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COVID-19 research v0.347 CXADR Alison Coffey commented on gene: CXADR: Evidence Summary from Illumina curation team: The coxsackie and adenovirus receptor (CXADR or CAR), also known as CAR-like membrane protein (CLMP), was first identified as a high affinity receptor for adenovirus serotypes 2 and 5 and coxsackie viruses group B. CXADR is developmentally regulated and plays an important role in cardiac development. The protein is a transmembrane receptor and plays a key role in controlling adhesion between adjacent epithelial cells. It is also implicated in controlling both recruitment of immune cells and in tumorigenesis (Zapater et al. 2017). Vehik et al. (2018) concluded that a SNP within the CXADR region is associated with islet autoimmunity. In response to exogenous TNF?, CAR promotes transmigration of leukocytes both in vitro and in vivo. suggesting that CAR may be an important receptor in the control of inflammation. As neutrophils and T cells play a role in host immunity, these data suggest that CAR may be ideally positioned to modulate the immune response from the epithelial or endothelial cell compartments. (Morton et al 2016). CAR expression and infectivity with adenovirus (Ad) are increased in cystic fibrosis airway epithelial cells (Sharma et al. 2017).
COVID-19 research v0.347 BANF1 Alison Coffey commented on gene: BANF1: Evidence Summary from Illumina curation team: BANF1 is an abundant, highly conserved DNA binding protein involved in multiple pathways including mitosis, nuclear assembly, viral infection, chromatin and gene regulation and the DNA damage response. It is also essential for early development in metazoans and relevant to human physiology. Variants in the gene are associated with Nestor-Guillermo progeria syndrome (OMIM #614008). Different viral infections can lead to changes in the subcellular distribution of BANF1 infections with a B1 kinase-deficient vaccinia virus cause re-localization at sites of viral DNA accumulation in the cytoplasm, while no change in localization is found during infection with wild-type vaccinia. By contrast, in cells infected with Herpes Simplex Virus Type-1 (HSV-1) BAF localizes to the nucleus, where HSV-1 viral DNA replicates. BANF1 actively protects the genome by intercepting foreign DNA. This protective function is exploited by retroviruses for inhibiting self-destructing autointegration of retroviral DNA, thereby promoting integration of viral DNA into the host chromosome. However, with other viruses, including the poxvirus vaccinia and HSV-1, BANF1 has an antiviral activity by blocking viral DNA replication (PMID 2607214: Jamin et al. 2015).
COVID-19 research v0.347 VPS33A Alison Coffey commented on gene: VPS33A: Evidence Summary from Illumina curation team: VPS33A is a member of the Sec1/Munc18-related (SM) protein family and a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes (Vasilev et al. 2020). Both complexes are heterohexamers and share four subunits. VPS33A, VPS11, VPS16 and VPS18, involved in endolysosomal pathway. Deficiency of VPS33A was shown to affect susceptibility to certain viruses in cell culture, including Ebola and Marburg viruses (Carette et al. 2011), however no human studies confirming this association were identified.
COVID-19 research v0.347 TLR7 Alison Coffey commented on gene: TLR7: Evidence Summary from Illumina curation team: The TLR7 gene encodes for toll -like receptor 7 protein, an endosomal receptor that plays a key role in innate and adaptive immunity. Toll-like receptors are pattern recognition receptors, which control host immune response against pathogens through recognition of molecular signatures. TLR7 recognizes uridine-containing single strand RNAs (ssRNAs) of viral origin or guanosine analog (reviewed by Freund et al. 2019). Tlr7 deficient mice show an increased susceptibility to West Nile Virus (Town et al. (2009) and recently, Mukherjee et al. (2019) identified TLR7 polymorphisms associated with susceptibility to viral infections in an East Asian population Mukherjee et al. (2019).
COVID-19 research v0.347 PDGFRA Alison Coffey commented on gene: PDGFRA: Evidence Summary from Illumina curation team: The PDGFRA gene encodes the platelet-derived growth factor receptor alpha protein, a tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC, binding of which leads to the activation of several signaling cascades, and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. PDGFRA has been demonstrated to be a critical receptor for human cytomegalovirus infection (PMID 18701889: Soroceanu et al. 2008). Di Pasquale et al. (2003) (PMID 14502277). also confirmed the role of PDGFRA and PDGFRB as receptors for adeno-associated virus type 5 (AAV-5). PMID 18701889: Soroceanu et al. 2008 - PDGFRA is specifically phosphorylated by both laboratory and clinical isolates of human cytomegalovirus (CMV) in various human cell types, resulting in activation of the phosphoinositide-3-kinase signaling pathway. Cells in which PDGFRA was genetically deleted or functionally blocked were nonpermissive to human CMV entry, viral gene expression, or infectious virus production. Reintroducing the human PDGFRA gene into knockout cells restored susceptibility to viral entry and essential viral gene expression. Blockade of receptor function with a humanized PDGFRA blocking antibody (IMC-3G3) or targeted inhibition of its kinase activity with a small molecule (Gleevec) completely inhibited human CMV viral internalization and gene expression in human epithelial, endothelial, and fibroblast cells. Viral entry in cells harboring endogenous PDGFRA was competitively inhibited by pretreatment with PDGF-AA. It was demonstrated that human CMV glycoprotein B directly interacts with PDGFRA, resulting in receptor tyrosine phosphorylation, and that glycoprotein B neutralizing antibodies inhibit human CMV-induced PDGFRA phosphorylation. The authors concluded that PDGFRA is a critical receptor required for human CMV infection, and thus a target for novel antiviral therapies.
COVID-19 research v0.347 NLRP6 Alison Coffey commented on gene: NLRP6: Evidence Summary from Illumina curation team: The NLRP6 gene encoding the NOD-like receptor family pyrin domain containing 6 is a member of the NLR family of proteins, that is highly expressed within the intestine and liver. The NLRP6 inflammasome plays an established role in the regulation of inflammation and host defence against microbes. Wang et al. (2015) demonstrated that NLRP6 also regulates intestinal antiviral innate immunity. NLRP6 knockout mice show increased susceptibility to infection from the single stranded RNA viruses; encephalomyocarditis virus and murine norovirus 1(MNV-1). Nlrp6 binds viral RNA via the RNA helicase Dhx15, the complex triggers the induction of type I/III interferons (IFNs) through the mitochondrial antiviral signaling protein (MAVS). Type I/III IFNs stimulate the expression of antiviral IFN-stimulated genes (ISGs), including Nlrp6 itself (Wang et al. 2015).
COVID-19 research v0.347 MX2 Alison Coffey commented on gene: MX2: Evidence Summary from Illumina curation team: MX2, also known as MXB is an interferon-induced dynamin like GTPAse with antiviral activity, which has been shown to affect the nuclear uptake and/or stability of the HIV-1 replication complex and the subsequent chromosomal integration of the proviral DNA (Goujon et al. 2013, Liu et al. 2015). However, resistance of several HIV strains to MX2-driven inhibition has been reported (Liu et al. 2015). Inhibition of other viruses, including HCV, Japanese encephalitis virus and Dengue virus of the Flaviviridae family as well as simian immunodeficiency virus and Herpesviruses has been reported (Goujon et al. 2013, Yi et al. 2019). In contrast to MX1, MX2 does not appear to be involved in regulation of several other viral infections, including influenza and Zika virus (Melen et al. 1996; Yi et al. 2019). Additionally, MX2 may be involved in nucleocytoplasmic transport and bears a nuclear localisation signal that appears essential for HCV inhibition (Melen et al. 1996; King et al. 2004, Yi et al. 2019). Of note, MX2 was described as an interferon response marker gene in preprint studies investigating expression profiles and related mechanisms in SARS-CoV-2 infection (Fagone et al. 2020, Li et al. 2020). Overall, inhibition of viral infection by MX2 appears to be virus type- and strain-specific, and some viruses potentially have developed mechanisms to resist MX2 function. No reports of any SNP associations of MX2 with viral susceptibility in humans have been identified.
COVID-19 research v0.347 KIAA0319L Alison Coffey commented on gene: KIAA0319L: Evidence Summary from Illumina curation team: KIAA0319L, also known as AAVR or AAVRL, encodes the KIAA0319 like protein, a type-I transmembrane protein which acts as an essential receptor for adeno-associated virus (AAV) and is involved in adeno-associated virus infection through endocytosis system (PMID 26814968: Pillay et al. 2016). Genetic ablation of AAVR renders a wide range of mammalian cell types highly resistant to AAV infection. Adeno-associated virus vectors are widely used in virus-based gene therapy because of their broad tissue tropism, non-pathogenic nature and low immunogenicity. PMID 26814968: Pillay et al. (2016) - used a haploid genetic screen to identify the type I transmembrane protein KIAA0319L as an essential receptor that mediates AAV entry and renamed this protein the AAV receptor (AAVR). The function of AAVR was confirmed by using CRISPRCas9 to knock out the receptor and by using anti-AAVR blocking antibodies; both treatments rendered cells highly resistant to AAV infection with several serotypes, including AAV2, which is the most commonly used serotype for gene therapy in clinical trials. Finally, Aavr knockout mice were more resistant to AAV-mediated gene therapy than mice that expressed AAVR. PMID 28679762: Pillay et al. (2017) - Further defines AAV-AAVR interactions, genetically and biochemically.
COVID-19 research v0.347 ITGB3 Alison Coffey commented on gene: ITGB3: Evidence Summary from Illumina curation team: ITGB3 encodes integrin beta-3 (CD61), a member of the integrin family of transmembrane proteins. Integrins are heterodimeric transmembrane proteins involved in cell adhesion and migration, and organization of the cytoskeleton. Integrin b3 has been shown to act as a coreceptor for many viruses including Herpes virus 8/HHV-8, Coxsackievirus A9, Hantaan virus, Cytomegalovirus/HHV-5, and West Nile virus (Gavrilovskaya et al. 2008; Roivainen et al. 1994; Garrigues et al 2008; Schmidt et al. 2013; Wang et al. 2005). Viruses such as the arena virus LASV and Dengue virus may manipulate and increase the expression level of ITGB3 (Zapata et al, 2013; In vitro exposure of human PBMC to a pathogenic arenavirus (LASV) increases the expression of ITGB3 (Zapata et al, 2013; Noisakran et al, 2012). Valdebenito et al. 2019 recently reported a genetic single-nucleotide polymorphism associated with infection susceptibility to Andes virus in a Chilean population.
COVID-19 research v0.347 ITGAV Alison Coffey commented on gene: ITGAV: Evidence Summary from Illumina curation team: ITGAV or ALPHA-V is a component of the integrin family of transmembrane proteins. Integrins primary biological functions involve cell adhesion and migration, organization of the cytoskeleton, and other cellular functions. Alpha-V-containing integrins combine an alpha-V subunit with 1 of 5 beta subunits. Several families of viruses are known to use alpha-V-containing integrins for cell attachment and entry, including human adenovirus type 2/5, human CMV, HIV-1, EBV, rotavirus, Coxsackievirus, and Ebola virus (Hussein et al. 2015; LaFoya et al. 2018).
COVID-19 research v0.347 ILF3 Alison Coffey commented on gene: ILF3: Evidence Summary from Illumina curation team: The ILF3 gene encodes two alternatively spliced and ubiquitously expressed RNA binding protein isoforms, NF110 and NF90. NF110 and NF90 have been shown to interact with viral RNAs and proteins to inhibit the replication of a number of viruses, including PV-RIPO, a chimeric poliovirus and human rhinovirus; HIV-1, and vesicular stomatitis virus (VSV) (reviewed Castella et al. 2015). Conversely, NF110 and NF90 have also been associated with the enhancement of viral replication in the case of DNA hepatitis B virus (HBV), ssRNA viruses from the Flaviviridae family, hepatitis C virus and influenza B (FLUBV) (reviewed Castella et al. 2015; Patzina et al, 2017). Recently, Watson et al (2020) demonstrated a role for the ILF3 isoforms in enhancing the translation of IFNB1 and ISGs in response to a viral infection. Depletion of NF90/NF110 from HeLa cells using siRNA resulted in an impaired antiviral activity with a reduction in the expression of ISG proteins and conditioned medium generated in ILF3-depleted cells conferred less resistance to Echovirus 7 infection. The specific depletion of NF110 was shown to cause a decrease in the association of IFNB1 mRNA with the polysomal fractions in poly(I:C) stimulated conditions (Watson et al. 2020).
COVID-19 research v0.347 IL9 Alison Coffey commented on gene: IL9: Evidence Summary from Illumina curation team: IL9 encodes interleukin 9, which is a stimulatory cytokine that regulates inflammatory immunity (Goswami and Kaplan 2011). It has been demonstrated that high levels of IL-9 are present in nasopharyngeal aspirate of infants with disease of the respiratory tract caused by the Human respiratory syncytial virus (RSV) (Semple et al. 2007). Studies conducted on mice showed that that the severity of lung pathology correlates with IL-9 cytokine production and that Th9 cells, which produce IL-9, play an important role in the development of airway eosinophilia and bronchial hyperresponsiveness (Dodd et al. 2009; Saeki et al. 2016). IL9 polymorphisms have also been linked to sex-restricted differences in lung function, allergen sensitization, IgE levels, and the severity of respiratory syncytial virus infection (Schuurhof et al. 2010; Aschard et al. 2009).
COVID-19 research v0.347 IL3 Alison Coffey commented on gene: IL3: Evidence Summary from Illumina curation team: IL3 encodes a growth-promoting cytokine called interleukin 3, which is a member of the beta common cytokine family. IL-3 (Dougan et al. 2019). IL-3 acts to regulate inflammation induced by pathogens as well as in autoimmune disease and cancer. T cell production of IL-3 during inflammation plays a role in the activation of plasmacytoid dendritic cells during viral infection. IL-3 has also been suggested to play a host-protective role against herpes simplex virus (HSV) infection (Chan et al. 1990).
COVID-19 research v0.347 IFNA1 Alison Coffey commented on gene: IFNA1: Evidence Summary from Illumina curation team: IFNA1 encodes IFN alpha, and belongs to the family of type I IFNs which bind to and activate the IFNAR receptor complex. Type I Interferons (IFN-I) mediate numerous immune interactions during viral infections, they establish an antiviral state as well as invoke and regulate innate and adaptive immune cells that eliminate infection (Lukele et al. 2019, review; Wang et al.2019 review).
COVID-19 research v0.347 HAVCR1 Alison Coffey commented on gene: HAVCR1: Evidence Summary from Illumina curation team: HAVCR1 encodes the human hepatitis A virus (HAV) cellular receptor 1 (CD365, TIM1, KIM1) a phospholipid receptor which is expressed in mucosal epthelium from a range of tissues including trachea, conjunctiva and cornea (Kondratowicz et al. 2011). HAVCR1 acts as a cell receptor or entry factor for a number of enveloped viruses including Hepatitis A, Ebolavirus, Marberg virus and Dengue virus (Kondratowicz et al. 2011; Costfreda et al. 2018; Meertens et al. 2012).
COVID-19 research v0.347 GPR183 Alison Coffey commented on gene: GPR183: Evidence Summary from Illumina curation team: The GPR183 gene has been shown to be upregulated following infection with Epstein-Barr virus and aids in leukocyte migration into airways in response to allergens (Shen et al. 2017). GPR183 knockout mice exhibit enhanced pro-inflammatory cytokine release following an inflammation-inducing stimulus (Ruthiwska et al. 2018). In addition, recent work that has not yet been peer-reviewed found GPR183 expression on macrophages in severe Covid 19 patients (Liao et al.; https://doi.org/10.1101/2020.02.23.20026690). EBV seropositivity was also associated with fever and increased inflammation in Covid 19 patients in non-peer-reviewed work by Chen et al. (10.21203/rs.3.rs-21580/v1).
COVID-19 research v0.347 GPATCH3 Alison Coffey commented on gene: GPATCH3: Evidence Summary from Illumina curation team: Nie et al. (2017) showed that GPATCH3 is a negative regulator of the innate immune response to RNA viruses. Reduction of GPATCH3 levels using shRNA resulted in enhanced induction and transcription of SeV (ssRNA virus) downstream antiviral genes such as IFNB1, in multiple cell lines compared to controls. Similar effects were not observed in cells infected with DNA viruses, HCMV or HSV120. Coimmunoprecipitation and colocalisation experiments indicated that GPATCH3 negative regulation is mediated through a direct interaction of mitochondrial localised, MAVS (VISA). MAVS plays an established role in the innate antiviral immune responses against to RNA viruses.
COVID-19 research v0.347 GNAQ Alison Coffey commented on gene: GNAQ: Evidence Summary from Illumina curation team: The GNAQ gene encodes the Gq protein alpha subunit and belongs to the Gq/11 subfamily of heterotrimeric G proteins. GNAQ is ubiquitously expressed in mammalian cells and couples a wide variety of receptors to channel proteins, enzymes, and other effector molecules. Wang et al. (2019) found that Gnaq expression was downregulated during viral infection and that Gnaq siRNA transfection of host cells protected against infection from vesicular stomatitis virus (VSV) and HSV type 1 infection. Viral replication was also reduced in Gnaq deficient macrophages in cell culture and Gnaq-deficient mice were more resistant than wildtype mice to VSV infection. Further cell culture experiments showed that Gnaq modulated its antiviral response through the canonical PLC-b/Ca2+ signalling (Wang et al. 2019). PMID: 31324725 Wang et al. (2019) - Wang et al. demonstrated that GNAQ negatively regulates the antiviral innate immune responses in a calcineurin-dependent manner. Viral infection downregulates GNAQ expression in cell culture. mRNA expression levels were measured upon infection with VSV in mouse PEMs, BMMs,the fibroblast line L929 and the macrophage mouse line RAW264.7. Fig1. GNAQ negatively regulates host defence against viruses. Gnaq-specific siRNA knockdown reduced VSV infection in PEMS, overexpression of GNAQ in HEK293 cells increased VSV infection (Fig 2). PEMS and BMMs from myeloid cellspecific Gnaq-deficient mice showed reduced replication of VSV and HSV1 compared to WT. VSV replication and titers in the liver, spleen, and lung of Gnaq-deficient mice were all significantly lower than wt litter mates. Gnaq deficiency increases host resistance to viral infection (Fig 3). IFN-b (both mRNA and protein) was significantly enhanced in Gnaq-knockdown PEMs, Poly I;C (mimicking RNA viral infection), VSV infection and HSV-1 infection enhanced IgnBeta production in Gnaq-knockdown PEMs. In cell lines and in vivo, GNAQ negatively regulates IFN-beta production (Fig 4). GNAQ modulates antiviral innate immune responses through canonical PLC-b/Ca2+ signalling. Chemical inhibitors of the pathway reduced cell resistance to infection (Fig 5).
COVID-19 research v0.347 CLDN9 Alison Coffey commented on gene: CLDN9: Evidence Summary from Illumina curation team: CLDN9 gene encodes for the Claudin-9 protein. The claudin family constitutes a large group of four- transmembrane domain proteins that are essential for the formation of tight junctions responsible for the control of paracellular transport. Studies have demonstrated that CLDN9 and CLDN6 mediate the entry of the hepatitis C virus (HCV) into both hepatic and non-hepatic cell lines (Zheng et al. 2007) however, HCV infection is not dependent on the presence of CLDN9 (Fofana et al. 2013).
COVID-19 research v0.347 CLDN6 Alison Coffey commented on gene: CLDN6: Evidence Summary from Illumina curation team: CLDN6 gene encodes the Claudin-6 protein. The claudin family constitutes of a large group of four- transmembrane domain proteins that are essential for the formation of tight junctions responsible for the control of paracellular transport. Studies have demonstrated that CLDN6 and CLDN9 mediate the entry of the Hepatitis C virus (HCV) into both liver and non-liver cells (Zheng et al. 2007) however, HCV infection is not dependent on the presence of CLDN6 (Haid et al. 2014; Fofana et al. 2013).
COVID-19 research v0.347 CDKN1B Alison Coffey commented on gene: CDKN1B: Evidence Summary from Illumina curation team: CDKN1B, or p27(KIP1), is a cyclin-dependent kinase inhibitor that blocks the cell cycle in the G0/G1 phase upon differentiation signals or cellular insult (OMIM 600778). Karlas et al. (2010) identified p27/KIP as an inhibitor of influenza A viral replication in a genomewide RNA interference screen. The result was validated in the p27/KIP knockout mouse model, the viral load within these mice was significantly reduced two days after infection compared to control mice.
COVID-19 research v0.347 CD207 Alison Coffey commented on gene: CD207: Evidence Summary from Illumina curation team: The CD207 gene encodes the CD207 protein, also known as langerin, a cell surface C-type lectin expressed on Langerhans cells, the immature dendritic cells of the epidermis and mucosa. CD207 has a role as a pattern recognition receptor for a number of viruses including the Influenza A Virus (Ng et al. 2016), HIV-1 and HSV (reviewed by de Jong et al. 2010) and measles virus (van der Vlist et al. 2011).
COVID-19 research v0.347 CCR7 Alison Coffey commented on gene: CCR7: Evidence Summary from Illumina curation team: The CCR7 gene encodes the C-C chemokine receptor 7, a chemokine receptor which is a member of the G protein-coupled receptor superfamily. CCR7 plays an important role in the homing of central memory and nave T cells to peripheral lymphoid organs. The binding of CCR7 ligands CCL19 and CCL21 during viral infection promotes activation and differentiation of CCR7 expressing cells, as well as changes in their migration properties to modulate the immune response (reviewed Yan et al. 2019). Some viral proteins target CCR7 and reduce its expression during viral infection (reviewed Yan et al. 2019), for example, the HIV-1 accessory protein, Vpu, interacts directly with CCR7 to cause its retention within the trans Golgi network of primary CD4+ T cells (Ramirez et al. 2014).
