Submission Details

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). Later publications report patients presenting with both phenotypes favoring the lumping of these two disease entities (PMIDs:27076228 , 28302518) as PIK3R1-related immunodeficiency and SHORT syndrome. SHORT syndrome is a rare disorder characterised 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 recognisable 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), immunodeficieny 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. Evidence supporting this gene-disease relationship includes case-level data and experimental data. PIK3R1 encodes p85α which regulates the catalytic subunit p110δ (encoded by PIK3CD) for the main class I PI3K in leukocytes. The first one binds to the second one by the inter-SH2 domain. Therefore, mutations that lead to the loss of this domain of the protein impair its binding ability and the formation of heterodimers. The consequence in lymphocytes is that the p110δ catalytic subunit is deregulated and over-activated, resulting in an increase of the PI3K signaling-dependent processes. 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, inheritance pattern, and phenotypic variability. Agammaglobulinemia 7 (OMIM: 615214) has been curated separately.

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.