorder characterized by short stature, hyperextensibility of joints and/or hernias, ocular depression, Rieger anomaly and delays of tooth eruption, which provide the condition's acronym. In addition, there is a recognizable facial gestalt, insulin resistance, nephrocalcinosis and hearing deficits. Speech development is often delayed but cognition is usually normal. Also known as activated PI3K-δ syndrome 2 (APDS2), immunodeficiency 36 is a primary immunodeficiency with a highly heterogeneous clinical phenotype. This disease is characterized primarily by recurrent respiratory tract infections, lymphoproliferation, and antibody deficiency. Other features include growth retardation, mild neurodevelopmental delay, and autoimmunity. At least 7 unique *PIK3R1* variants (splice donor and splice acceptor) have been reported in humans with APDS2 or APDS2 plus SHORT syndrome and at least 7 additional (missense, frameshift, and nonsense) variants have been reported in SHORT syndrome patients, predominately in the C-terminal SH2 domain. All reported variants associated with APDS2 or SHORT syndrome produce altered protein products, rather than leading to loss of protein expression, with pathogenicity arising from disruption of specific functional domains. *PIK3R1* encodes the p85α subunit, which regulates the catalytic subunit p110δ (encoded by *PIK3CD)* for the main class I PI3K in leukocytes. This interaction occurs via the inter-SH2 domain, which is essential for heterodimer formation and inhibition of PI3K activity in the basal state. Mutations that disrupt this domain impair binding and heterodimer formation. As a result, the p110δ catalytic subunit becomes deregulated and overactivated in lymphocytes, leading to increased PI3K signaling-dependent processes. The common exon 10 skipping variant results in an in-frame deletion of amino acids 434–475, which is not subject to nonsense-mediated decay. This deletion disrupts the inter-SH2 domain and produces a truncated protein that abolishing p85α-mediated inhibition of p110δ leading to hyperactivation of PI3K signaling. Summary of Case Level Data: Variants in this gene have been reported in at least 19 probands in at least 5 publications (PMIDs: 23810378, 23810382, 25133428, 25488983, 27076228, 27221134, 28302518). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. EXPERIMENTAL EVIDENCE: This gene-disease association is supported by its function in regulation of immunity, growth, and metabolism as part of the PI3K pathway (PMID: 16847462) where it interacts with *PIK3CD* (PMID: 9113989). As well as the functional alteration studies in patient cells (PMID: 25133428, PMID:25488983, PMID: 23810379). Lucas et al. (2014) found that heterozygous *PIK3R1* mutations promote pathological, constitutive hyperactivation of PI3K and AKT, which leads to activation of the mTORC1 complex and phosphoinhibition of GSK3α/β and FOXO1/3. However, insulin stimulation of the PI3K pathway was reduced. Additionally, a knockout mouse model (PMID: 11062485) supports the role of *PIK3R1* in related pathways and a knockin model (PMID: 26974159) recapitulated features of SHORT syndrome. In summary, there is definitive evidence to support the relationship between *PIK3R1* and autosomal dominant immunodeficiency and SHORT syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. Of note, *PIK3R1* has also been associated with autosomal recessive Agammaglobulinemia 7. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism (altered protein versus loss of protein), inheritance pattern, and phenotypic variability. Agammaglobulinemia 7 (OMIM: 615214) has been curated separately.

Inheritance Pattern: AD

Disease ID:MONDO:0011096

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0010026

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:1060136

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014453

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014453

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0010026

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0010026

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0014083

Submitter: ClinGen

PIK3R1 was first reported in relation to autosomal recessive, Agammaglobulinemia 7 in 1995 (M de la Morena et al., PMID: 7705412). Agammaglobulinemia is a primary immunodeficiency characterized by profoundly low or absent serum antibodies, and low or absent circulating B cells due to arrest of B cell development at very early stage. Autosomal recessive inheritance of agammaglobulinemia shares a phenotype similar to that of the X-linked form but has only been observed in a small number of families (Ferrari et al., 2007). At least 2 unique variants (nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. PIK3R1 has been noted to be associated with the following disease entities: autosomal recessive Agammaglobulinemia 7, autosomal dominant Immunodeficiency 36, and autosomal dominant SHORT syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been Split into multiple disease entities, Agammaglobulinemia 7 (OMIM: 615214), Immunodeficiency 36 (OMIM: 616005), and SHORT syndrome (OMIM: 269880). The split curation for Immunodeficiency 36 (OMIM: 616005) and SHORT syndrome (OMIM: 269880) have been curated separately. Summary of Case Level Data (3 points): Variants in this gene have been reported in at least 2 probands in 3 publications (PMID:7705412, PMID: 22351933, and PMID: 29178053). This gene-disease association is supported by animal models and expression studies demonstrating the critical function of PI3K p85α gene products in B cell development, proliferation, and survival (Fruman et al., PMID:9888855). P85α deficient mice showed reduced numbers of peripheral mature B cells and decreased serum immunoglobulin. The B cells that developed had diminished proliferative responses to antibody to immunoglobulin M, antibody to CD40, and lipopolysaccharide stimulation. In contrast, T cell development and proliferation was normal. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Antibody deficiencies GCEP on the meeting date May 18, 2021 (SOP Version 8).

Inheritance Pattern: AD

Disease ID:MONDO:0010026

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0010026

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014083

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014083

Submitter: G2P