COVID-19 research v0.347 ATG5 Alison Coffey commented on gene: ATG5: Evidence Summary from Illumina curation team: The ATG5 gene encodes a core autophagy protein which forms a complex with ATG12 and ATG16L that is important for autophagophore elongation. Autophagy plays a key antiviral role in various human infections by modulating different aspects of the immune response (Reviewed Tao et al. 2020; Ahmed et al.2018). ATG5 may play a role in cytokine regulation, in vitro, ATG5 depleted primary human blood macrophages produced lower levels of CXCL10 and IFNa when infected with influenza A virus (Law et al. 2007). ATG5 deficient mice also show reduced Ifn and Il22 secretion when infected with the single stranded RNA vesicular stomatitis virus (VSV) (Lee et al. 2007). Using a mouse model with a conditional depletion of ATG5 within dendritic cells, Lee et al. 2010 showed that ATG5 is required for antigen presentation by dendritic cells, as a result of reduced MHC-II antigen presentation, these mice, when intradermally injected with HSV-1, showed significantly lower IFNgamma production by CD4+ T cells. (Lee et al., 2010). The ATG5 complex is targeted by some viruses to enhance infection, for example, the foot and mouth disease virus (FMDV) targets the ATG5-ATG12 complex for degradation through its viral protein 3Cpro, similarly, depletion of ATG5 and ATG12 in vitro, by siRNA increased susceptibility to FMDV infection by reducing activation of the NF-?B and IRF3 pathways (Fan et al 2017).
COVID-19 research v0.347 ATG16L1 Alison Coffey commented on gene: ATG16L1: Evidence Summary from Illumina curation team: The ATG16L gene encodes a core autophagy protein which forms a complex with ATG5 and ATG12 that is important for autophagophore elongation (Lavoie et al. 2019). Autophagy plays a key antiviral role in various human infections by modulating different aspects of the immune response (Reviewed Tao et al. 2020; Ahmed et al. 2018). The ATG16L complex is also targeted by some viruses to enhance infection. The Zika virus protease, targets ATG16L, dramatically depleting its levels during Zika virus infection (Hill et al. 2018). Conversely, Hepatitis B virus (HBV), an enveloped pararetrovirus, stimulates autophagy to favor its production. In vitro, RNA interference-mediated silencing of Atg16L1 interfered with viral core/nucleocapsid (NC) formation and stability, strongly diminishing virus replication (Fletcher et al. 2018).
COVID-19 research v0.347 AIM2 Alison Coffey commented on gene: AIM2: Evidence summary from Illumina curation team: AIM2 performs an established role within the innate immune system as a pattern recognition receptor which senses microbial dsDNA. In vitro experiments have shown that AIM2 recognises cytosolic dsDNA from a number of viruses and consequently drives pyroptosis through formation of an inflammasome complex (Sharma et al. 2019). Aim2-deficient mice show an attenuated immune response upon infection with mCNV when compared to wildtype mice (Rathinam et al. 2010). PMID: 31372985 Sharma et al. 2019 (Review) AIM2 encodes a pattern recognition receptor which senses microbial dsDNA. In vitro experiments show AIM2 recognises cytosolic dsDNA from a number of viruses and consequently drives pyroptosis through formation of an inflammasome complex. AIM2 expression is upregulated in response to infection by RNA viruses and contributes to secretion of IL-1beta, the mechanism for the recognition of RNA viruses is unclear. Table 1 summarises the list of in vitro AIM2 virus studies. PMID: 20351692: Rathinam et al. 2010 In vivo, Aim2-deficient mice, Aim2- infected with mCMV have reduced IL-18 concentrations in the serum compared to wildtype mice, and severely attenuated IFN-? production by NK cells, events, which are critical for the early control of viral replication (Figure 7b, d, e) The spleen of infected Aim2-/- mice demonstrated elevated viral titre compared to the wildtype (Fig 7h, i). PMID: 26590313 Schattgen et al. 2018 Aim2 knockout mice, infected with influenza A virus (RNA virus) showed an exaggerated response to immune response. Authors suggest that host DNA released from damaged cells during IAV infection and sensed by AIM2 leads to limitation of immune mediated damage to infected tissues.
COVID-19 research v0.346 CXCR3 Catherine Snow Publications for gene: CXCR3 were set to 27412416; 19039768; 30109979; 26318079; 30467622
COVID-19 research v0.345 CXCR3 Catherine Snow Publications for gene: CXCR3 were set to
COVID-19 research v0.344 CXCR3 Catherine Snow reviewed gene: CXCR3: Rating: AMBER; Mode of pathogenicity: None; Publications: 27412416, 19039768, 30109979, 26318079, 30467622; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v0.344 ATG16L1 Rebecca Foulger Publications for gene: ATG16L1 were set to
COVID-19 research v0.343 ATG16L1 Rebecca Foulger Classified gene: ATG16L1 as Amber List (moderate evidence)
COVID-19 research v0.343 ATG16L1 Rebecca Foulger Gene: atg16l1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.342 ATG16L1 Rebecca Foulger Classified gene: ATG16L1 as Red List (low evidence)
COVID-19 research v0.342 ATG16L1 Rebecca Foulger Added comment: Comment on list classification: Gene was originally added to panel as Red following initial triage by Illumina curation team (Alison Coffey and Julie Taylor). Updated rating to Amber to match revised Illumina review after literature curation.
COVID-19 research v0.342 ATG16L1 Rebecca Foulger Gene: atg16l1 has been classified as Red List (Low Evidence).
COVID-19 research v0.341 IRF1 Julie Taylor reviewed gene: IRF1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31155227, 31156620, 24719409, 21478870, 80092222; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 IDE Alison Coffey reviewed gene: IDE: Rating: AMBER; Mode of pathogenicity: ; Publications: 17055432, 20593027, 28388673; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 HDAC6 Alison Coffey reviewed gene: HDAC6: Rating: GREEN; Mode of pathogenicity: ; Publications: 27959772, 31736889, 26746851, 25482409; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 DEFA1 Alison Coffey reviewed gene: DEFA1: Rating: AMBER; Mode of pathogenicity: ; Publications: 32457744; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 DAG1 Alison Coffey reviewed gene: DAG1: Rating: GREEN; Mode of pathogenicity: ; Publications: 16254364, 19324387, 17360738, 21185048:15857984; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CXADR Alison Coffey reviewed gene: CXADR: Rating: AMBER; Mode of pathogenicity: ; Publications: 28545889, 31792456, 27527752, 27193388; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 BECN1 Alison Coffey reviewed gene: BECN1: Rating: AMBER; Mode of pathogenicity: ; Publications: 32265919, 19635843, 18248095, 18005679; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 BANF1 Alison Coffey reviewed gene: BANF1: Rating: RED; Mode of pathogenicity: ; Publications: 2607214; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CXCL8 Alison Coffey reviewed gene: CXCL8: Rating: GREEN; Mode of pathogenicity: ; Publications: 3244677, 32161940, 15585888; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 VPS33A Alison Coffey reviewed gene: VPS33A: Rating: RED; Mode of pathogenicity: ; Publications: 21866103, 31936524; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 VPS11 Alison Coffey reviewed gene: VPS11: Rating: RED; Mode of pathogenicity: ; Publications: 21866103, 25375324, 26953343, 26958914; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 TLR7 Alison Coffey reviewed gene: TLR7: Rating: GREEN; Mode of pathogenicity: ; Publications: 19200759, 31481269, 29964062, 30699960; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 RNASEL Alison Coffey reviewed gene: RNASEL: Rating: GREEN; Mode of pathogenicity: ; Publications: 27595182, 16235172, 20479874, 9351818, 31156620, 22356654; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 PVR Alison Coffey reviewed gene: PVR: Rating: AMBER; Mode of pathogenicity: ; Publications: 28870470, 25113908, 19815499, 12943679, 17621371, 28800489, 2597248; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 PTX3 Alison Coffey reviewed gene: PTX3: Rating: AMBER; Mode of pathogenicity: ; Publications: 31031772, 18292565, 25695775, 18292565, 19968561; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 PDGFRA Alison Coffey reviewed gene: PDGFRA: Rating: AMBER; Mode of pathogenicity: ; Publications: 18701889, 14502277; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 NPC1 Alison Coffey reviewed gene: NPC1: Rating: AMBER; Mode of pathogenicity: ; Publications: 21866103, 2186610, 26771495, 27238017; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 NLRP6 Alison Coffey reviewed gene: NLRP6: Rating: AMBER; Mode of pathogenicity: ; Publications: 26494172, 32386845 ; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 NECTIN1 Alison Coffey reviewed gene: NECTIN1: Rating: AMBER; Mode of pathogenicity: ; Publications: 1175687, 12072525, 19805039; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 MX2 Alison Coffey reviewed gene: MX2: Rating: AMBER; Mode of pathogenicity: ; Publications: 24048477, 25571928, 30333168, 8798556, 15184662, 32345362 ; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 MIR155 Alison Coffey reviewed gene: MIR155: Rating: AMBER; Mode of pathogenicity: ; Publications: 32233818, 217121651, 1746328969, 20852130, 28139244, 23686237, 26072128, 32308197, 23601686, 23275599, 24516198; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 KLF2 Alison Coffey reviewed gene: KLF2: Rating: GREEN; Mode of pathogenicity: ; Publications: 17141159, 19592277, 22988032, 29125549, 27855271; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 KIAA0319L Alison Coffey reviewed gene: KIAA0319L: Rating: GREEN; Mode of pathogenicity: ; Publications: 26814968, 28679762; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 ITGB3 Alison Coffey reviewed gene: ITGB3: Rating: GREEN; Mode of pathogenicity: ; Publications: 9618541, 7519807, 18045938, 23658209, 15834425, 22987294, 24069471, 30791508; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 ITGAV Alison Coffey reviewed gene: ITGAV: Rating: GREEN; Mode of pathogenicity: ; Publications: 29393909, 26321473; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 IRF2 Alison Coffey reviewed gene: IRF2: Rating: GREEN; Mode of pathogenicity: ; Publications: 31155227, 21478870, 22615998, 8402903, 10208925, 22113474, 27899441; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 ILF3 Alison Coffey reviewed gene: ILF3: Rating: AMBER; Mode of pathogenicity: ; Publications: 25327818, 31701124, 28869005; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 IL9 Alison Coffey reviewed gene: IL9: Rating: AMBER; Mode of pathogenicity: ; Publications: 21368237, 17940602, 19915054, 27297515, 20503287, 19536153; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 IL3 Alison Coffey reviewed gene: IL3: Rating: AMBER; Mode of pathogenicity: ; Publications: 2176641, 30995500; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 IFNE Alison Coffey reviewed gene: IFNE: Rating: GREEN; Mode of pathogenicity: ; Publications: 31734130, 23449591, 28045025, 29187603; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 IFNA1 Alison Coffey reviewed gene: IFNA1: Rating: GREEN; Mode of pathogenicity: ; Publications: 31155227, 31771760; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 HAVCR1 Alison Coffey reviewed gene: HAVCR1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23084921, 29321304, 29437974, 21536871, 9658108; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 GPR183 Alison Coffey reviewed gene: GPR183: Rating: AMBER; Mode of pathogenicity: ; Publications: 29374507, 28125291, preprint: https://doi.org/10.1101/2020.02.23.20026690, preprint: 10.21203/rs.3.rs-21580/v1; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 GPATCH3 Alison Coffey reviewed gene: GPATCH3: Rating: AMBER; Mode of pathogenicity: ; Publications: 28414768; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 GNAQ Alison Coffey reviewed gene: GNAQ: Rating: AMBER; Mode of pathogenicity: ; Publications: 31324725; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 FOLR1 Alison Coffey reviewed gene: FOLR1: Rating: AMBER; Mode of pathogenicity: ; Publications: 11461707, preprint: https://doi.org/10.1101/618306; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 DICER1 Alison Coffey reviewed gene: DICER1: Rating: GREEN; Mode of pathogenicity: ; Publications: 17181864, 18325616, 26085159, 24303839, 28591694, 30015086, 25176334, 16554838, 21385408, 32141569, 23849790, 25883138, 24115437, 27273616, 30872283, 30682089, 32291557, 16009718, 17613256, 22438534, 28473628; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CLDN9 Alison Coffey reviewed gene: CLDN9: Rating: RED; Mode of pathogenicity: ; Publications: 17804490, 23864633; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CLDN6 Alison Coffey reviewed gene: CLDN6: Rating: RED; Mode of pathogenicity: ; Publications: 17804490, 23775920, 23864633; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CDKN1B Alison Coffey reviewed gene: CDKN1B: Rating: RED; Mode of pathogenicity: ; Publications: 20081832; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CD28 Alison Coffey reviewed gene: CD28: Rating: AMBER; Mode of pathogenicity: ; Publications: 29329537, 32299202; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CD207 Alison Coffey reviewed gene: CD207: Rating: AMBER; Mode of pathogenicity: ; Publications: 21030306, 21739428, 26468543; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CCR7 Alison Coffey reviewed gene: CCR7: Rating: AMBER; Mode of pathogenicity: ; Publications: 31632965, 24910430; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 CCR2 Alison Coffey reviewed gene: CCR2: Rating: GREEN; Mode of pathogenicity: ; Publications: 21131425, 30498200, 28178200, 31777682; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 ATG5 Alison Coffey reviewed gene: ATG5: Rating: AMBER; Mode of pathogenicity: ; Publications: 30510929, 32265919, 28102839, 20473322, 20171125, 17272685; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 ATG16L1 Alison Coffey reviewed gene: ATG16L1: Rating: AMBER; Mode of pathogenicity: ; Publications: 30666959, 29367244, 32265919, 30510929; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 ATF3 Alison Coffey reviewed gene: ATF3: Rating: AMBER; Mode of pathogenicity: ; Publications: 28355270, 28821775, 26416280; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.341 AIM2 Alison Coffey reviewed gene: AIM2: Rating: GREEN; Mode of pathogenicity: ; Publications: 31372985, 20351692, 26590313; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.340 FEZ1 Ivone Leong Publications for gene: FEZ1 were set to
COVID-19 research v0.339 DEFA1 Rebecca Foulger commented on gene: DEFA1
COVID-19 research v0.339 CXCL8 Rebecca Foulger commented on gene: CXCL8
COVID-19 research v0.339 MX2 Rebecca Foulger commented on gene: MX2
COVID-19 research v0.339 HAVCR1 Rebecca Foulger commented on gene: HAVCR1
COVID-19 research v0.339 DEFA1 Rebecca Foulger gene: DEFA1 was added
gene: DEFA1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: DEFA1 was set to Unknown
Publications for gene: DEFA1 were set to 32457744
COVID-19 research v0.339 CXCL8 Rebecca Foulger gene: CXCL8 was added
gene: CXCL8 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: CXCL8 was set to Unknown
Publications for gene: CXCL8 were set to 15585888; 32161940; 3244677
COVID-19 research v0.339 MX2 Rebecca Foulger gene: MX2 was added
gene: MX2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: MX2 was set to Unknown
Publications for gene: MX2 were set to 15184662; 24048477; 25571928; 8798556; 32345362; 30333168
COVID-19 research v0.339 HAVCR1 Rebecca Foulger gene: HAVCR1 was added
gene: HAVCR1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: HAVCR1 was set to Unknown
Publications for gene: HAVCR1 were set to 29321304; 21536871; 23084921; 29437974; 9658108
COVID-19 research v0.338 CD244 Ivone Leong reviewed gene: CD244: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.338 CD200 Sarah Leigh gene: CD200 was added
gene: CD200 was added to COVID-19 research. Sources: OMIM
Mode of inheritance for gene: CD200 was set to Unknown
COVID-19 research v0.338 VPS4A Sarah Leigh gene: VPS4A was added
gene: VPS4A was added to COVID-19 research. Sources: OMIM
Mode of inheritance for gene: VPS4A was set to Unknown
COVID-19 research v0.338 TPH1 Sarah Leigh gene: TPH1 was added
gene: TPH1 was added to COVID-19 research. Sources: OMIM
Mode of inheritance for gene: TPH1 was set to Unknown
COVID-19 research v0.338 TNFSF4 Sarah Leigh gene: TNFSF4 was added
gene: TNFSF4 was added to COVID-19 research. Sources: OMIM
Mode of inheritance for gene: TNFSF4 was set to Unknown
Phenotypes for gene: TNFSF4 were set to {Myocardial infarction, susceptibility to} 608446
COVID-19 research v0.338 TLR5 Sarah Leigh gene: TLR5 was added
gene: TLR5 was added to COVID-19 research. Sources: OMIM
Mode of inheritance for gene: TLR5 was set to Unknown
Phenotypes for gene: TLR5 were set to {Legionnaire disease, susceptibility to} 608556
COVID-19 research v0.338 TLR4 Sarah Leigh gene: TLR4 was added
gene: TLR4 was added to COVID-19 research. Sources: OMIM
Mode of inheritance for gene: TLR4 was set to Unknown
COVID-19 research v0.337 CD244 Ivone Leong Publications for gene: CD244 were set to
COVID-19 research v0.336 CASP1 Ivone Leong reviewed gene: CASP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.336 IRF1 Rebecca Foulger commented on gene: IRF1
COVID-19 research v0.336 IDE Rebecca Foulger commented on gene: IDE
COVID-19 research v0.336 HDAC6 Rebecca Foulger commented on gene: HDAC6
COVID-19 research v0.336 FEZ1 Rebecca Foulger commented on gene: FEZ1
COVID-19 research v0.336 DSG2 Rebecca Foulger commented on gene: DSG2
COVID-19 research v0.336 DAG1 Rebecca Foulger commented on gene: DAG1
COVID-19 research v0.336 CXADR Rebecca Foulger commented on gene: CXADR
COVID-19 research v0.336 BECN1 Rebecca Foulger commented on gene: BECN1
COVID-19 research v0.336 BANF1 Rebecca Foulger commented on gene: BANF1
COVID-19 research v0.336 ABCC1 Rebecca Foulger commented on gene: ABCC1
COVID-19 research v0.336 ABCB1 Rebecca Foulger commented on gene: ABCB1
COVID-19 research v0.336 FCMR Rebecca Foulger commented on gene: FCMR
COVID-19 research v0.336 VPS33A Rebecca Foulger commented on gene: VPS33A
COVID-19 research v0.336 VPS11 Rebecca Foulger commented on gene: VPS11
COVID-19 research v0.336 TNFSF10 Rebecca Foulger commented on gene: TNFSF10
COVID-19 research v0.336 TLR7 Rebecca Foulger commented on gene: TLR7
COVID-19 research v0.336 RNASEL Rebecca Foulger commented on gene: RNASEL
COVID-19 research v0.336 PVR Rebecca Foulger commented on gene: PVR
COVID-19 research v0.336 PTX3 Rebecca Foulger commented on gene: PTX3
COVID-19 research v0.336 PDGFRA Rebecca Foulger commented on gene: PDGFRA
COVID-19 research v0.336 NPC1 Rebecca Foulger commented on gene: NPC1
COVID-19 research v0.336 NLRP6 Rebecca Foulger commented on gene: NLRP6
COVID-19 research v0.336 NECTIN1 Rebecca Foulger commented on gene: NECTIN1
COVID-19 research v0.336 MIR155 Rebecca Foulger commented on gene: MIR155
COVID-19 research v0.336 KLF2 Rebecca Foulger commented on gene: KLF2
COVID-19 research v0.336 KIAA0319L Rebecca Foulger commented on gene: KIAA0319L
COVID-19 research v0.336 ITGB3 Rebecca Foulger commented on gene: ITGB3
COVID-19 research v0.336 ITGAV Rebecca Foulger commented on gene: ITGAV
COVID-19 research v0.336 IRF2 Rebecca Foulger commented on gene: IRF2
COVID-19 research v0.336 ILF3 Rebecca Foulger commented on gene: ILF3
COVID-19 research v0.336 IL9 Rebecca Foulger commented on gene: IL9
COVID-19 research v0.336 IL3 Rebecca Foulger commented on gene: IL3
COVID-19 research v0.336 IFNE Rebecca Foulger commented on gene: IFNE
COVID-19 research v0.336 IFNA1 Rebecca Foulger commented on gene: IFNA1
COVID-19 research v0.336 GPR183 Rebecca Foulger commented on gene: GPR183
COVID-19 research v0.336 GPATCH3 Rebecca Foulger commented on gene: GPATCH3
COVID-19 research v0.336 GNAQ Rebecca Foulger commented on gene: GNAQ
COVID-19 research v0.336 FOLR1 Rebecca Foulger commented on gene: FOLR1
COVID-19 research v0.336 EIF3M Rebecca Foulger commented on gene: EIF3M
COVID-19 research v0.336 EGFR Rebecca Foulger commented on gene: EGFR
COVID-19 research v0.336 DICER1 Rebecca Foulger commented on gene: DICER1
COVID-19 research v0.336 CXCR3 Rebecca Foulger commented on gene: CXCR3
COVID-19 research v0.336 CLDN9 Rebecca Foulger commented on gene: CLDN9
COVID-19 research v0.336 CLDN6 Rebecca Foulger commented on gene: CLDN6
COVID-19 research v0.336 CDKN1B Rebecca Foulger commented on gene: CDKN1B
COVID-19 research v0.336 CD28 Rebecca Foulger commented on gene: CD28
COVID-19 research v0.336 CD244 Rebecca Foulger commented on gene: CD244
COVID-19 research v0.336 CD207 Rebecca Foulger commented on gene: CD207
COVID-19 research v0.336 CCR7 Rebecca Foulger commented on gene: CCR7
COVID-19 research v0.336 CCR2 Rebecca Foulger commented on gene: CCR2
COVID-19 research v0.336 CASP1 Rebecca Foulger commented on gene: CASP1
COVID-19 research v0.336 ATG5 Rebecca Foulger commented on gene: ATG5
COVID-19 research v0.336 ATG16L1 Rebecca Foulger commented on gene: ATG16L1
COVID-19 research v0.336 ATF3 Rebecca Foulger commented on gene: ATF3
COVID-19 research v0.336 AIM2 Rebecca Foulger commented on gene: AIM2
COVID-19 research v0.335 CASP1 Ivone Leong Publications for gene: CASP1 were set to
COVID-19 research v0.334 ABCC1 Ivone Leong reviewed gene: ABCC1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.334 ABCB1 Ivone Leong edited their review of gene: ABCB1: Added comment: Searching through PubMed, most of the papers related to ABCB1 are to do with drug efficacy and ABCB1's affect on HIV-1 treatments. Therefore, this gene should remain rated Red.; Changed rating: RED
COVID-19 research v0.334 ABCB1 Ivone Leong Added comment: Comment on publications: PMID: 18547906 showed that ABCB1 SNP (C3435T) is associated with virological efficacy in treatments for HIV infected pateints.

PMID: 26922556 showed that SNPS in ABCB1 may influence HCV infectivity.
COVID-19 research v0.334 ABCB1 Ivone Leong Publications for gene: ABCB1 were set to
COVID-19 research v0.333 IRF1 Rebecca Foulger gene: IRF1 was added
gene: IRF1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: IRF1 was set to Unknown
COVID-19 research v0.333 IDE Rebecca Foulger gene: IDE was added
gene: IDE was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: IDE was set to Unknown
COVID-19 research v0.333 HDAC6 Rebecca Foulger gene: HDAC6 was added
gene: HDAC6 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: HDAC6 was set to Unknown
COVID-19 research v0.333 FEZ1 Rebecca Foulger gene: FEZ1 was added
gene: FEZ1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: FEZ1 was set to Unknown
COVID-19 research v0.333 DSG2 Rebecca Foulger gene: DSG2 was added
gene: DSG2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: DSG2 was set to Unknown
COVID-19 research v0.333 DAG1 Rebecca Foulger gene: DAG1 was added
gene: DAG1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: DAG1 was set to Unknown
COVID-19 research v0.333 CXADR Rebecca Foulger gene: CXADR was added
gene: CXADR was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: CXADR was set to Unknown
COVID-19 research v0.333 BECN1 Rebecca Foulger gene: BECN1 was added
gene: BECN1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: BECN1 was set to Unknown
COVID-19 research v0.333 BANF1 Rebecca Foulger gene: BANF1 was added
gene: BANF1 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: BANF1 was set to Unknown
COVID-19 research v0.333 ABCC1 Rebecca Foulger gene: ABCC1 was added
gene: ABCC1 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: ABCC1 was set to Unknown
COVID-19 research v0.333 ABCB1 Rebecca Foulger gene: ABCB1 was added
gene: ABCB1 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: ABCB1 was set to Unknown
COVID-19 research v0.333 FCMR Rebecca Foulger gene: FCMR was added
gene: FCMR was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: FCMR was set to Unknown
COVID-19 research v0.333 VPS33A Rebecca Foulger gene: VPS33A was added
gene: VPS33A was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: VPS33A was set to Unknown
COVID-19 research v0.333 VPS11 Rebecca Foulger gene: VPS11 was added
gene: VPS11 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: VPS11 was set to Unknown
COVID-19 research v0.333 TNFSF10 Rebecca Foulger gene: TNFSF10 was added
gene: TNFSF10 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: TNFSF10 was set to Unknown
COVID-19 research v0.333 TLR7 Rebecca Foulger gene: TLR7 was added
gene: TLR7 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: TLR7 was set to Unknown
COVID-19 research v0.333 RNASEL Rebecca Foulger gene: RNASEL was added
gene: RNASEL was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: RNASEL was set to Unknown
COVID-19 research v0.333 PVR Rebecca Foulger gene: PVR was added
gene: PVR was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: PVR was set to Unknown
COVID-19 research v0.333 PTX3 Rebecca Foulger gene: PTX3 was added
gene: PTX3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: PTX3 was set to Unknown
COVID-19 research v0.333 PDGFRA Rebecca Foulger gene: PDGFRA was added
gene: PDGFRA was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: PDGFRA was set to Unknown
COVID-19 research v0.333 NPC1 Rebecca Foulger gene: NPC1 was added
gene: NPC1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: NPC1 was set to Unknown
COVID-19 research v0.333 NLRP6 Rebecca Foulger gene: NLRP6 was added
gene: NLRP6 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: NLRP6 was set to Unknown
COVID-19 research v0.333 NECTIN1 Rebecca Foulger gene: NECTIN1 was added
gene: NECTIN1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: NECTIN1 was set to Unknown
COVID-19 research v0.333 MIR155 Rebecca Foulger gene: MIR155 was added
gene: MIR155 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: MIR155 was set to Unknown
COVID-19 research v0.333 KLF2 Rebecca Foulger gene: KLF2 was added
gene: KLF2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: KLF2 was set to Unknown
COVID-19 research v0.333 KIAA0319L Rebecca Foulger gene: KIAA0319L was added
gene: KIAA0319L was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: KIAA0319L was set to Unknown
COVID-19 research v0.333 ITGB3 Rebecca Foulger gene: ITGB3 was added
gene: ITGB3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: ITGB3 was set to Unknown
COVID-19 research v0.333 ITGAV Rebecca Foulger gene: ITGAV was added
gene: ITGAV was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: ITGAV was set to Unknown
COVID-19 research v0.333 IRF2 Rebecca Foulger gene: IRF2 was added
gene: IRF2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: IRF2 was set to Unknown
COVID-19 research v0.333 ILF3 Rebecca Foulger gene: ILF3 was added
gene: ILF3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: ILF3 was set to Unknown
COVID-19 research v0.333 IL9 Rebecca Foulger gene: IL9 was added
gene: IL9 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: IL9 was set to Unknown
COVID-19 research v0.333 IL3 Rebecca Foulger gene: IL3 was added
gene: IL3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: IL3 was set to Unknown
COVID-19 research v0.333 IFNE Rebecca Foulger gene: IFNE was added
gene: IFNE was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: IFNE was set to Unknown
COVID-19 research v0.333 IFNA1 Rebecca Foulger gene: IFNA1 was added
gene: IFNA1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: IFNA1 was set to Unknown
COVID-19 research v0.333 GPR183 Rebecca Foulger gene: GPR183 was added
gene: GPR183 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: GPR183 was set to Unknown
COVID-19 research v0.333 GPATCH3 Rebecca Foulger gene: GPATCH3 was added
gene: GPATCH3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: GPATCH3 was set to Unknown
COVID-19 research v0.333 GNAQ Rebecca Foulger gene: GNAQ was added
gene: GNAQ was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: GNAQ was set to Unknown
COVID-19 research v0.333 FOLR1 Rebecca Foulger gene: FOLR1 was added
gene: FOLR1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: FOLR1 was set to Unknown
COVID-19 research v0.333 EIF3M Rebecca Foulger gene: EIF3M was added
gene: EIF3M was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: EIF3M was set to Unknown
COVID-19 research v0.333 EGFR Rebecca Foulger gene: EGFR was added
gene: EGFR was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: EGFR was set to Unknown
COVID-19 research v0.333 DICER1 Rebecca Foulger gene: DICER1 was added
gene: DICER1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: DICER1 was set to Unknown
COVID-19 research v0.333 CXCR3 Rebecca Foulger gene: CXCR3 was added
gene: CXCR3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: CXCR3 was set to Unknown
COVID-19 research v0.333 CLDN9 Rebecca Foulger gene: CLDN9 was added
gene: CLDN9 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: CLDN9 was set to Unknown
COVID-19 research v0.333 CLDN6 Rebecca Foulger gene: CLDN6 was added
gene: CLDN6 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: CLDN6 was set to Unknown
COVID-19 research v0.333 CDKN1B Rebecca Foulger gene: CDKN1B was added
gene: CDKN1B was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: CDKN1B was set to Unknown
COVID-19 research v0.333 CD28 Rebecca Foulger gene: CD28 was added
gene: CD28 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: CD28 was set to Unknown
COVID-19 research v0.333 CD244 Rebecca Foulger gene: CD244 was added
gene: CD244 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: CD244 was set to Unknown
COVID-19 research v0.333 CD207 Rebecca Foulger gene: CD207 was added
gene: CD207 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: CD207 was set to Unknown
COVID-19 research v0.333 CCR7 Rebecca Foulger gene: CCR7 was added
gene: CCR7 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: CCR7 was set to Unknown
COVID-19 research v0.333 CCR2 Rebecca Foulger gene: CCR2 was added
gene: CCR2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: CCR2 was set to Unknown
COVID-19 research v0.333 CASP1 Rebecca Foulger gene: CASP1 was added
gene: CASP1 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: CASP1 was set to Unknown
COVID-19 research v0.333 ATG5 Rebecca Foulger gene: ATG5 was added
gene: ATG5 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: ATG5 was set to Unknown
COVID-19 research v0.333 ATG16L1 Rebecca Foulger gene: ATG16L1 was added
gene: ATG16L1 was added to COVID-19 research. Sources: Expert Review Red,OMIM,Expert list
Mode of inheritance for gene: ATG16L1 was set to Unknown
COVID-19 research v0.333 ATF3 Rebecca Foulger gene: ATF3 was added
gene: ATF3 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Amber
Mode of inheritance for gene: ATF3 was set to Unknown
COVID-19 research v0.333 AIM2 Rebecca Foulger gene: AIM2 was added
gene: AIM2 was added to COVID-19 research. Sources: Expert list,OMIM,Expert Review Green
Mode of inheritance for gene: AIM2 was set to Unknown
Rhabdomyolysis and metabolic muscle disorders v1.39 DMD Sarah Leigh Tag Skewed X-inactivation tag was added to gene: DMD.
COVID-19 research v0.332 ACE2 Catherine Snow reviewed gene: ACE2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.332 ZFHX3 Sarah Leigh edited their review of gene: ZFHX3: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 WSCD1 Sarah Leigh edited their review of gene: WSCD1: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 UNC5CL Sarah Leigh edited their review of gene: UNC5CL: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 TAPT1 Sarah Leigh edited their review of gene: TAPT1: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 SPNS3 Sarah Leigh edited their review of gene: SPNS3: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 RPAIN Sarah Leigh edited their review of gene: RPAIN: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 PROM1 Sarah Leigh edited their review of gene: PROM1: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 PKD1L3 Sarah Leigh edited their review of gene: PKD1L3: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 NUP88 Sarah Leigh edited their review of gene: NUP88: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 MLKL Sarah Leigh edited their review of gene: MLKL: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 MIS12 Sarah Leigh edited their review of gene: MIS12: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 LDB2 Sarah Leigh edited their review of gene: LDB2: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 KARS Sarah Leigh edited their review of gene: KARS: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 HYDIN Sarah Leigh edited their review of gene: HYDIN: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 CC2D2A Sarah Leigh edited their review of gene: CC2D2A: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.332 BCAR1 Sarah Leigh edited their review of gene: BCAR1: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown
COVID-19 research v0.331 TMPRSS2 Catherine Snow Mode of inheritance for gene: TMPRSS2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
COVID-19 research v0.330 CD14 Catherine Snow Mode of inheritance for gene: CD14 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
COVID-19 research v0.329 CASP3 Catherine Snow Mode of inheritance for gene: CASP3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
COVID-19 research v0.328 BLK Catherine Snow Mode of inheritance for gene: BLK was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to Unknown
COVID-19 research v0.327 BLK Catherine Snow edited their review of gene: BLK: Changed mode of inheritance: Unknown
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.; to: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence (PMID:31735293). Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent phenotype.; to: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent feature.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Classified gene: TMX2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Added to panel by Konstantinos Varvagiannis, who re-reviewed as Green following additional evidence. Subsequent Green review by Zornitza Stark. As detailed by Konstantinos, sufficient unrelated cases for inclusion on the panel, and seizures are a frequent phenotype.
Early onset or syndromic epilepsy v2.69 TMX2 Rebecca Foulger Gene: tmx2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.68 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures; Primary microcephaly, cortical malformation and epileptic encephalopathy
Early onset or syndromic epilepsy v2.67 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730 to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730; seizures
Early onset or syndromic epilepsy v2.66 TMX2 Rebecca Foulger Phenotypes for gene: TMX2 were changed from Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration to Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730
Intellectual disability v3.73 CXorf56 Rebecca Foulger changed review comment from: Comment on mode of inheritance: OMIM records XL inheritance for MIM:301013 with X-linked inactivation. In PMID:29374277 carrier females had skewed X-inactivation whereas the affected female did not. In PMID:31822863 X-linked skewing was seen in both affected females and the unaffected carrier.; to: Comment on mode of inheritance: OMIM records XL inheritance for MIM:301013 noting X-linked inactivation in the comments. In PMID:29374277 carrier females had skewed X-inactivation whereas the affected female did not. In PMID:31822863 X-linked skewing was seen in both affected females and the unaffected carrier. Have set MOI to XLD for now, to capture affected females and males.
Intellectual disability v3.73 CXorf56 Rebecca Foulger Classified gene: CXorf56 as Green List (high evidence)
Intellectual disability v3.73 CXorf56 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Gene was added to panel by Konstantinos Varvagiannis, with a subsequent Green review by Zornitza Stark. Sufficient cases in PMIDs:29374277 and 31822863. The reported pattern of X-inactivation differs between the papers, but sufficient cases and relevant phenotype for inclusion on the panel.
Intellectual disability v3.73 CXorf56 Rebecca Foulger Gene: cxorf56 has been classified as Green List (High Evidence).
Intellectual disability v3.72 CXorf56 Rebecca Foulger Added comment: Comment on mode of inheritance: OMIM records XL inheritance for MIM:301013 with X-linked inactivation. In PMID:29374277 carrier females had skewed X-inactivation whereas the affected female did not. In PMID:31822863 X-linked skewing was seen in both affected females and the unaffected carrier.
Intellectual disability v3.72 CXorf56 Rebecca Foulger Mode of inheritance for gene: CXorf56 was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v3.71 CXorf56 Rebecca Foulger commented on gene: CXorf56: PMID:31822863. Rocha et al., 2019 report on 9 affected individuals (3 unrelated families) with mild to severe ID and variants in CXorf56. In comparison to PMID:29374277, X-linked skewing was seen in both affected females and the unaffected carrier had complete inactivation of the carrier X-chromosome.
Intellectual disability v3.71 CXorf56 Rebecca Foulger commented on gene: CXorf56
Intellectual disability v3.71 UGP2 Rebecca Foulger Classified gene: UGP2 as Green List (high evidence)
Intellectual disability v3.71 UGP2 Rebecca Foulger Added comment: Comment on list classification: Gene added to panel and rated Green by Konstantinos Varvagiannis. Subsequently reviewed Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (DD seen in all patients in PMID:31820119) for inclusion on panel: 20 patients from 13 unrelated families all with the same variant identified in PMID:31820119 (2019 publication). Therefore updated rating from Grey to Green.
Intellectual disability v3.71 UGP2 Rebecca Foulger Gene: ugp2 has been classified as Green List (High Evidence).
Intellectual disability v3.70 UGP2 Rebecca Foulger Phenotypes for gene: UGP2 were changed from Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face to Epileptic encephalopathy, early infantile, 83, 618744; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face
Intellectual disability v3.69 TRAPPC4 Rebecca Foulger Classified gene: TRAPPC4 as Green List (high evidence)
Intellectual disability v3.69 TRAPPC4 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Konstantinos Varvagiannis. Subsequent Green review by Zornitza Stark. Updated rating from Grey to Green: 7 children from 3 unrelated families with MIM:618741 reported by, Van Bergen et al. (2020) with a recurring homozygous splice site variant in TRAPPC4 resulting in a splice site alteration, the skipping of exon 3, a frameshift, and premature termination (Leu120AspfsTer9). The variant segregated within the disorder within the families and was only found in heterozygous state in gnomAD. Appropriate phenotype and cases just reach threshold for inclusion.
Intellectual disability v3.69 TRAPPC4 Rebecca Foulger Gene: trappc4 has been classified as Green List (High Evidence).
Intellectual disability v3.68 TRAPPC4 Rebecca Foulger Phenotypes for gene: TRAPPC4 were changed from Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment to Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, 618741
Early onset or syndromic epilepsy v2.65 TRAPPC4 Rebecca Foulger Classified gene: TRAPPC4 as Green List (high evidence)
Early onset or syndromic epilepsy v2.65 TRAPPC4 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Konstantinos Varvagiannis. Subsequent Green review by Zornitza Stark. Updated rating from Grey to Green: 7 children from 3 unrelated families with MIM:618741 reported by, Van Bergen et al. (2020) with a recurring homozygous splice site variant in TRAPPC4 resulting in a splice site alteration, the skipping of exon 3, a frameshift, and premature termination (Leu120AspfsTer9). The variant segregated within the disorder within the families and was only found in heterozygous state in gnomAD. Appropriate phenotype and cases just reach threshold for inclusion.
Early onset or syndromic epilepsy v2.65 TRAPPC4 Rebecca Foulger Gene: trappc4 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.64 TRAPPC4 Rebecca Foulger Phenotypes for gene: TRAPPC4 were changed from Feeding difficulties; Progressive microcephaly; Intellectual disability; Seizures; Spastic tetraparesis; Abnormality of the face; Scoliosis; Cortical visual impairment; Hearing impairment to Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, 618741
Early onset or syndromic epilepsy v2.63 TRPM3 Rebecca Foulger Tag for-review tag was added to gene: TRPM3.
Early onset or syndromic epilepsy v2.63 TRPM3 Rebecca Foulger commented on gene: TRPM3: Excluding the individual harbouring a VUS, 7 individuals from PMID:31278393 (Dyment et al 2019) had the same de novo heterozygous variant in TRPM3 (p.Val837Met). This paper was considered when previously reviewed by GLHs. An Amber rating was chosen because public databases confirm that heterozygous loss-of-function variants of TRPM3 are observed in the general population (heterozygous gnomAD truncating variants occur in 18 of 25 canonical coding exons) and therefore the authors reasoned that simple haploinsufficiency was unlikely to be the mechanism of disease in their cohort. Therefore added 'for-review' tag, for reassesment at next GLH review.
COVID-19 research v0.327 APOE Eleanor Williams changed review comment from: PMID: 32451547 - Kuo et al 2020 - Using UK biobank data they found that the ApoE e4 allele ( rs429358) increases risks of being hospitalized with COVID-19, independent of pre-existing dementia, cardiovascular disease, and type-2 diabetes. ApoE e4 allele frequency is higher in people of African ancestry than in Europeans, and
preliminary results suggest that ApoE e4 prevalence makes a modest contribution to the excess incidence of COVID-19 in Blacks. (Originially added to the panel as preprint: https://doi.org/10.1101/2020.05.07.20094409)
Sources: Literature; to: PMID: 32451547 - Kuo et al 2020 - Using UK biobank data they found that the ApoE e4 allele ( rs429358) increases risks of being hospitalized with COVID-19, independent of pre-existing dementia, cardiovascular disease, and type-2 diabetes. ApoE e4e4 homozygotes were more likely to be COVID-19 test positives compared to e3e3 homozygotes. ApoE e4 allele frequency is higher in people of African ancestry than in Europeans, and preliminary results suggest that ApoE e4 prevalence makes a modest contribution to the excess incidence of COVID-19 in Blacks. (Originially added to the panel as preprint: https://doi.org/10.1101/2020.05.07.20094409)
Sources: Literature
COVID-19 research v0.327 APOE Eleanor Williams Publications for gene: APOE were set to https://doi.org/10.1101/2020.05.07.20094409
COVID-19 research v0.326 APOE Eleanor Williams changed review comment from: Preprint: https://doi.org/10.1101/2020.05.07.20094409 Kuo et al 2020 - Using UK biobank data they found that the ApoE e4 allele ( rs429358) increases risks of being hospitalized with COVID-19, independent of pre-existing dementia, cardiovascular disease, and type-2 diabetes.
ApoE e4 allele frequency is higher in people of African ancestry than in Europeans, and
preliminary results suggest that ApoE e4 prevalence makes a modest contribution to the
excess incidence of COVID-19 in Blacks.
Sources: Literature; to: PMID: 32451547 - Kuo et al 2020 - Using UK biobank data they found that the ApoE e4 allele ( rs429358) increases risks of being hospitalized with COVID-19, independent of pre-existing dementia, cardiovascular disease, and type-2 diabetes. ApoE e4 allele frequency is higher in people of African ancestry than in Europeans, and
preliminary results suggest that ApoE e4 prevalence makes a modest contribution to the excess incidence of COVID-19 in Blacks. (Originially added to the panel as preprint: https://doi.org/10.1101/2020.05.07.20094409)
Sources: Literature
Early onset or syndromic epilepsy v2.63 TUBA8 Rebecca Foulger Classified gene: TUBA8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.63 TUBA8 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber for now, following Zornitza Stark's recent (Jan 2020) review. Additional case in PMID:31481326 (2020) but 2 Pakistani families (4 patients) previously reported may be related so remains a borderline case.
Early onset or syndromic epilepsy v2.63 TUBA8 Rebecca Foulger Gene: tuba8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.62 TUBA8 Rebecca Foulger commented on gene: TUBA8: Reviewing 2020 review comment by Zornitza noting additional publication: PMID:31481326. PMID:31481326. Lee et al., 2020 used targeted gene sequencing to identify malformations of cortical development in 81 patients. A homozygous TUBA8 p.Asn356ProfsTer63 variant was identified in one patient with 'Polymicrogyria, agenesis of CC, ventriculomegaly'. All patients had a confirmed diagnosis of epilepsy or DD.
COVID-19 research v0.326 ABO Catherine Snow Mode of inheritance for gene: ABO was changed from Other to Unknown
Early onset or syndromic epilepsy v2.62 UGP2 Rebecca Foulger Classified gene: UGP2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.62 UGP2 Rebecca Foulger Added comment: Comment on list classification: Gene added to panel and rated Green by Konstantinos Varvagiannis. Subsequently reviewed Green by Zornitza Stark. Sufficient evidence and appropriate phenotype (MIM:618744) for inclusion on panel: 20 patients from 13 unrelated families all with the same variant identified in PMID:31820119 (2019 publication). Therefore updated rating from Grey to Green.
Early onset or syndromic epilepsy v2.62 UGP2 Rebecca Foulger Gene: ugp2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.61 UGP2 Rebecca Foulger Phenotypes for gene: UGP2 were changed from Seizures; Global developmental delay; Intellectual disability; Feeding difficulties; Abnormality of vision; Abnormality of the face to Epileptic encephalopathy, early infantile, 83, 618744; seizures
Early onset or syndromic epilepsy v2.60 WDR45B Rebecca Foulger commented on gene: WDR45B: Added 'for-review' tag based on Zornitza's Green review on a gene where an Amber rating was decided at the last GLH review. Of the publications listed, PMID:28503735 (Suleiman et al) report 3 families (2 with seizures). PMID:21937992. Najmabadi et al 2011 identify WDR45B (WDR45L) as a candidate gene for ID. PMID:27431290 (Anazi et al., 2017) identified likely pathogenic alleles in WDR45B in ID individuals. Little information provided about WDR45B phenotype.
Early onset or syndromic epilepsy v2.60 WDR45B Rebecca Foulger Tag for-review tag was added to gene: WDR45B.
CAKUT v1.151 RPGRIP1L Sarah Leigh changed review comment from: Comment on list classification: Rating changed from green to red, as the phenotypic features associated with RPGRIP1L variants are ciliopathies. It is green on Renal ciliopathies (https://panelapp.genomicsengland.co.uk/panels/725/gene/RPGRIP1L/) and Rare multisystem ciliopathy disorders (https://panelapp.genomicsengland.co.uk/panels/150/gene/RPGRIP1L/) panels.; to: Comment on list classification: Rating changed from green to red, as the phenotypic features associated with RPGRIP1L variants are ciliopathies and therefore not appropriate for the CAKUT panel. It is green on Renal ciliopathies (https://panelapp.genomicsengland.co.uk/panels/725/gene/RPGRIP1L/) and Rare multisystem ciliopathy disorders (https://panelapp.genomicsengland.co.uk/panels/150/gene/RPGRIP1L/) panels.
CAKUT v1.151 RRM2B Sarah Leigh Classified gene: RRM2B as Red List (low evidence)
CAKUT v1.151 RRM2B Sarah Leigh Added comment: Comment on list classification: Rating changed from green to red, as the phenotypic features associated with RRM2B variants are metabolic renal disease / renal tubulopathy. RRM2B is green on Mitochondrial disorders (https://panelapp.genomicsengland.co.uk/panels/112/gene/RRM2B/) and Inborn errors of metabolism (https://panelapp.genomicsengland.co.uk/panels/467/gene/RRM2B/) panels.
CAKUT v1.151 RRM2B Sarah Leigh Gene: rrm2b has been classified as Red List (Low Evidence).
Intellectual disability v3.67 WDR45B Rebecca Foulger Phenotypes for gene: WDR45B were changed from AUTOSOMAL RECESSIVE MENTAL RETARDATION to AUTOSOMAL RECESSIVE MENTAL RETARDATION; Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977
Intellectual disability v3.67 WDR45B Rebecca Foulger Publications for gene: WDR45B were set to 21937992; 28503735
CAKUT v1.150 NIPBL Sarah Leigh Publications for gene: NIPBL were set to 8291537; 16799922; 15146186; 15146185; 15318302
CAKUT v1.149 NIPBL Sarah Leigh Classified gene: NIPBL as Green List (high evidence)
CAKUT v1.149 NIPBL Sarah Leigh Gene: nipbl has been classified as Green List (High Evidence).
CAKUT v1.148 NIPBL Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 13 variants reported, however, there seems to be little evidence of renal involvement.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 13 variants reported. PMID 8291540 presents extensive evidence for renal involvement in 61 Cornelia de Lange syndrome 1 cases; including structural anomalies of the kidney system in 25 (41%): absent or poor corticomedullary differentiation (8 cases), pelvic dilation (6 cases), vesicoureteral reflux (5 cases), small kidney (3 cases), isolated renal cyst (3 cases), renal ectopia (2 cases), renal function reduced (9 cases).
Early onset or syndromic epilepsy v2.60 WDR45B Rebecca Foulger Publications for gene: WDR45B were set to 21937992; 28503735
Early onset or syndromic epilepsy v2.59 ANKRD11 Rebecca Foulger Classified gene: ANKRD11 as Green List (high evidence)
Early onset or syndromic epilepsy v2.59 ANKRD11 Rebecca Foulger Added comment: Comment on list classification: Added to panel and reviewed Green by Tracy Lester. Although KBG syndrome has variable symptoms, epilepsy can be amongst the phenotypes. Based on literature review and Tracy Lester's review, updated rating from Grey to Green.
Early onset or syndromic epilepsy v2.59 ANKRD11 Rebecca Foulger Gene: ankrd11 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.58 ANKRD11 Rebecca Foulger commented on gene: ANKRD11: PMID:27900361. Kleyner et al., 2016 describe a 13 yr old male with phenotypes including epilepsy, severe DD, distinct facial features and hand anomalies. Exome sequencing identified a novel de novo heterozygous LOF single bp duplication (c.6015dupA) in ANKRD11, leading to a premature stop codon.
Early onset or syndromic epilepsy v2.58 ANKRD11 Rebecca Foulger commented on gene: ANKRD11: PMID:25543316. Samanta et al., 2015 report a 7 yr old boy with a ANKRD11 variant and developmental delay, focal epilepsy and behavioral concerns. He had frequent focal seizures but had enjoyed seizure-free state intermittently up to 9 months. He also had rare secondarily generalized tonic–clonic seizures, less than one episode in a year. After normal EEGs age 1 and 3, an EEG age 5 revealed EEG abnormalities.
Early onset or syndromic epilepsy v2.58 ANKRD11 Rebecca Foulger Publications for gene: ANKRD11 were set to 29565525
Early onset or syndromic epilepsy v2.57 ANKRD11 Rebecca Foulger commented on gene: ANKRD11
Early onset or syndromic epilepsy v2.57 ANKRD11 Rebecca Foulger Phenotypes for gene: ANKRD11 were changed from KBG syndrome to KBG syndrome, 148050
CAKUT v1.148 RPGRIP1L Sarah Leigh Classified gene: RPGRIP1L as Red List (low evidence)
CAKUT v1.148 RPGRIP1L Sarah Leigh Added comment: Comment on list classification: Rating changed from green to red, as the phenotypic features associated with RPGRIP1L variants are ciliopathies. It is green on Renal ciliopathies (https://panelapp.genomicsengland.co.uk/panels/725/gene/RPGRIP1L/) and Rare multisystem ciliopathy disorders (https://panelapp.genomicsengland.co.uk/panels/150/gene/RPGRIP1L/) panels.
CAKUT v1.148 RPGRIP1L Sarah Leigh Gene: rpgrip1l has been classified as Red List (Low Evidence).
COVID-19 research v0.325 SLAMF6 Catherine Snow gene: SLAMF6 was added
gene: SLAMF6 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SLAMF6 was set to Unknown
Publications for gene: SLAMF6 were set to 30366106
Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SLAMF6.

Natural cytotoxicity receptors, such as NKp46, NKp44, and NKp30 (NCR3), are selectively expressed on NK cells and cooperate in the induction of NK cell activity

Yigit et al (2019) summarised research in "SLAMF6 in health and disease: Implications for therapeutic targeting"
Sources: Expert list
COVID-19 research v0.324 SIGIRR Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SIGIRR.

Molgora et al. (2017) reported that IL-1R8 serves as a checkpoint for natural killer (NK) cell maturation and effector function. Its genetic blockade unleashes NK cell-mediated resistance to hepatic carcinogenesis, hematogenous liver and lung metastasis, and cytomegalovirus infection
Sources: Expert list; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SIGIRR.

Molgora et al. (2017) reported that IL-1R8 serves as a checkpoint for natural killer (NK) cell maturation and effector function. Its genetic blockade unleashes NK cell-mediated resistance to hepatic carcinogenesis, hematogenous liver and lung metastasis, and cytomegalovirus infection

Li et al. (2019) who worked with mice. Found that stabilization of Sigirr by USP13 describes a novel anti-inflammatory pathway in diseases that could provide a new strategy to modulate immune activation.
Sources: Expert list
COVID-19 research v0.324 SIGIRR Catherine Snow Publications for gene: SIGIRR were set to 29072292
COVID-19 research v0.323 SIGIRR Catherine Snow gene: SIGIRR was added
gene: SIGIRR was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SIGIRR was set to Unknown
Publications for gene: SIGIRR were set to 29072292
Review for gene: SIGIRR was set to RED
Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SIGIRR.

Molgora et al. (2017) reported that IL-1R8 serves as a checkpoint for natural killer (NK) cell maturation and effector function. Its genetic blockade unleashes NK cell-mediated resistance to hepatic carcinogenesis, hematogenous liver and lung metastasis, and cytomegalovirus infection
Sources: Expert list
COVID-19 research v0.322 SLC11A1 Catherine Snow gene: SLC11A1 was added
gene: SLC11A1 was added to COVID-19 research. Sources: Literature,Expert list
Mode of inheritance for gene: SLC11A1 was set to Unknown
Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SLC11A1

Multiple association studies with TB only, no viral associations
Sources: Literature, Expert list
DDG2P v2.8 KMT2E Rebecca Foulger Added comment: Comment on phenotypes: Removed MIM ID 616579 from phenotype field, as MIM:616579 is associated with a different gene (CHAMP1).
DDG2P v2.8 KMT2E Rebecca Foulger Phenotypes for gene: KMT2E were changed from INTELLECTUAL DISABILITY 616579; Neurodevelopmental disorder and Epilepsy 618512 to INTELLECTUAL DISABILITY; Neurodevelopmental disorder and Epilepsy 618512
DDG2P v2.7 GNAI1 Rebecca Foulger Publications for gene: GNAI1 were set to
DDG2P v2.6 CNOT3 Rebecca Foulger Publications for gene: CNOT3 were set to
COVID-19 research v0.321 SLC2A1 Ivone Leong Classified gene: SLC2A1 as Amber List (moderate evidence)
COVID-19 research v0.321 SLC2A1 Ivone Leong Gene: slc2a1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.320 SLC2A1 Ivone Leong gene: SLC2A1 was added
gene: SLC2A1 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SLC2A1 was set to Unknown
Publications for gene: SLC2A1 were set to 15767416; 22308487
Review for gene: SLC2A1 was set to AMBER
Added comment: GLUT1 is a receptor for HTLV and suggested that perturbations in glucose metabolism resulting from interactions of HTLV envelope glycoproteins with GLUT1 are likely to contribute to HTLV-associated disorders (PMID: 15767416).

PMID: 22308487 shows that IL-7 induced upregulation of Glut1 changes glucos uptake and causes T lymphocyptes susceptible to HIV-1 infection.
Sources: Expert list
COVID-19 research v0.319 STAT6 Ivone Leong gene: STAT6 was added
gene: STAT6 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: STAT6 was set to Unknown
Publications for gene: STAT6 were set to 22000020; 21762972
Review for gene: STAT6 was set to RED
Added comment: Immune system gene: STAT6 mediates immune signaling in response to cytokines at the plasma membrane and to virus infection at the endoplasmic reticulum. Mice lacking Stat6 were susceptible to virus infection. Chen et al. (2011) (PMID: 22000020).

PMID: 21762972 found that STAT6 increases viral replication in the skin of patients with atopic dermatitis (chronic inflammatory skin disease) with a history of eczema herpeticum.
Sources: Expert list
COVID-19 research v0.318 TBX21 Ivone Leong Classified gene: TBX21 as Amber List (moderate evidence)
COVID-19 research v0.318 TBX21 Ivone Leong Gene: tbx21 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.317 TBX21 Ivone Leong gene: TBX21 was added
gene: TBX21 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: TBX21 was set to Unknown
Publications for gene: TBX21 were set to 15806396; 17378728; 19473434; 29399747
Phenotypes for gene: TBX21 were set to {Asthma, aspirin-induced, susceptibility to}, 208550; susceptibility to chronic HBV and HCV infection
Review for gene: TBX21 was set to AMBER
Added comment: TBX21 is a Th1-specific T-box transcription factor that controls the expression of the hallmark Th1 cytokine, interferon-gamma (PMID: 15806396).

PMID: 17378728 found that variations at allele -1499 and haplotype D (--/AC) in the TBX21 promoter region contribute to susceptibility to HBV infection in the Chinese population.

PMID: 19473434 found that T-1993C polymorphism in the TBX21 promoter influences susceptibility to persistent HBV infection.

PMID: 29399747 found that rs4794067 (T-1993C) is significantly correlated with increased risk of HCV chronic infection (dominant model: OR = 5.690, 95% CI = 2.024-16.000) and susceptibility (dominant model: OR = 5.658, 95% CI = 2.514-12.735).
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 ZNF34 Sarah Leigh reviewed gene: ZNF34: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 ZFP36 Sarah Leigh reviewed gene: ZFP36: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 ZC3HC1 Sarah Leigh reviewed gene: ZC3HC1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 TUBGCP3 Sarah Leigh reviewed gene: TUBGCP3: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 TSPAN14 Sarah Leigh reviewed gene: TSPAN14: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 TNIP1 Sarah Leigh reviewed gene: TNIP1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 SLC13A4 Sarah Leigh reviewed gene: SLC13A4: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 ODC1 Sarah Leigh reviewed gene: ODC1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 MTPAP Sarah Leigh reviewed gene: MTPAP: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 MICA Sarah Leigh reviewed gene: MICA: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 MED13L Sarah Leigh reviewed gene: MED13L: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 IVNS1ABP Sarah Leigh reviewed gene: IVNS1ABP: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 FOXM1 Sarah Leigh reviewed gene: FOXM1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 FBRS Sarah Leigh reviewed gene: FBRS: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 CXorf36 Sarah Leigh reviewed gene: CXorf36: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.175 ABI3 Sarah Leigh reviewed gene: ABI3: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.316 ZNF34 Sarah Leigh Deleted their comment
COVID-19 research v0.316 ZFP36 Sarah Leigh Deleted their comment
COVID-19 research v0.316 ZC3HC1 Sarah Leigh Deleted their comment
COVID-19 research v0.316 TUBGCP3 Sarah Leigh Deleted their comment
COVID-19 research v0.316 TSPAN14 Sarah Leigh Deleted their comment
COVID-19 research v0.316 TNIP1 Sarah Leigh Deleted their comment
COVID-19 research v0.316 SLC13A4 Sarah Leigh Deleted their comment
COVID-19 research v0.316 ODC1 Sarah Leigh Deleted their comment
COVID-19 research v0.316 MTPAP Sarah Leigh Deleted their comment
COVID-19 research v0.316 MICA Sarah Leigh Deleted their comment
COVID-19 research v0.316 MED13L Sarah Leigh Deleted their comment
COVID-19 research v0.316 IVNS1ABP Sarah Leigh Deleted their comment
COVID-19 research v0.316 FOXM1 Sarah Leigh Deleted their comment
COVID-19 research v0.316 FBRS Sarah Leigh Deleted their comment
COVID-19 research v0.316 CXorf36 Sarah Leigh Deleted their comment
COVID-19 research v0.316 ABI3 Sarah Leigh Deleted their comment
COVID-19 research v0.316 STK17B Ivone Leong gene: STK17B was added
gene: STK17B was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: STK17B was set to Unknown
Publications for gene: STK17B were set to 19017949; 19017948; 17364498; 17966037
Review for gene: STK17B was set to RED
Added comment: Drak2 -/- mice were susceptible to other models of autoimmunity and were normally resistant to acute viral infection.
Sources: Expert list
COVID-19 research v0.315 ZNF34 Sarah Leigh commented on gene: ZNF34: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 ZFP36 Sarah Leigh commented on gene: ZFP36: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 ZC3HC1 Sarah Leigh commented on gene: ZC3HC1: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 TUBGCP3 Sarah Leigh commented on gene: TUBGCP3: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 TSPAN14 Sarah Leigh commented on gene: TSPAN14: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 TNIP1 Sarah Leigh commented on gene: TNIP1: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 SLC13A4 Sarah Leigh commented on gene: SLC13A4: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 ODC1 Sarah Leigh commented on gene: ODC1: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 MTPAP Sarah Leigh commented on gene: MTPAP: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 MICA Sarah Leigh commented on gene: MICA: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 MED13L Sarah Leigh commented on gene: MED13L: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 IVNS1ABP Sarah Leigh commented on gene: IVNS1ABP: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 FOXM1 Sarah Leigh commented on gene: FOXM1: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 FBRS Sarah Leigh commented on gene: FBRS: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.315 CXorf36 Sarah Leigh commented on gene: CXorf36: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988). New gene name DIPK2B
COVID-19 research v0.315 ABI3 Sarah Leigh commented on gene: ABI3: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 ZNF34 Sarah Leigh gene: ZNF34 was added
gene: ZNF34 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ZNF34 was set to Unknown
Phenotypes for gene: ZNF34 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 ZFP36 Sarah Leigh gene: ZFP36 was added
gene: ZFP36 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ZFP36 was set to Unknown
Phenotypes for gene: ZFP36 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 ZC3HC1 Sarah Leigh gene: ZC3HC1 was added
gene: ZC3HC1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ZC3HC1 was set to Unknown
Phenotypes for gene: ZC3HC1 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 TUBGCP3 Sarah Leigh gene: TUBGCP3 was added
gene: TUBGCP3 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TUBGCP3 was set to Unknown
Phenotypes for gene: TUBGCP3 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 TSPAN14 Sarah Leigh gene: TSPAN14 was added
gene: TSPAN14 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TSPAN14 was set to Unknown
Phenotypes for gene: TSPAN14 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 TNIP1 Sarah Leigh gene: TNIP1 was added
gene: TNIP1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: TNIP1 was set to Unknown
Phenotypes for gene: TNIP1 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 SLC13A4 Sarah Leigh gene: SLC13A4 was added
gene: SLC13A4 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: SLC13A4 was set to Unknown
Phenotypes for gene: SLC13A4 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 ODC1 Sarah Leigh gene: ODC1 was added
gene: ODC1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ODC1 was set to Unknown
Phenotypes for gene: ODC1 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 MTPAP Sarah Leigh gene: MTPAP was added
gene: MTPAP was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MTPAP was set to Unknown
Phenotypes for gene: MTPAP were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 MICA Sarah Leigh gene: MICA was added
gene: MICA was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MICA was set to Unknown
Phenotypes for gene: MICA were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 MED13L Sarah Leigh gene: MED13L was added
gene: MED13L was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: MED13L was set to Unknown
Phenotypes for gene: MED13L were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 IVNS1ABP Sarah Leigh gene: IVNS1ABP was added
gene: IVNS1ABP was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IVNS1ABP was set to Unknown
Phenotypes for gene: IVNS1ABP were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 FOXM1 Sarah Leigh gene: FOXM1 was added
gene: FOXM1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: FOXM1 was set to Unknown
Phenotypes for gene: FOXM1 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 FBRS Sarah Leigh gene: FBRS was added
gene: FBRS was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: FBRS was set to Unknown
Phenotypes for gene: FBRS were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 CXorf36 Sarah Leigh gene: CXorf36 was added
gene: CXorf36 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CXorf36 was set to Unknown
Phenotypes for gene: CXorf36 were set to primary immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.174 ABI3 Sarah Leigh gene: ABI3 was added
gene: ABI3 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ABI3 was set to Unknown
Phenotypes for gene: ABI3 were set to primary immunodeficiency
COVID-19 research v0.314 SLFN12L Ivone Leong gene: SLFN12L was added
gene: SLFN12L was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SLFN12L was set to Unknown
Review for gene: SLFN12L was set to RED
Added comment: Mouse model-Immune system. Mice homozygous for the Slfn2 elektra mutation exhibited enhanced susceptibility to bacterial and viral infections and diminished numbers of T cells and inflammatory monocytes that failed to proliferate after infection and died via the intrinsic apoptotic pathway in response to diverse proliferative stimuli. Slfn2 homologous to SFLN12 and SLFN12L
Sources: Expert list
COVID-19 research v0.313 SLFN12 Ivone Leong gene: SLFN12 was added
gene: SLFN12 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SLFN12 was set to Unknown
Review for gene: SLFN12 was set to RED
Added comment: Mouse model-Immune system. Mice homozygous for the Slfn2 elektra mutation exhibited enhanced susceptibility to bacterial and viral infections and diminished numbers of T cells and inflammatory monocytes that failed to proliferate after infection and died via the intrinsic apoptotic pathway in response to diverse proliferative stimuli. Slfn2 homologous to SFLN12 and SLFN12L
Sources: Expert list
COVID-19 research v0.312 SLC20A2 Ivone Leong gene: SLC20A2 was added
gene: SLC20A2 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SLC20A2 was set to Unknown
Review for gene: SLC20A2 was set to RED
Added comment: GLVR2 is a receptor for amphotropic virus. Non-human viruses listed.
Sources: Expert list
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.9 SOX6 Eleanor Williams Phenotypes for gene: SOX6 were changed from craniosynostosis; intellectual disability to craniosynostosis
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.8 SOX6 Eleanor Williams Phenotypes for gene: SOX6 were changed from to craniosynostosis; intellectual disability
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.7 SOX6 Eleanor Williams Publications for gene: SOX6 were set to
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.6 SOX6 Eleanor Williams changed review comment from: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the first this is unknown.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.; to: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the first this is unknown. 16 other patients from 14 families were also reported with variants in SOX6 but no craniosynostosis phenotype.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.6 SOX6 Eleanor Williams Added comment: Comment on mode of inheritance: All patients reported by Tolchin et al were heterozygous
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.6 SOX6 Eleanor Williams Mode of inheritance for gene: SOX6 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.5 SOX6 Eleanor Williams Classified gene: SOX6 as Green List (high evidence)
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.5 SOX6 Eleanor Williams Added comment: Comment on list classification: 4 patients reported with genomic alterations affecting SOX6 are now reported.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.5 SOX6 Eleanor Williams Gene: sox6 has been classified as Green List (High Evidence).
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.4 SOX6 Eleanor Williams commented on gene: SOX6: PMID: 32442410 -Tolchin et al 2020 - report 3 unrelated patients (CHUP-1;406931, UK-1;412103 and UK-2;412119) with either deletion of exons 5–7 or nonsense variants (c.242C>G p.Ser81*, c.277C>T p.Arg93*). Patients had a range of phenotypes including mild to moderate intellectual disability, attention deficit/ADHD and either oxycephaly or scaphocephaly. The first two patients had de-novo variants, in the first this is unknown.

PMID: 16258006 - Tagariello et al 2004 - a male infant presenting at birth with brachycephaly, proptosis, midfacial hypoplasia, and low set ears. The complete coding sequence of the FGFR2 and FGFR3 genes were screened but no variants found. The P252R mutation in the FGFR1 gene was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupts the SOX6 gene, known to be involved in skeletal growth and differentiation processes.
Respiratory ciliopathies including non-CF bronchiectasis v1.7 SPEF2 Zornitza Stark gene: SPEF2 was added
gene: SPEF2 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Expert list
Mode of inheritance for gene: SPEF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPEF2 were set to 31151990; 31278745; 31048344; 31942643
Phenotypes for gene: SPEF2 were set to Spermatogenic failure 43, MIM#618751; Primary ciliary dyskinesia-like phenotype
Review for gene: SPEF2 was set to AMBER
Added comment: 4 families reported with bi-allelic variants and sperm morphological abnormalities plus recurrent sinopulmonary infections and bronchiectasis, consistent with a PCD-like phenotype. Morphological abnormalities of the respiratory cilia were not observed. Mouse model recapitulated the infertility phenotype but also had hydrocephalus and sinusitis, again arguing for broader impact on ciliary function. Note other reports of individuals with bi-allelic variants and no respiratory phenotype reported. Given respiratory phenotype is milder and currently it is unclear in what proportion of individuals it is present, suggest Amber rating on this panel for now.
Sources: Expert list
Respiratory ciliopathies including non-CF bronchiectasis v1.7 TTC12 Zornitza Stark gene: TTC12 was added
gene: TTC12 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Expert list
Mode of inheritance for gene: TTC12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC12 were set to 31978331
Phenotypes for gene: TTC12 were set to Ciliary dyskinesia
Review for gene: TTC12 was set to GREEN
gene: TTC12 was marked as current diagnostic
Added comment: Four unrelated families with LoF variants reported with a respiratory phenotype.
Sources: Expert list
Respiratory ciliopathies including non-CF bronchiectasis v1.7 RPGR Zornitza Stark reviewed gene: RPGR: Rating: GREEN; Mode of pathogenicity: None; Publications: 10094550, 12920075, 16055928; Phenotypes: Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness, MIM# 300455; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females; Current diagnostic: yes
Respiratory ciliopathies including non-CF bronchiectasis v1.7 OFD1 Zornitza Stark reviewed gene: OFD1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.7 DNAJB13 Zornitza Stark reviewed gene: DNAJB13: Rating: AMBER; Mode of pathogenicity: None; Publications: 27486783; Phenotypes: Ciliary dyskinesia, primary, 34, MIM# 617091; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v1.7 FOXJ1 Zornitza Stark reviewed gene: FOXJ1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31630787; Phenotypes: Hydrocephalus, chronic destructive airway disease, randomization of left/right body asymmetry; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Respiratory ciliopathies including non-CF bronchiectasis v1.7 NEK10 Zornitza Stark edited their review of gene: NEK10: Changed phenotypes: Ciliary dyskinesia, primary, 44, MIM# 618781; Set current diagnostic: yes
Respiratory ciliopathies including non-CF bronchiectasis v1.7 NEK10 Zornitza Stark gene: NEK10 was added
gene: NEK10 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Expert list
Mode of inheritance for gene: NEK10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEK10 were set to 31959991
Phenotypes for gene: NEK10 were set to Ciliary dyskinesia, primary, 44, MIM# 618781
Review for gene: NEK10 was set to GREEN
Added comment: Nine individuals from 5 unrelated families, some functional data demonstrating hypoplastic or shorter cilia, and reduced overall ciliary motion compared to controls. No individuals had situs inversus but most had recurrent sinusitis and bronchiectasis.
Sources: Expert list
Respiratory ciliopathies including non-CF bronchiectasis v1.7 CFAP57 Zornitza Stark gene: CFAP57 was added
gene: CFAP57 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Other
Mode of inheritance for gene: CFAP57 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CFAP57 were set to bioRxiv 773028 doi: https://doi.org/10.1101/773028
Phenotypes for gene: CFAP57 were set to Primary ciliary dyskinesia
Review for gene: CFAP57 was set to RED
Added comment: Gene not in PubMed but recently published in bioRxiv in single patient with hom nonsense variants and Primary ciliary dyskinesia. Some functional data provided.
Sources: Other
Respiratory ciliopathies including non-CF bronchiectasis v1.7 CFAP54 Zornitza Stark edited their review of gene: CFAP54: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Respiratory ciliopathies including non-CF bronchiectasis v1.7 CFAP54 Zornitza Stark reviewed gene: CFAP54: Rating: RED; Mode of pathogenicity: None; Publications: 26224312; Phenotypes: ; Mode of inheritance: None
Respiratory ciliopathies including non-CF bronchiectasis v1.7 CFAP46 Zornitza Stark reviewed gene: CFAP46: Rating: RED; Mode of pathogenicity: None; Publications: 29843777; Phenotypes: Heterotaxy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Neurological ciliopathies v1.7 ARL3 Zornitza Stark gene: ARL3 was added
gene: ARL3 was added to Neurological ciliopathies. Sources: Expert list
Mode of inheritance for gene: ARL3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL3 were set to 30269812; 16565502
Phenotypes for gene: ARL3 were set to Joubert syndrome 35 MIM#61816
Review for gene: ARL3 was set to GREEN
gene: ARL3 was marked as current diagnostic
Added comment: 4 individuals from 2 unrelated consanguineous families with a phenotype resembling Joubert syndrome with homozygous missense mutations affecting the same residue (R149C, R149H), and supporting in vitro functional assays. An Arl3 null mouse model has a ciliary disease phenotype affecting the kidney, biliary tract, pancreas, and retina.
Sources: Expert list
Skeletal ciliopathies v1.3 PMM2 Zornitza Stark reviewed gene: PMM2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type Ia, MIM# 212065; Mode of inheritance: None
Skeletal ciliopathies v1.3 KIAA0586 Zornitza Stark gene: KIAA0586 was added
gene: KIAA0586 was added to Skeletal ciliopathies. Sources: Expert list
Mode of inheritance for gene: KIAA0586 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0586 were set to 26166481
Phenotypes for gene: KIAA0586 were set to Short-rib thoracic dysplasia 14 with polydactyly, MIM# 616546
Review for gene: KIAA0586 was set to AMBER
Added comment: Four unrelated families reported with a severe neurological/skeletal phenotype. However, note same variant identified in three of the families, indicative of founder effect. Gene is also associated with Joubert syndrome.
Sources: Expert list
Skeletal ciliopathies v1.3 CSPP1 Zornitza Stark gene: CSPP1 was added
gene: CSPP1 was added to Skeletal ciliopathies. Sources: Expert list
Mode of inheritance for gene: CSPP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSPP1 were set to 24360808
Phenotypes for gene: CSPP1 were set to Joubert syndrome 21, MIM# 615636
Review for gene: CSPP1 was set to GREEN
gene: CSPP1 was marked as current diagnostic
Added comment: Classically associated with Joubert syndrome; however, note 4 individuals reported with features consistent with Jeune asphyxiating thoracic dystrophy, including short ribs, bell-shaped chest, and pulmonary hypoplasia.
Sources: Expert list
COVID-19 research v0.311 SERINC5 Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SERINC5

Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV)
Sudderuddin et al (2020) found that SERINC5 on the cell surface is down regulated upon HIV infection
Sources: Literature; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SERINC5.

Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV)
Sudderuddin et al (2020) found that SERINC5 on the cell surface is down regulated upon HIV infection
Sources: Literature
COVID-19 research v0.311 SERINC5 Catherine Snow Classified gene: SERINC5 as Amber List (moderate evidence)
COVID-19 research v0.311 SERINC5 Catherine Snow Gene: serinc5 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.310 SERINC5 Catherine Snow gene: SERINC5 was added
gene: SERINC5 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SERINC5 was set to Unknown
Publications for gene: SERINC5 were set to 26416734; 31918727
Review for gene: SERINC5 was set to AMBER
Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".

Currently no gene disease association for SERINC5

Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV)
Sudderuddin et al (2020) found that SERINC5 on the cell surface is down regulated upon HIV infection
Sources: Literature
COVID-19 research v0.309 SERINC3 Catherine Snow Publications for gene: SERINC3 were set to
COVID-19 research v0.308 SERINC3 Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".
No current gene disease relationship in OMIM.
The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS.

Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 (607165), inhibited infectivity of human immunodeficiency virus (HIV)-1 (see 609423) and murine leukemia retrovirus (MLV)
Sources: Literature; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".
No current gene disease relationship in OMIM.
The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS.

Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3, inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV)
Sources: Literature
COVID-19 research v0.308 SERINC3 Catherine Snow Classified gene: SERINC3 as Amber List (moderate evidence)
COVID-19 research v0.308 SERINC3 Catherine Snow Gene: serinc3 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.307 SERINC3 Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".
No current gene disease relationship in OMIM.
The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS.
Sources: Literature; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".
No current gene disease relationship in OMIM.
The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS.

Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 (607165), inhibited infectivity of human immunodeficiency virus (HIV)-1 (see 609423) and murine leukemia retrovirus (MLV)
Sources: Literature
COVID-19 research v0.307 SERINC3 Catherine Snow gene: SERINC3 was added
gene: SERINC3 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SERINC3 was set to Unknown
Review for gene: SERINC3 was set to AMBER
Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".
No current gene disease relationship in OMIM.
The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS.
Sources: Literature
COVID-19 research v0.306 SDC1 Catherine Snow gene: SDC1 was added
gene: SDC1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SDC1 was set to Unknown
Publications for gene: SDC1 were set to 12530973
Review for gene: SDC1 was set to RED
Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus".
NO gene disease association for SDC1. Bobardt et al. (2003) suggested that SDC-rich endothelial cells lining the vasculature can provide a microenvironment that boosts HIV replication in T cells.
Sources: Literature
COVID-19 research v0.305 SCN4A Catherine Snow changed review comment from: No further evidence since. Matthews et al. (2011) reported a family with PMC due to the heterozygous T1313M mutation. Before correct diagnosis, the youngest affected individual presented with neonatal inspiratory stridor and poor feeding. Laryngoscopy showed findings consistent with laryngomalacia. He continued to have stridor for the first 6 months of life, and later motor milestones were mildly delayed. In early childhood, he was noted to have frequent episodic muscle weakness and stiffness associated with cold weather. At age 4 years, he continued to have episodes of inspiratory stridor exacerbated by viral illness, cold weather, and prolonged laughing or crying. His mother, grandfather, and great-uncle reported similar episodes of muscle stiffness and weakness exacerbated by cold and exercise.
Sources: Literature; to: No further evidence reported since. Matthews et al. (2011) PMID 21220685 reported a family with PMC due to the heterozygous T1313M mutation. Before correct diagnosis, the youngest affected individual presented with neonatal inspiratory stridor and poor feeding. Laryngoscopy showed findings consistent with laryngomalacia. He continued to have stridor for the first 6 months of life, and later motor milestones were mildly delayed. In early childhood, he was noted to have frequent episodic muscle weakness and stiffness associated with cold weather. At age 4 years, he continued to have episodes of inspiratory stridor exacerbated by viral illness, cold weather, and prolonged laughing or crying. His mother, grandfather, and great-uncle reported similar episodes of muscle stiffness and weakness exacerbated by cold and exercise.
Sources: Literature
COVID-19 research v0.305 SCN4A Catherine Snow gene: SCN4A was added
gene: SCN4A was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SCN4A was set to Unknown
Publications for gene: SCN4A were set to 21220685
Review for gene: SCN4A was set to RED
Added comment: No further evidence since. Matthews et al. (2011) reported a family with PMC due to the heterozygous T1313M mutation. Before correct diagnosis, the youngest affected individual presented with neonatal inspiratory stridor and poor feeding. Laryngoscopy showed findings consistent with laryngomalacia. He continued to have stridor for the first 6 months of life, and later motor milestones were mildly delayed. In early childhood, he was noted to have frequent episodic muscle weakness and stiffness associated with cold weather. At age 4 years, he continued to have episodes of inspiratory stridor exacerbated by viral illness, cold weather, and prolonged laughing or crying. His mother, grandfather, and great-uncle reported similar episodes of muscle stiffness and weakness exacerbated by cold and exercise.
Sources: Literature
COVID-19 research v0.304 TMPRSS2 Eleanor Williams reviewed gene: TMPRSS2: Rating: ; Mode of pathogenicity: None; Publications: https://doi.org/10.1101/2020.05.15.098616; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.304 SLC6A19 Eleanor Williams gene: SLC6A19 was added
gene: SLC6A19 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SLC6A19 was set to Unknown
Added comment: Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients.
Sources: Literature
COVID-19 research v0.303 ACE2 Eleanor Williams changed review comment from: Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural
Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2.; to: Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2.
COVID-19 research v0.303 ACE2 Eleanor Williams edited their review of gene: ACE2: Added comment: Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural
Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2.; Changed publications: 32015507, https://doi.org/10.1101/2020.05.15.098616
COVID-19 research v0.303 TMPRSS4 Eleanor Williams gene: TMPRSS4 was added
gene: TMPRSS4 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: TMPRSS4 was set to Unknown
Publications for gene: TMPRSS4 were set to https://doi.org/10.1101/2020.05.12.091314
Added comment: Preprint: Wruck and Adjaye https://doi.org/10.1101/2020.05.12.091314 - describe a meta-analysis focussing on the transcriptome data from human lung epithelial cells including samples infected with SARS-CoV-2 from a study described by Blanco Melo et al.12. The exploration was directed to co-expression with the known CoV-2 receptor ACE2. 72 genes significantly co-expressed with ACE2. Of the transmembrane serine proteases, the most significantly coexpressed with ACE2 was TMPRSS4, suggesting it to be a putative druggable target.
Pathway analysis revealed papilloma virus infection amongst the most significantly correlated pathways.
Sources: Literature
COVID-19 research v0.302 MBL2 Eleanor Williams commented on gene: MBL2
COVID-19 research v0.302 OAS1 Eleanor Williams reviewed gene: OAS1: Rating: ; Mode of pathogenicity: None; Publications: https://doi.org/10.1101/2020.05.13.093690; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.302 TMPRSS11A Eleanor Williams gene: TMPRSS11A was added
gene: TMPRSS11A was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: TMPRSS11A was set to Unknown
Publications for gene: TMPRSS11A were set to https://doi.org/10.1101/2020.05.13.093690
Review for gene: TMPRSS11A was set to RED
Added comment: Preprint: Klaassen et al https://doi.org/10.1101/2020.05.13.093690 - performed analysis of variants in FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population and identified 22 variants with potential functional effect. Then used in-silico prediction and comparative population analysis and found 2 rare variants p.Lys48Arg and p.Arg328Gln. For both of these variants, PolyPhen-2, SIFT and MutPred2
algorithms predict benign/tolerated effect but the protein structure of TMPRSS11a is not well known.
Sources: Literature
COVID-19 research v0.301 PRSS1 Eleanor Williams gene: PRSS1 was added
gene: PRSS1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: PRSS1 was set to Unknown
Publications for gene: PRSS1 were set to https://doi.org/10.1101/2020.05.13.093690
Added comment: Preprint: Klaassen et al https://doi.org/10.1101/2020.05.13.093690 - performed analysis of variants in FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population and identified 22 variants with potential functional effect. Then used in-silico prediction and comparative population analysis and found two rare variants in the PRSS1 gene, c.592-8C>T and p.Asn54Lys. Variant c.592-8C>T was previously detected
in patients with cystic fibrosis presenting with chronic pancreatitis and p.Asn54Lys is predicted to be possibly damaging.
Sources: Literature
COVID-19 research v0.300 PLG Eleanor Williams gene: PLG was added
gene: PLG was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: PLG was set to Unknown
Publications for gene: PLG were set to https://doi.org/10.1101/2020.05.13.093690
Review for gene: PLG was set to RED
Added comment: Preprint: Klaassen et al https://doi.org/10.1101/2020.05.13.093690 - performed analysis of variants in FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population and identified 22 variants with potential functional effect. Then used in-silico prediction and comparative population analysis and found 6 rare variants in PLG. p.Arg261His and p.Ala494Val are predicted to be probably damaging/deleterious.
Sources: Literature
COVID-19 research v0.299 FURIN Eleanor Williams commented on gene: FURIN: Preprint: Klaassen et al https://doi.org/10.1101/2020.05.13.093690 - performed analysis of variants in FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population and identified 22 variants with potential functional effect. Then used in-silico prediction and comparative population analysis and found two rare variants in FURIN p.Thr33Ala and p.Gly146Ser. p.Gly146Ser. is predicted to be deleterious and may change its ability
to cleave furin-like sites in the S protein of the SARS-CoV-2.
COVID-19 research v0.299 ACE2 Eleanor Williams changed review comment from: Preprint: Pach et al https://doi.org/10.1101/2020.05.14.092767 - by looking at species that are susceptible and non-susceptible to SARS-COV-2, they have developed dynamic computational models for ACE2-
RBD complexes of different species allowing us to anticipate the effects of amino acid sequence
variation of ACE2 on viral entry; to: Preprint: Pach et al https://doi.org/10.1101/2020.05.14.092767 - by looking at species that are susceptible and non-susceptible to SARS-COV-2, they have developed dynamic computational models for ACE2-RBD complexes of different species allowing us to anticipate the effects of amino acid sequence variation of ACE2 on viral entry
COVID-19 research v0.299 ACE2 Eleanor Williams commented on gene: ACE2: Preprint: Pach et al https://doi.org/10.1101/2020.05.14.092767 - by looking at species that are susceptible and non-susceptible to SARS-COV-2, they have developed dynamic computational models for ACE2-
RBD complexes of different species allowing us to anticipate the effects of amino acid sequence
variation of ACE2 on viral entry
COVID-19 research v0.299 MUC5B Eleanor Williams edited their review of gene: MUC5B: Changed publications: https://doi.org/10.1101/2020.05.12.20099333
COVID-19 research v0.299 MUC5B Eleanor Williams gene: MUC5B was added
gene: MUC5B was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: MUC5B was set to Unknown
Review for gene: MUC5B was set to RED
Added comment: Preprint: van Moorsel et al https://doi.org/10.1101/2020.05.12.20099333 The mucin MUC5B is an important component of the innate immune response and expression levels are associated with the MUC5B promoter polymorphism, rs35705950. They compared patients with severe COVID-19 to controls and found the MUC5B rs35705950 promoter polymorphism associates with COVID-19. The risk allele (T) for idiopathic pulmonary fibrosis (IPF) is protective against the development of severe COVID-19 disease.
Sources: Literature
Anophthalmia or microphthalmia v1.23 FAT1 Zornitza Stark gene: FAT1 was added
gene: FAT1 was added to Anophthalmia or microphthalmia. Sources: Expert list
Mode of inheritance for gene: FAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAT1 were set to 30862798; 26905694
Phenotypes for gene: FAT1 were set to facial dysmorphism; colobomatous microphthalmia; ptosis; syndactyly with or without nephropathy
Review for gene: FAT1 was set to GREEN
gene: FAT1 was marked as current diagnostic
Added comment: 5 families reported with eye abnormalities in addition to the renal phenotype.
Sources: Expert list
Early onset or syndromic epilepsy v2.56 ANKRD11 Tracy Lester gene: ANKRD11 was added
gene: ANKRD11 was added to Genetic epilepsy syndromes. Sources: Expert Review
Mode of inheritance for gene: ANKRD11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ANKRD11 were set to 29565525
Phenotypes for gene: ANKRD11 were set to KBG syndrome
Penetrance for gene: ANKRD11 were set to Complete
Review for gene: ANKRD11 was set to GREEN
Added comment: KBG syndrome - EEG abnormalities, with or without seizures, have been reported in about 50% of affected individuals [Skjei et al 2007]. Age of onset can range from infancy to the teenage years [Low et al 2016]. The type of epilepsy is variable. Although tonic-clonic seizures are most common, no one specific type of epilepsy has been associated with the syndrome. Treatment with antiepileptic medication has proven effective in the majority of affected individuals. Many have remission of symptoms after adolescence [Lo-Castro et al 2013]. A few affected individuals have reportedly had severe seizures at a young age (described as infantile spasms / epileptic encephalopathy), in some cases drug resistant [C Ockeloen, personal communication; Samanta & Willis 2015]. - taken from GeneReviews, KBG syndrome, last updated Mar2018.
Penetrance of KBG syndrome is thought to be complete, but with variable expressivity.
Also associated with 16q24.3 deletions.
Sources: Expert Review
COVID-19 research v0.298 ACE2 Eleanor Williams commented on gene: ACE2: Preprint: https://doi.org/10.1101/2020.05.12.20098160 - Shovlin and Vizcaychip - variants in 213,158 exomes/genomes were integrated for ACE2 . ACMG/AMP-based pathogenicity criteria were applied. Modelling the ″COVID-resistant ″ state where pathogenic alleles would be beneficial, nine null alleles met PVS1. Thirty-seven variants met PM1 based on critical location +/-PP3 based on computational modelling. Modelling a ″COVID-susceptible ″ state, 31 variants in four upstream open reading frames and 5′ untranslated regions could meet PM1, and may have differential effects if aminoglycoside antibiotics were prescribed for pneumonia and sepsis.
COVID-19 research v0.298 SCARB1 Eleanor Williams Classified gene: SCARB1 as Amber List (moderate evidence)
COVID-19 research v0.298 SCARB1 Eleanor Williams Added comment: Comment on list classification: Rating Amber as there is some evidence that variants in this gene are associated with response to Hepatitus C virus
COVID-19 research v0.298 SCARB1 Eleanor Williams Gene: scarb1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.297 SCARB1 Eleanor Williams edited their review of gene: SCARB1: Changed publications: 12356718, 28827115, 29715527
COVID-19 research v0.297 SCARB1 Eleanor Williams gene: SCARB1 was added
gene: SCARB1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SCARB1 was set to Unknown
Added comment: Not associated with any relevant disease phenotype in OMIM. SCARB1 is also known as SRB1

PMID: 12356718 - Scarselli et al 2002 - Characterization of hepatitis C virus (HCV) envelope glycoprotein E2 binding after chemical or enzymic modification of the cell surface led to the identification of the scavenger receptor type B class I (SR-BI) as the E2 receptor on HepG2 cells.

PMID: 28827115 - Sadeghi et al 2017 - SCARB1 rs10846744 (CC) genotype (P=0.001) was strongly associated with sustained virological response

PMID: 28363797 - Westhaus et al 2018 - Non-synonymous variants: S112F and T175A have greatly reduced Hepatitus C virus (HCV) receptor function. When present on the cell surface, these variants are impaired in their ability to interact with HCV E2. Non-coding variants: The G allele in rs3782287 is associated with decreased viral load.

PMID: 29715527 - Naffari et al 2018 -looked at treatment responses in 395 treatment-naïve patients with chronic Hepatitus C Virus (CHC) genotype 1 treated with pegylated interferon-α and ribavirin. Rapid virologic response (RVR), complete early virologic response (cEVR) , and sustained virologic responseSVR were significantly associated with SCARB1 rs10846744 (CC).
Sources: Literature
COVID-19 research v0.296 PYCARD Eleanor Williams gene: PYCARD was added
gene: PYCARD was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: PYCARD was set to Unknown
Publications for gene: PYCARD were set to 18288107
Review for gene: PYCARD was set to RED
Added comment: Not associated with a disease phenotype in OMIM.

PYCARD is also known as ASC

PMID: 18288107 Muruve et al. 2008 - internalized adenoviral DNA induces maturation of pro-IL1B in macrophages, which is dependent on NALP3 and ASC, components of the innate cytosolic molecular complex termed the inflammasome. ASC-deficient mice display reduced innate inflammatory responses to adenovirus particles.
Sources: Literature
COVID-19 research v0.295 PQBP1 Eleanor Williams gene: PQBP1 was added
gene: PQBP1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: PQBP1 was set to Unknown
Publications for gene: PQBP1 were set to 26046437
Review for gene: PQBP1 was set to RED
Added comment: Not associated with a viral susceptibility phenotype in OMIM.

PMID: 26046437 - Yoh et al 2015 - found PQBP1 directly binds to reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate an IRF3-dependent innate response
Sources: Literature
COVID-19 research v0.294 OCLN Eleanor Williams gene: OCLN was added
gene: OCLN was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: OCLN was set to Unknown
Publications for gene: OCLN were set to 19182773; 31328852
Review for gene: OCLN was set to RED
Added comment: Not associated with any viral susceptibility phenotypes in OMIM.

Evidence that OCLN is involved in HCV cell entry

PMID: 19182773 - Ploss et al 2009 - show that human occludin is an essential HCV cell entry factor that is able to render murine cells infectable with HCVpp. Similarly, OCLN is required for the HCV-susceptibility of human cells, because its overexpression in uninfectable cells specifically enhanced HCVpp uptake, whereas its silencing in permissive cells impaired both HCVpp and HCVcc infection.

PMID: 31328852 - Lavie et al 2019 - looked at which residues in OCLN affect hepatitis C virus (HCV) entry. In the context of full-length OCLN, mutation of I279 and W281 residues only partially affected infection and cell surface localization.
Sources: Literature
COVID-19 research v0.293 NRP2 Eleanor Williams gene: NRP2 was added
gene: NRP2 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: NRP2 was set to Unknown
Publications for gene: NRP2 were set to 30057110; 29120745
Review for gene: NRP2 was set to RED
Added comment: Not associated with a disease phenotype in OMIM or Gene2Phenotype.

PMID: 30057110: Martinez-Martin et al. (2018) identified NRP2 as a host receptor for human cytomegalovirus (HCMV) pentamer.

PMID: 29120745 -Raaben et al 2017 - A genome-wide haploid genetic screen identified the transmembrane protein neuropilin 2 (NRP2) and tetraspanin CD63 as factors for Lujo virus (LUJV) glycoprotein-mediated infection. Overexpression of NRP2 or its N-terminal domain enhances VSV-LUJV infection, and cells lacking NRP2 are deficient in wild-type LUJV infection.
Sources: Literature
COVID-19 research v0.292 NCR3 Eleanor Williams gene: NCR3 was added
gene: NCR3 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: NCR3 was set to Unknown
Publications for gene: NCR3 were set to 26094914; 24845613; 30325780
Phenotypes for gene: NCR3 were set to {Malaria, mild, susceptibility to}, 609148
Review for gene: NCR3 was set to RED
Added comment: Associated with {Malaria, mild, susceptibility to} #609148 in OMIM. It is also known as NKp30.

Evidence that level of NCR3/NKp30 expression is reduced in those infected with virus, and increased in those who remain uninfected. No reports that SNVs in the NCR3 gene affect suceptibility to viral infection.

PMID: 26094914 - Mantovani et al 2015 - six different splice variants of the NKp30-encoding gene NCR3, which are known to be expressed on the cell surface. NKp30 receptor expression on NK cells and all isoforms were reduced in chronic hepatitis C virus(HCV)-infected patients.

PMID: 24845613 - Sugden et al 2014 - enhanced expression of NKp30 on NK cells resulted in protection from developing HCV infection in multiply exposed uninfected individuals

PMID: 30325780 - Lucar et al 2019 - report in HIV-2 patients a very significant reduced expression of the activating NKp30 receptor on NK cells.
Sources: Literature
COVID-19 research v0.291 MYH9 Eleanor Williams commented on gene: MYH9: Not associated with any relevant phenotypes in OMIM.
COVID-19 research v0.291 MYH9 Eleanor Williams edited their review of gene: MYH9: Changed rating: RED
COVID-19 research v0.291 MYH9 Eleanor Williams gene: MYH9 was added
gene: MYH9 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: MYH9 was set to Unknown
Publications for gene: MYH9 were set to 20944748; 27112594; 31649651; 29879459
Review for gene: MYH9 was set to AMBER
Added comment: PMID: 20944748 - Arii et al. (2010) showed that nonmuscle myosin heavy chain IIA (NMHC-IIA), a subunit of nonmuscle myosin IIA (NM-IIA), functions as a herpes simplex virus-1 (HSV-1) entry receptor by interacting with glycoprotein B.

PMID: 27112594 - Gao et al (2016) report the identification of non-muscle myosin heavy chain 9 (MYH9) as an essential factor for PRRSV infection

Several other papers describing the role of MYH9 with porcine reproductive and respiratory syndrome virus invasion e.g. 31649651;29879459
Sources: Literature
COVID-19 research v0.290 MTOR Rebecca Foulger Classified gene: MTOR as Red List (low evidence)
COVID-19 research v0.290 MTOR Rebecca Foulger Added comment: Comment on list classification: A number of papers provide evidence that some viruses use mTOR signaling to promote their replication (e.g. PMID:28953980), and how inhibition of PI3K/TOR signaling inhibits viral replication (e.g. PMID:29475942). No variant studies on TOR so Red rating appropriate for now.
COVID-19 research v0.290 MTOR Rebecca Foulger Gene: mtor has been classified as Red List (Low Evidence).
COVID-19 research v0.289 MTOR Rebecca Foulger commented on gene: MTOR: PMID:19543266. Araki et al. (2009) demonstrated that mTOR is a major regulator of memory CD8 T-cell differentiation. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced the quantity and quality of virus-specific CD8 T cells. Rapamycin treatment also enhanced memory T-cell responses in nonhuman primates following vaccination with modified vaccinia virus Ankara.
COVID-19 research v0.289 MTOR Rebecca Foulger Phenotypes for gene: MTOR were changed from 19543266 to 19543266; 29475942; 28953980
COVID-19 research v0.288 MTOR Rebecca Foulger gene: MTOR was added
gene: MTOR was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: MTOR was set to Unknown
Phenotypes for gene: MTOR were set to 19543266
Added comment: MTOR was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Red. Notes from Julie Taylor and Alison Coffey (Illumina): mTOR is a major regulator of memory CD8 T-cell differentiation.
Sources: Other
COVID-19 research v0.287 MST1R Rebecca Foulger Classified gene: MST1R as Red List (low evidence)
COVID-19 research v0.287 MST1R Rebecca Foulger Added comment: Comment on list classification: Kept rating as Red for now: Possible involvement in viral-induced carcinomas, but most evidence for a role in the viral life cycle comes from animal models.
COVID-19 research v0.287 MST1R Rebecca Foulger Gene: mst1r has been classified as Red List (Low Evidence).
COVID-19 research v0.286 MST1R Rebecca Foulger Added comment: Comment on publications: Note that in the literature, MST1R is often referred to as RON for the human and Stk for the rodent orthologs.
COVID-19 research v0.286 MST1R Rebecca Foulger Publications for gene: MST1R were set to 15557181; 22974584; 16527351
COVID-19 research v0.285 MST1R Rebecca Foulger commented on gene: MST1R: PMID:22974584 Chou et al., 2012 demonstrate involvement of MST1R (RON) in Epstein-Barr virus (EBV)-associated Nasopharyngeal carcinoma (NPC).
COVID-19 research v0.285 MST1R Rebecca Foulger commented on gene: MST1R: PMID:15557181. Lee et al. (2004) proposed that HIV-1 may directly or indirectly target MST1R (RON) to disrupt normal signals that actively suppress inflammation to assure a microenvironment favorable for virus replication.
COVID-19 research v0.285 MST1R Rebecca Foulger Publications for gene: MST1R were set to
COVID-19 research v0.284 MST1R Rebecca Foulger gene: MST1R was added
gene: MST1R was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: MST1R was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MST1R were set to {Nasopharyngeal carcinoma, susceptibility to, 3}, 617075
Added comment: MST1R was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Red.
Sources: Other
COVID-19 research v0.283 MRC1 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Red to Amber. Functional data in PMID:12645947 shows role of MRC1 in binding HIV-1, and PMID:24969847 shows association of MRC1 SNP and sustained viral response to Hepatitis-C virus.; to: Comment on list classification: Updated rating from Red to Amber. Functional data in PMID:12645947 shows role of MRC1 in binding HIV-1, and PMID:24969847 shows association of MRC1 SNP and sustained viral response to Hepatitis-C virus. Papers also demonstrate variants are associated with susceptibility to other infectious diseases including leprosy (PMID:22392581) and pulmonary tuburculosis (PMID:23653008, 22393309).
COVID-19 research v0.283 MRC1 Rebecca Foulger Publications for gene: MRC1 were set to 12645947; 24016730; 24969847
COVID-19 research v0.282 MRC1 Rebecca Foulger Classified gene: MRC1 as Amber List (moderate evidence)
COVID-19 research v0.282 MRC1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber. Functional data in PMID:12645947 shows role of MRC1 in binding HIV-1, and PMID:24969847 shows association of MRC1 SNP and sustained viral response to Hepatitis-C virus.
COVID-19 research v0.282 MRC1 Rebecca Foulger Gene: mrc1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.281 MRC1 Rebecca Foulger Publications for gene: MRC1 were set to 12645947; 24016730
COVID-19 research v0.280 MRC1 Rebecca Foulger commented on gene: MRC1: PMID:24969847. Peng et al., 2014 evaluated whether polymorphisms of MRC-1 and IL-28B genes are associated with the treatment outcome of patients infected with hepatitis C (HCV). Among the MRC-1 SNPs, rs691005 was found to be associated with sustained viral responses (SVR) in HCV-1-infected patients.
COVID-19 research v0.280 MRC1 Rebecca Foulger changed review comment from: HIVEP1 was identified through an OMIM search for potential viral susceptibility genes. Added to panel based on initial triage by Illumina (Tier 5 grouping) and additional curation. Notes from Julie Taylor and Alison Coffey (Illumina): One function of the receptor is to bind high-mannose structures on the surface of potentially pathogenic viruses, bacteria, and fungi, so that they can be neutralized by phagocytic engulfment.
Sources: Other; to: MRC1 was identified through an OMIM search for potential viral susceptibility genes. Added to panel based on initial triage by Illumina (Tier 5 grouping) and additional curation. Notes from Julie Taylor and Alison Coffey (Illumina): One function of the receptor is to bind high-mannose structures on the surface of potentially pathogenic viruses, bacteria, and fungi, so that they can be neutralized by phagocytic engulfment.
Sources: Other
COVID-19 research v0.280 MRC1 Rebecca Foulger Publications for gene: MRC1 were set to 12645947
COVID-19 research v0.279 MRC1 Rebecca Foulger Publications for gene: MRC1 were set to
COVID-19 research v0.278 MRC1 Rebecca Foulger commented on gene: MRC1: PMID:12645947. Nguyen and Hildreth (2003) showed that MRC1 (also called MMR) mediated the initial association of human immunodeficiency virus with macrophages lacking expression of DCSIGN, concluding that MRC1 (MMR) has a substantial role in binding and transmission of HIV-1 by macrophages.
CAKUT v1.147 ROR2 Sarah Leigh Added comment: Comment on mode of inheritance: Based on Gen2Phen confirmed rating of disease association including hydronephrosis in Robinow syndrome autosomal dominant and in ROR2-related disorders autosomal recessive.
CAKUT v1.147 ROR2 Sarah Leigh Mode of inheritance for gene: ROR2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.278 MRC1 Rebecca Foulger gene: MRC1 was added
gene: MRC1 was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: MRC1 was set to Unknown
Added comment: HIVEP1 was identified through an OMIM search for potential viral susceptibility genes. Added to panel based on initial triage by Illumina (Tier 5 grouping) and additional curation. Notes from Julie Taylor and Alison Coffey (Illumina): One function of the receptor is to bind high-mannose structures on the surface of potentially pathogenic viruses, bacteria, and fungi, so that they can be neutralized by phagocytic engulfment.
Sources: Other
CAKUT v1.146 ROR2 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene, where hydronephrosis is reported in Robinow syndrome autosomal dominant and in ROR2-related disorders autosomal recessive.
At least 8 variants reported have been reported in Robinow syndrome recessive in the literature (PMID 10932187;19640924;18831060), however, renal anomolies were only reported in one case (PMID 15952209).; to: Comment on list classification: Associated with relevant phenotype in OMIM and as Confirmed Gen2Phen gene, where hydronephrosis is reported in Robinow syndrome autosomal dominant and in ROR2-related disorders autosomal recessive.
At least 8 variants reported have been reported in Robinow syndrome, autosomal recessive 268310 in the literature (PMID 10932187;19640924;18831060), however, renal anomolies were only reported in one case (PMID 15952209).

Green rating is based on Expert review by Zornitza Stark that ~10% of cases of Robinow syndrome, autosomal recessive 268310 have renal abnormalities and because of the Confirmed Gen2Phen rating.
COVID-19 research v0.277 MIF Rebecca Foulger changed review comment from: PMID:30944975. de Souza et al 2019 demonstrate in mince that MIF is expressed during RSV infection and controls the release of pro-inflammatory cytokines from macrophages in an in vitro model.; to: PMID:30944975. de Souza et al 2019 demonstrate in mice that MIF is expressed during RSV infection and controls the release of pro-inflammatory cytokines from macrophages in an in vitro model.
COVID-19 research v0.277 MIF Rebecca Foulger Classified gene: MIF as Amber List (moderate evidence)
COVID-19 research v0.277 MIF Rebecca Foulger Added comment: Comment on list classification: Upgraded rating from Red to Amber. Several animal models showing that MIF is expressed during viral infection (PMIDs:30944975, 31292300, 17909632) plus study of MIF polymorphisms and West Nile virus infection in PMID:26638028.
COVID-19 research v0.277 MIF Rebecca Foulger Gene: mif has been classified as Amber List (Moderate Evidence).
CAKUT v1.146 ROR2 Sarah Leigh Classified gene: ROR2 as Green List (high evidence)
CAKUT v1.146 ROR2 Sarah Leigh Gene: ror2 has been classified as Green List (High Evidence).
COVID-19 research v0.276 MIF Rebecca Foulger commented on gene: MIF: PMID:31292300. Smith et al., 2019 showed that, during influenza viral infection, Mif-deficient mice have less inflammation, viral load, and mortality compared with WT control mice.
COVID-19 research v0.276 MIF Rebecca Foulger commented on gene: MIF: PMID:26638028. Das et al., 2016 examined functional polymorphisms in MIF in a cohort of 454 North American patients with neuroinvasive West Nile virus (WNV) disease and found patients homozygous for high-expression MIF allels to be >20 fold more likely to have WNV encephalitis.
COVID-19 research v0.276 MIF Rebecca Foulger commented on gene: MIF: PMID:30944975. de Souza et al 2019 demonstrate in mince that MIF is expressed during RSV infection and controls the release of pro-inflammatory cytokines from macrophages in an in vitro model.
CAKUT v1.145 ROR2 Sarah Leigh Classified gene: ROR2 as Amber List (moderate evidence)
CAKUT v1.145 ROR2 Sarah Leigh Gene: ror2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.144 ROR2 Sarah Leigh Classified gene: ROR2 as Green List (high evidence)
CAKUT v1.144 ROR2 Sarah Leigh Gene: ror2 has been classified as Green List (High Evidence).
CAKUT v1.143 ROR2 Sarah Leigh Classified gene: ROR2 as Amber List (moderate evidence)
CAKUT v1.143 ROR2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene, where hydronephrosis is reported in Robinow syndrome autosomal dominant and in ROR2-related disorders autosomal recessive.
At least 8 variants reported have been reported in Robinow syndrome recessive in the literature (PMID 10932187;19640924;18831060), however, renal anomolies were only reported in one case (PMID 15952209).
CAKUT v1.143 ROR2 Sarah Leigh Gene: ror2 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.276 MIF Rebecca Foulger changed review comment from: Comment on list classification: MIF was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel initially as Red. Notes from Julie Taylor and Alison Coffey (Illumina): Arjona et al. (2007) found that blocking Mif action in mice either by antibody, small molecule antagonist, or gene deletion increased resistance to West Nile Virus lethality.; to: Comment on list classification: MIF was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping), added to panel initially as Red awaiting further curation. Notes from Julie Taylor and Alison Coffey (Illumina): Arjona et al. (2007) found that blocking Mif action in mice either by antibody, small molecule antagonist, or gene deletion increased resistance to West Nile Virus lethality.
COVID-19 research v0.276 MIF Rebecca Foulger changed review comment from: Comment on list classification: MIF was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel initially as Red.; to: Comment on list classification: MIF was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel initially as Red. Notes from Julie Taylor and Alison Coffey (Illumina): Arjona et al. (2007) found that blocking Mif action in mice either by antibody, small molecule antagonist, or gene deletion increased resistance to West Nile Virus lethality.
COVID-19 research v0.276 MIF Rebecca Foulger Classified gene: MIF as Red List (low evidence)
COVID-19 research v0.276 MIF Rebecca Foulger Added comment: Comment on list classification: MIF was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel initially as Red.
COVID-19 research v0.276 MIF Rebecca Foulger Gene: mif has been classified as Red List (Low Evidence).
COVID-19 research v0.275 MIF Rebecca Foulger Phenotypes for gene: MIF were changed from to {Rheumatoid arthritis, systemic juvenile, susceptibility to}, 604302
COVID-19 research v0.274 MIF Rebecca Foulger gene: MIF was added
gene: MIF was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: MIF was set to Unknown
Publications for gene: MIF were set to 17909632
Added comment: PMID:17909632. Arjona et al. (2007) showed that patients with acute West Nile virus (WNV) infection had increased levels of MIF in plasma and cerebrospinal fluid. Studies in mice showed that MIF is involved in WNV pathogenesis.
Sources: Other
COVID-19 research v0.273 MICA Rebecca Foulger Classified gene: MICA as Amber List (moderate evidence)
COVID-19 research v0.273 MICA Rebecca Foulger Added comment: Comment on list classification: MICA was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, upgraded rating from Red to Amber: A number of publications report association between MICA variants and HBV‐related hepatocellular carcinoma. Additional papers investigate MICA polymorphisms and response to viral infections/recovery (e.g. PMIDs:28925058, 15029237).
COVID-19 research v0.273 MICA Rebecca Foulger Gene: mica has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.272 MICA Rebecca Foulger Publications for gene: MICA were set to https://doi.org/10.1101/499988; 28925058; 31033131; 15029237
COVID-19 research v0.271 MICA Rebecca Foulger Publications for gene: MICA were set to https://doi.org/10.1101/499988; 28925058; 31033131
COVID-19 research v0.270 MICA Rebecca Foulger commented on gene: MICA: PMID:15029237. Karacki et al., 2004 investigated whether MICA polymorphisms are associated with HCV recovery. They compared the frequency of all known MICA polymorphisms in 2 large cohorts of people who recovered from either HCV or HBV infection and controls. Of the 27 unique MICA polymorphisms examined, only one was detected more often in persons who had cleared HCV infection, compared with controls: MICA*015. However <4% of all those examined with viral clearance were MICA*015 positive. They cannot exclude the possibility that MICA*015 is tightly linked to another allele that is responsible for the association.
CAKUT v1.142 ROR2 Sarah Leigh Publications for gene: ROR2 were set to
COVID-19 research v0.270 MICA Rebecca Foulger changed review comment from: Publications on association between MICA variants and hepatitis B virus (HBV) infection and HBV‐related hepatocellular carcinoma (PMIDs:31419949, 29584564).; to: Several publications on association between MICA variants and hepatitis B virus (HBV) infection and HBV‐related hepatocellular carcinoma (PMIDs:31419949, 29584564,25270965).
COVID-19 research v0.270 MICA Rebecca Foulger commented on gene: MICA: Publications on association between MICA variants and hepatitis B virus (HBV) infection and HBV‐related hepatocellular carcinoma (PMIDs:31419949, 29584564).
COVID-19 research v0.270 MICA Rebecca Foulger Phenotypes for gene: MICA were changed from to primary immunodeficiency
COVID-19 research v0.269 MICA Rebecca Foulger Publications for gene: MICA were set to
COVID-19 research v0.268 MICA Rebecca Foulger commented on gene: MICA: PMID:28925058. Luo et al., 2017 examined MICA/MIBC gene polymorphisms and respiratory syncytial virus (RSV) infection in 135 paediatric patients with and without pneuomina after RSV infection. Allele MICA*002:01/A9 and haplotype MICA*002:01-MICB*005:02 were negatively associated with RSV respiratory tract infections.
COVID-19 research v0.268 MICA Rebecca Foulger commented on gene: MICA
COVID-19 research v0.268 SLC1A5 Catherine Snow gene: SLC1A5 was added
gene: SLC1A5 was added to COVID-19 research. Sources: Expert list
Mode of inheritance for gene: SLC1A5 was set to Unknown
Review for gene: SLC1A5 was set to RED
Added comment: The SLC1A5 gene encodes a sodium-dependent neutral amino acid transporter that can act as a receptor for RD114/type D retrovirus, associated viruses are non-human
Sources: Expert list
Albinism or congenital nystagmus v1.5 BLOC1S6 Eleanor Williams Classified gene: BLOC1S6 as Green List (high evidence)
Albinism or congenital nystagmus v1.5 BLOC1S6 Eleanor Williams Added comment: Comment on list classification: Promoting from amber to red, as there are now 3 cases reported.
Albinism or congenital nystagmus v1.5 BLOC1S6 Eleanor Williams Gene: bloc1s6 has been classified as Green List (High Evidence).
Albinism or congenital nystagmus v1.4 BLOC1S6 Eleanor Williams Tag for-review tag was added to gene: BLOC1S6.
Albinism or congenital nystagmus v1.4 BLOC1S6 Eleanor Williams commented on gene: BLOC1S6
Renal ciliopathies v1.16 KIF14 Catherine Snow Classified gene: KIF14 as Amber List (moderate evidence)
Renal ciliopathies v1.16 KIF14 Catherine Snow Gene: kif14 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.267 LILRB1 Rebecca Foulger commented on gene: LILRB1: PMID:29528338. Davidson et al., 2018 tested whether LILRB1 genotype influences HCMV susceptibility by analysing LILRB1 genotypes (5 SNPs) in a group of 67 Canadian transplant patients. There was no association between LILRB1 SNPs and virus replication within the entire STCS population, but when the analyses were restricted to kidney transplant recipients, a significant association of rs10423364 was found with HCMV infection.
COVID-19 research v0.267 LILRB1 Rebecca Foulger commented on gene: LILRB1: PMID:32321755. Yu et al., 2020 studied a polymorphic 3-kb region within LILRB1 intron 1 that binds the transcription factor YY1 to regulate LILRB1 levels.
COVID-19 research v0.267 LILRB1 Rebecca Foulger commented on gene: LILRB1: PMID:30461037. Cadena-Mota et al., 2018 show that cytomegalovirus infection has a major effect on LILRB1 expression in NK and other mononuclear cells, and polymorphisms in the LILRB1 regulatory region appear to have a modulatory influence over this effect.
COVID-19 research v0.267 LILRB1 Rebecca Foulger Classified gene: LILRB1 as Amber List (moderate evidence)
COVID-19 research v0.267 LILRB1 Rebecca Foulger Added comment: Comment on list classification: HIVEP1 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Amber. PMID:29528338 study investigates LILRB1 genotype and viral susceptibility and finds an association within transplant patients (but not within the population as a whole).
COVID-19 research v0.267 LILRB1 Rebecca Foulger Gene: lilrb1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.266 LILRB1 Rebecca Foulger commented on gene: LILRB1
COVID-19 research v0.266 LILRB1 Rebecca Foulger gene: LILRB1 was added
gene: LILRB1 was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: LILRB1 was set to Unknown
Publications for gene: LILRB1 were set to 30461037; 32321755; 29528338
Phenotypes for gene: LILRB1 were set to HCMV susceptibility
CAKUT v1.141 ROR2 Sarah Leigh Phenotypes for gene: ROR2 were changed from Robinow syndrome, autosomal recessive, MIM# 268310 to Robinow syndrome, autosomal recessive 268310
Primary immunodeficiency or monogenic inflammatory bowel disease v2.173 BLOC1S6 Eleanor Williams Tag for-review tag was added to gene: BLOC1S6.
CAKUT v1.140 ROBO2 Sarah Leigh Classified gene: ROBO2 as Green List (high evidence)
CAKUT v1.140 ROBO2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 4 families, together with supportive mouse models.
CAKUT v1.140 ROBO2 Sarah Leigh Gene: robo2 has been classified as Green List (High Evidence).
CAKUT v1.139 ROBO2 Sarah Leigh Phenotypes for gene: ROBO2 were changed from Vesicoureteral reflux 2, 610878; Vesicoureteral Reflux to Vesicoureteral reflux 2 610878
Primary immunodeficiency or monogenic inflammatory bowel disease v2.173 BLOC1S6 Eleanor Williams Classified gene: BLOC1S6 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.173 BLOC1S6 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. The immune dysfunction phenotype is not as clear as the platelet anomalies and ocular / oculocutaneous albinism phenotype. Therefore rating this gene as amber for now.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.173 BLOC1S6 Eleanor Williams Gene: bloc1s6 has been classified as Amber List (Moderate Evidence).
CAKUT v1.138 WNT5A Catherine Snow Classified gene: WNT5A as Amber List (moderate evidence)
CAKUT v1.138 WNT5A Catherine Snow Added comment: Comment on list classification: WNT5A associated with Robinow syndrome. Although renal disorder is associated with syndrome limited known variants reported in literature. Lots of functional models in mice therefore rating as Amber due to lack of human variants
CAKUT v1.138 WNT5A Catherine Snow Gene: wnt5a has been classified as Amber List (Moderate Evidence).
CAKUT v1.137 WNT5A Catherine Snow Publications for gene: WNT5A were set to 27002738; 31032853
CAKUT v1.137 WNT5A Catherine Snow Publications for gene: WNT5A were set to 27002738
CAKUT v1.136 WNT5A Catherine Snow Publications for gene: WNT5A were set to
COVID-19 research v0.265 KHDRBS1 Rebecca Foulger Classified gene: KHDRBS1 as Amber List (moderate evidence)
COVID-19 research v0.265 KHDRBS1 Rebecca Foulger Added comment: Comment on list classification: KHDRBS1 (SAM68) was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Amber. Functional evidence to suggest KHDRBS1 (SAM68) may serve as a proviral factor facilitate viral replication through interaction with the viral genome. A number of papers report interaction of KHDRBS1 (SAM68) and viral elements (e.g. PMIDs:26695943, 26202240, 27057671, 15701759) to positive regulate viral infection (although the viral processes affected differ between papers).
COVID-19 research v0.265 KHDRBS1 Rebecca Foulger Gene: khdrbs1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.264 KHDRBS1 Rebecca Foulger commented on gene: KHDRBS1: Notes from Julie Taylor and Alison Coffey (Illumina): KHDRBS1 belongs to the evolutionarily conserved signal transduction activator of RNA (STAR) family of RNA-binding proteins. These proteins play key roles during cell differentiation and development (summary by Bianchi et al., 2010). Cote et al. (2003, PMID:12529443) noted that KHDRBS1 (SAM68) can export unspliced human immunodeficiency virus (HIV) RNAs, and they found that treatment of cells with methylase inhibitors prevented the ability of KHDRBS1 (SAM68) to export unspliced HIV RNAs from transfected COS-7 cells.
COVID-19 research v0.264 KHDRBS1 Rebecca Foulger gene: KHDRBS1 was added
gene: KHDRBS1 was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: KHDRBS1 was set to Unknown
Publications for gene: KHDRBS1 were set to 12529443; 26695943; 26202240; 27057671; 15701759; 31068419
Added comment: PMID:31068419. Qin et al., 2019 report that KHDRBS1 (SAM68) promotes hepatitis C virus (HCV) replication without affecting viral translation. HCV infection triggers the translocation of the SAM68 protein from the nucleus to the cytoplasm, where it interacts with the HCV RNA genome.
Sources: Other
CAKUT v1.135 ROBO2 Sarah Leigh Publications for gene: ROBO2 were set to
COVID-19 research v0.263 HIVEP1 Rebecca Foulger Classified gene: HIVEP1 as Red List (low evidence)
COVID-19 research v0.263 HIVEP1 Rebecca Foulger Added comment: Comment on list classification: HIVEP1 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Red. Not yet associated with an OMIM disorder. No direct evidence for a role in viral infection, but binds a DNA sequence that is common in the enhancer elements of numerous viral promoters including simian virus 40, cytomegalovirus and HIV.
COVID-19 research v0.263 HIVEP1 Rebecca Foulger Gene: hivep1 has been classified as Red List (Low Evidence).
COVID-19 research v0.262 HIVEP1 Rebecca Foulger Added comment: Comment on publications: Note that PMID:24719322 (Modulation of TLR3, TLR4 and TLR7 Mediated IFN-β, Rantes and TNFα Production by HIVEP1) was withdrawn by the author.
COVID-19 research v0.262 HIVEP1 Rebecca Foulger Publications for gene: HIVEP1 were set to
CAKUT v1.134 NIPBL Sarah Leigh Classified gene: NIPBL as Amber List (moderate evidence)
CAKUT v1.134 NIPBL Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 13 variants reported, however, there seems to be little evidence of renal involvement.
CAKUT v1.134 NIPBL Sarah Leigh Gene: nipbl has been classified as Amber List (Moderate Evidence).
CAKUT v1.133 TBC1D1 Catherine Snow Classified gene: TBC1D1 as Green List (high evidence)
CAKUT v1.133 TBC1D1 Catherine Snow Added comment: Comment on list classification: Functional work in mouse and one paper with four unrelated individuals with pedigree analysis show evidence for a role of TBC1D1 variants in CAKUT pathogenesis. Although only identified in PMID: 26572137 paper sufficient evidence to rate TBC1D1 as Green
CAKUT v1.133 TBC1D1 Catherine Snow Gene: tbc1d1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.172 BCL11B Eleanor Williams Classified gene: BCL11B as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.172 BCL11B Eleanor Williams Added comment: Comment on list classification: Following review by the Genomics England clinical team it was decided to promote this gene from red to amber pending further cases with an immune deficiency phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.172 BCL11B Eleanor Williams Gene: bcl11b has been classified as Amber List (Moderate Evidence).
CAKUT v1.132 NIPBL Sarah Leigh Publications for gene: NIPBL were set to 8291537; 16799922; 15146186; 15146185; 15318302
CAKUT v1.131 NIPBL Sarah Leigh Phenotypes for gene: NIPBL were changed from Cornelia de Lange syndrome 1, MIM# 122470 to Cornelia de Lange syndrome 1 122470
CAKUT v1.130 NIPBL Sarah Leigh Publications for gene: NIPBL were set to 8291537
CAKUT v1.129 VPS33B Catherine Snow Classified gene: VPS33B as Red List (low evidence)
CAKUT v1.129 VPS33B Catherine Snow Added comment: Comment on list classification: Downgraded following identification by expert review as VPS33B is a tubulopathy gene.
CAKUT v1.129 VPS33B Catherine Snow Gene: vps33b has been classified as Red List (Low Evidence).
CAKUT v1.128 STRA6 Catherine Snow Classified gene: STRA6 as Green List (high evidence)
CAKUT v1.128 STRA6 Catherine Snow Added comment: Comment on list classification: Sufficient number of unrelated cases identified in the literature to classify STRA6 Green for this panel
CAKUT v1.128 STRA6 Catherine Snow Gene: stra6 has been classified as Green List (High Evidence).
CAKUT v1.127 STRA6 Catherine Snow Publications for gene: STRA6 were set to 26373900; 17503335
CAKUT v1.127 STRA6 Catherine Snow Publications for gene: STRA6 were set to
CAKUT v1.126 SLIT2 Catherine Snow Classified gene: SLIT2 as Amber List (moderate evidence)
CAKUT v1.126 SLIT2 Catherine Snow Added comment: Comment on list classification: Gene identified as missing from panel by expert reviewer. Rating as Amber as gene disease only reported in PMID:26026792 no further evidence of this association and missing segregation information for some of the three individuals.
CAKUT v1.126 SLIT2 Catherine Snow Gene: slit2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.125 SLIT2 Catherine Snow Publications for gene: SLIT2 were set to
Paediatric disorders - additional genes v1.55 NADSYN1 Sarah Leigh Classified gene: NADSYN1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.55 NADSYN1 Sarah Leigh Gene: nadsyn1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.54 NADSYN1 Sarah Leigh Tag for-review tag was added to gene: NADSYN1.
Paediatric disorders - additional genes v1.54 NADSYN1 Sarah Leigh gene: NADSYN1 was added
gene: NADSYN1 was added to Paediatric disorders - additional genes. Sources: Expert list,Literature
Mode of inheritance for gene: NADSYN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NADSYN1 were set to 31883644
Phenotypes for gene: NADSYN1 were set to Vertebral, cardiac, renal, and limb defects syndrome 3 618845
Review for gene: NADSYN1 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in at least 4 families, together with supportive functional studies (PMID 31883644).
Sources: Expert list, Literature
CAKUT v1.124 NADSYN1 Sarah Leigh changed review comment from: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in at least 4 families.; to: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in at least 4 families, together with supportive functional studies (PMID 31883644).
COVID-19 research v0.261 HIVEP1 Rebecca Foulger commented on gene: HIVEP1
COVID-19 research v0.261 HIVEP1 Rebecca Foulger gene: HIVEP1 was added
gene: HIVEP1 was added to COVID-19 research. Sources: Other
Mode of inheritance for gene: HIVEP1 was set to Unknown
CAKUT v1.124 NADSYN1 Sarah Leigh Phenotypes for gene: NADSYN1 were changed from Multiple congenital abnormalities; absent kidneys; cardiac; limb; vertebral to Vertebral, cardiac, renal, and limb defects syndrome 3 618845
CAKUT v1.123 NADSYN1 Sarah Leigh Classified gene: NADSYN1 as Green List (high evidence)
CAKUT v1.123 NADSYN1 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 6 variants reported in at least 4 families.
CAKUT v1.123 NADSYN1 Sarah Leigh Gene: nadsyn1 has been classified as Green List (High Evidence).
CAKUT v1.122 SALL4 Catherine Snow Classified gene: SALL4 as Amber List (moderate evidence)
CAKUT v1.122 SALL4 Catherine Snow Added comment: Comment on list classification: This gene has evidence of a gene phenotype relationship from one active group however since 2006 no further gene disease relationship has been reported. SALL4 recently associated with leukemic hematopoiesis. Therefore due to lack of recent association rating gene as Amber
CAKUT v1.122 SALL4 Catherine Snow Gene: sall4 has been classified as Amber List (Moderate Evidence).
CAKUT v1.121 SALL4 Catherine Snow Phenotypes for gene: SALL4 were changed from SALL4- related disorders to Duane-radial ray syndrome, 607323
Neurological ciliopathies v1.7 EXOC3L2 Zornitza Stark edited their review of gene: EXOC3L2: Added comment: Four individuals from two unrelated families reported.; Changed rating: AMBER; Changed publications: 28749478, 27894351, 30327448; Changed phenotypes: hindbrain abnormalities, kidney and bone marrow abnormalities
Renal ciliopathies v1.15 DCDC2 Zornitza Stark edited their review of gene: DCDC2: Added comment: Two families with renal ciliopathy phenotype reported.

PMID: 25557784 - a single case (1 hom PTC) with nephronophthisis.

PMID: 31821705 - single report (1 hom PTC) with nephronophthisis with renal-hepatic ciliopathy with phenotypic characteristics that include hepatosplenomegaly, hepatic fibrosis with bile cholestasis, increased kidney echogenicity, and end-stage renal disease. MRI did not indicate cerebellar atrophy or MTS; Changed rating: AMBER; Changed publications: 25557784, 31821705; Changed phenotypes: Nephronophthisis 19, MIM#616217
Neurological ciliopathies v1.7 CCDC28B Zornitza Stark gene: CCDC28B was added
gene: CCDC28B was added to Neurological ciliopathies. Sources: Expert list
Mode of inheritance for gene: CCDC28B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC28B were set to 32139166
Phenotypes for gene: CCDC28B were set to Joubert syndrome
Review for gene: CCDC28B was set to AMBER
Added comment: Note new publication relating to this gene, which has previously been postulated to be a modifier for BBS. PMID: 32139166 - Single family with Joubert syndrome. Patient was homozygous for a missense, with polydactyly, severe ID, and the molar tooth sign observed in MRI. Sibling fetus MRI showed vermis hypoplasia, and was also homozygous for the variant. Parents confirmed unaffected carriers.

Borderline Amber/Red but note knockdown of CCDC28B in human TERT retinal pigment epithelial cells reduced both the number and length of cilia, providing some supportive evidence.
Sources: Expert list
Ophthalmological ciliopathies v1.4 C8orf37 Zornitza Stark reviewed gene: C8orf37: Rating: GREEN; Mode of pathogenicity: None; Publications: 27008867, 26854863, 22177090, 25113443, 2686542625802487; Phenotypes: Bardet-Biedl syndrome 21 617406, Cone-rod dystrophy 16 614500, Retinitis pigmentosa 64 614500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Renal ciliopathies v1.15 BBIP1 Zornitza Stark reviewed gene: BBIP1: Rating: AMBER; Mode of pathogenicity: None; Publications: 24026985, 32055034; Phenotypes: Bardet-Biedl syndrome 18, MIM#615995; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Non-CF bronchiectasis v1.22 CCDC39 Catherine Snow Classified gene: CCDC39 as Red List (low evidence)
Non-CF bronchiectasis v1.22 CCDC39 Catherine Snow Gene: ccdc39 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.21 CCDC39 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.21 CCDC40 Catherine Snow Classified gene: CCDC40 as Red List (low evidence)
Non-CF bronchiectasis v1.21 CCDC40 Catherine Snow Gene: ccdc40 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.20 CCDC40 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.20 DNAAF1 Catherine Snow Classified gene: DNAAF1 as Red List (low evidence)
Non-CF bronchiectasis v1.20 DNAAF1 Catherine Snow Gene: dnaaf1 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.19 DNAAF1 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.19 DNAAF2 Catherine Snow Classified gene: DNAAF2 as Red List (low evidence)
Non-CF bronchiectasis v1.19 DNAAF2 Catherine Snow Gene: dnaaf2 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.18 DNAAF2 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.18 DNAH11 Catherine Snow Classified gene: DNAH11 as Red List (low evidence)
Non-CF bronchiectasis v1.18 DNAH11 Catherine Snow Gene: dnah11 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.17 DNAH11 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.17 DNAH5 Catherine Snow Classified gene: DNAH5 as Red List (low evidence)
Non-CF bronchiectasis v1.17 DNAH5 Catherine Snow Gene: dnah5 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.16 DNAH5 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.16 DNAI1 Catherine Snow Classified gene: DNAI1 as Red List (low evidence)
Non-CF bronchiectasis v1.16 DNAI1 Catherine Snow Gene: dnai1 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.15 DNAI1 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.15 DNAL1 Catherine Snow Classified gene: DNAL1 as Red List (low evidence)
Non-CF bronchiectasis v1.15 DNAL1 Catherine Snow Gene: dnal1 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.14 DNAL1 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.14 DNAI2 Catherine Snow Classified gene: DNAI2 as Red List (low evidence)
Non-CF bronchiectasis v1.14 DNAI2 Catherine Snow Gene: dnai2 has been classified as Red List (Low Evidence).
Non-CF bronchiectasis v1.13 DNAI2 Catherine Snow Deleted their review
Non-CF bronchiectasis v1.13 DNAI2 Catherine Snow Deleted their comment
Non-CF bronchiectasis v1.13 DNAL1 Catherine Snow Classified gene: DNAL1 as Green List (high evidence)
Non-CF bronchiectasis v1.13 DNAL1 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.13 DNAL1 Catherine Snow Gene: dnal1 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.12 DNAI2 Catherine Snow Classified gene: DNAI2 as Green List (high evidence)
Non-CF bronchiectasis v1.12 DNAI2 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.12 DNAI2 Catherine Snow Gene: dnai2 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.11 DNAI1 Catherine Snow Classified gene: DNAI1 as Green List (high evidence)
Non-CF bronchiectasis v1.11 DNAI1 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.11 DNAI1 Catherine Snow Gene: dnai1 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.10 DNAH5 Catherine Snow Classified gene: DNAH5 as Green List (high evidence)
Non-CF bronchiectasis v1.10 DNAH5 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.10 DNAH5 Catherine Snow Gene: dnah5 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.9 DNAH11 Catherine Snow Classified gene: DNAH11 as Green List (high evidence)
Non-CF bronchiectasis v1.9 DNAH11 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.9 DNAH11 Catherine Snow Gene: dnah11 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.8 DNAAF2 Catherine Snow Classified gene: DNAAF2 as Green List (high evidence)
Non-CF bronchiectasis v1.8 DNAAF2 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.8 DNAAF2 Catherine Snow Gene: dnaaf2 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.7 DNAAF1 Catherine Snow Classified gene: DNAAF1 as Green List (high evidence)
Non-CF bronchiectasis v1.7 DNAAF1 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.7 DNAAF1 Catherine Snow Gene: dnaaf1 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.6 CCDC40 Catherine Snow Classified gene: CCDC40 as Green List (high evidence)
Non-CF bronchiectasis v1.6 CCDC40 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.6 CCDC40 Catherine Snow Gene: ccdc40 has been classified as Green List (High Evidence).
Non-CF bronchiectasis v1.5 CCDC39 Catherine Snow Classified gene: CCDC39 as Green List (high evidence)
Non-CF bronchiectasis v1.5 CCDC39 Catherine Snow Added comment: Comment on list classification: Flagged by expert reviewer that gene should be Green on this panel. Gene has been reviewed Green on the Respiratory ciliopathies including non-CF bronchiectasis for GMS and so updating 100k panel to represent this.
Non-CF bronchiectasis v1.5 CCDC39 Catherine Snow Gene: ccdc39 has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Deleted their comment
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Classified gene: MYOCD as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Added comment: Comment on list classification: Chirag Patel (Genetic Health Queensland)(16 Jan 2020) review on CAKUT panel: Four unrelated families. Mono allelic disease in males (megabladder), bi-allelic disease in males and females (megabladder and congenital heart disease). Cosegregation of MYOCD variants with the phenotype in 4 unrelated families by in vitro transactivation studies in which pathogenic variants resulted in abrogated SM gene expression and by the finding of megabladder in 2 distinct mouse models with reduced Myocd activity.
Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 4 variants reported in at least 4 unrelated cases, together with a supportive loss of function mouse model. PMID 31513549 concludes "that monoallelic loss-of-function variants in MYOCD cause congenital megabladder in males and that biallelic variants are associated with disease manifest in females that also involves the cardiovascular system".
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Gene: myocd has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Classified gene: MYOCD as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Added comment: Comment on list classification: Chirag Patel (Genetic Health Queensland)(16 Jan 2020) review on CAKUT panel: Four unrelated families. Mono allelic disease in males (megabladder), bi-allelic disease in males and females (megabladder and congenital heart disease). Cosegregation of MYOCD variants with the phenotype in 4 unrelated families by in vitro transactivation studies in which pathogenic variants resulted in abrogated SM gene expression and by the finding of megabladder in 2 distinct mouse models with reduced Myocd activity.
Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 4 variants reported in at least 4 unrelated cases, together with a supportive loss of function mouse model. PMID 31513549 concludes "that monoallelic loss-of-function variants in MYOCD cause congenital megabladder in males and that biallelic variants are associated with disease manifest in females that also involves the cardiovascular system".
Paediatric disorders - additional genes v1.53 MYOCD Sarah Leigh Gene: myocd has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.52 MYOCD Sarah Leigh Tag for-review tag was added to gene: MYOCD.
Paediatric disorders - additional genes v1.52 MYOCD Sarah Leigh gene: MYOCD was added
gene: MYOCD was added to Paediatric disorders - additional genes. Sources: Expert Review
Mode of inheritance for gene: MYOCD was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYOCD were set to 31513549
Phenotypes for gene: MYOCD were set to Megabladder, congenital 618719
Review for gene: MYOCD was set to AMBER
Added comment: Sources: Expert Review
CAKUT v1.120 MYOCD Sarah Leigh Classified gene: MYOCD as Green List (high evidence)
CAKUT v1.120 MYOCD Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 4 variants reported in at least 4 unrelated cases, together with a supportive loss of function mouse model. PMID 31513549 concludes "that monoallelic loss-of-function variants in MYOCD cause congenital megabladder in males and that biallelic variants are associated with disease manifest in females that also involves the cardiovascular system".
CAKUT v1.120 MYOCD Sarah Leigh Gene: myocd has been classified as Green List (High Evidence).
CAKUT v1.119 MYOCD Sarah Leigh Phenotypes for gene: MYOCD were changed from Megabladder; congenital heart disease; cardiomyopathy to Megabladder, congenital 618719
CAKUT v1.118 MYOCD Sarah Leigh Publications for gene: MYOCD were set to PMID: 31513549
CAKUT v1.117 NOTCH2 Sarah Leigh Classified gene: NOTCH2 as Green List (high evidence)
CAKUT v1.117 NOTCH2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 10 variants reported been reported in unrealated with features of Alagille syndrome (PMID 22209762).
CAKUT v1.117 NOTCH2 Sarah Leigh Gene: notch2 has been classified as Green List (High Evidence).
CAKUT v1.116 NOTCH2 Sarah Leigh Publications for gene: NOTCH2 were set to 22105858; 16773578
CAKUT v1.115 NOTCH2 Sarah Leigh Publications for gene: NOTCH2 were set to 22105858
Intellectual disability v3.66 ALKBH8 Rebecca Foulger Classified gene: ALKBH8 as Amber List (moderate evidence)
Intellectual disability v3.66 ALKBH8 Rebecca Foulger Added comment: Comment on list classification: Demoted from Green to Amber based on advice from the Genomics England Clinical Team. In email correspondence, Helen Brittain notes that this is a borderline gene in terms of evidence (two families, 6/7 individuals with seizures and not particularly extensive functional / supportive information). Zornitza's review on the Genetic Epilepsy Syndromes panel focuses on the differing ratings of ALKBH8 on the ID (Green) and Epilepsy (Amber) panels. Based on borderline evidence, I have demoted ALKBH8 to Amber on the ID panel to be consistent with the GLH consensus on the Epilepsy panel (R59 #402).
Intellectual disability v3.66 ALKBH8 Rebecca Foulger Gene: alkbh8 has been classified as Amber List (Moderate Evidence).
CAKUT v1.114 NOTCH2 Sarah Leigh Publications for gene: NOTCH2 were set to PMID: 22105858
CAKUT v1.113 NOTCH2 Sarah Leigh Added comment: Comment on phenotypes: Alagille syndrome 2 610205
CAKUT v1.113 NOTCH2 Sarah Leigh Phenotypes for gene: NOTCH2 were changed from Alagille syndrome 2; OMIM #610205 to Alagille syndrome 2 610205
Early onset or syndromic epilepsy v2.56 ALKBH8 Rebecca Foulger Tag for-review tag was added to gene: ALKBH8.
Early onset or syndromic epilepsy v2.56 ALKBH8 Rebecca Foulger commented on gene: ALKBH8: Kept rating as Amber following advice from the Genomics England Clinical Team since Amber was the GLH opinion. This is a borderline gene in terms of evidence (two families, 6/7 individuals with seizures and not particularly extensive functional / supportive information). Have added 'for-review' tag to highlight the Green review from Zornitza. Note that Zornitza's review focuses on the differing ratings of ALKBH8 on the ID and Epilepsy panels, which I will align for consistency: no new evidence in the review.
COVID-19 research v0.260 CXorf36 Sarah Leigh Tag new-gene-name tag was added to gene: CXorf36.
COVID-19 research v0.260 ZNF34 Sarah Leigh reviewed gene: ZNF34: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 ZFP36 Sarah Leigh reviewed gene: ZFP36: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 ZC3HC1 Sarah Leigh reviewed gene: ZC3HC1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 TUBGCP3 Sarah Leigh reviewed gene: TUBGCP3: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 TSPAN14 Sarah Leigh reviewed gene: TSPAN14: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 TNIP1 Sarah Leigh reviewed gene: TNIP1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 SLC13A4 Sarah Leigh reviewed gene: SLC13A4: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 ODC1 Sarah Leigh reviewed gene: ODC1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 MTPAP Sarah Leigh reviewed gene: MTPAP: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 MICA Sarah Leigh reviewed gene: MICA: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 MED13L Sarah Leigh reviewed gene: MED13L: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 IVNS1ABP Sarah Leigh reviewed gene: IVNS1ABP: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 FOXM1 Sarah Leigh reviewed gene: FOXM1: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 FBRS Sarah Leigh reviewed gene: FBRS: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 CXorf36 Sarah Leigh reviewed gene: CXorf36: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.260 ABI3 Sarah Leigh reviewed gene: ABI3: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.259 ZNF34 Sarah Leigh gene: ZNF34 was added
gene: ZNF34 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ZNF34 was set to Unknown
COVID-19 research v0.258 ZFP36 Sarah Leigh gene: ZFP36 was added
gene: ZFP36 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ZFP36 was set to Unknown
COVID-19 research v0.257 ZC3HC1 Sarah Leigh gene: ZC3HC1 was added
gene: ZC3HC1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ZC3HC1 was set to Unknown
COVID-19 research v0.256 TUBGCP3 Sarah Leigh gene: TUBGCP3 was added
gene: TUBGCP3 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: TUBGCP3 was set to Unknown
COVID-19 research v0.255 TSPAN14 Sarah Leigh gene: TSPAN14 was added
gene: TSPAN14 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: TSPAN14 was set to Unknown
COVID-19 research v0.254 TNIP1 Sarah Leigh gene: TNIP1 was added
gene: TNIP1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: TNIP1 was set to Unknown
COVID-19 research v0.253 SLC13A4 Sarah Leigh gene: SLC13A4 was added
gene: SLC13A4 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SLC13A4 was set to Unknown
COVID-19 research v0.252 ODC1 Sarah Leigh gene: ODC1 was added
gene: ODC1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ODC1 was set to Unknown
COVID-19 research v0.251 MTPAP Sarah Leigh gene: MTPAP was added
gene: MTPAP was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: MTPAP was set to Unknown
COVID-19 research v0.250 MICA Sarah Leigh gene: MICA was added
gene: MICA was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: MICA was set to Unknown
COVID-19 research v0.249 MED13L Sarah Leigh gene: MED13L was added
gene: MED13L was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: MED13L was set to Unknown
COVID-19 research v0.248 IVNS1ABP Sarah Leigh gene: IVNS1ABP was added
gene: IVNS1ABP was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: IVNS1ABP was set to Unknown
COVID-19 research v0.247 FOXM1 Sarah Leigh gene: FOXM1 was added
gene: FOXM1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: FOXM1 was set to Unknown
COVID-19 research v0.246 FBRS Sarah Leigh gene: FBRS was added
gene: FBRS was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: FBRS was set to Unknown
COVID-19 research v0.245 CXorf36 Sarah Leigh gene: CXorf36 was added
gene: CXorf36 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: CXorf36 was set to Unknown
COVID-19 research v0.244 ABI3 Sarah Leigh gene: ABI3 was added
gene: ABI3 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: ABI3 was set to Unknown
COVID-19 research v0.243 SOCS1 Sarah Leigh edited their review of gene: SOCS1: Changed publications: 12588885, 12588885, 18172216, https://doi.org/10.1101/499988
COVID-19 research v0.243 SOCS1 Sarah Leigh changed review comment from: PMID 12588885: In coxsackievirus-infected mice cardiac myocyte-specific transgenic expression of SOCS1 inhibited virus-induced signaling of JAK and STAT resulting in increased viral replication, cardiomyopathy, and mortality compared to controls. Inhibition of SOCS in cardiac myocytes increased myocyte resistance to the acute cardiac injury of enteroviral infection. It was suggested that inhibition of SOCS could augment the host-cell antiviral system and might prevent viral-mediated end-organ damage during the early stages of infection.
Sources: Literature; to: PMID 12588885: In coxsackievirus-infected mice cardiac myocyte-specific transgenic expression of SOCS1 inhibited virus-induced signaling of JAK and STAT resulting in increased viral replication, cardiomyopathy, and mortality compared to controls. Inhibition of SOCS in cardiac myocytes increased myocyte resistance to the acute cardiac injury of enteroviral infection. It was suggested that inhibition of SOCS could augment the host-cell antiviral system and might prevent viral-mediated end-organ damage during the early stages of infection.
https://doi.org/10.1101/499988 reports: Genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci).

Sources: Literature
COVID-19 research v0.243 SOCS1 Sarah Leigh gene: SOCS1 was added
gene: SOCS1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SOCS1 was set to Unknown
Publications for gene: SOCS1 were set to 12588885; 12588885; 18172216
Phenotypes for gene: SOCS1 were set to primary immunodeficiency
Review for gene: SOCS1 was set to AMBER
Added comment: PMID 12588885: In coxsackievirus-infected mice cardiac myocyte-specific transgenic expression of SOCS1 inhibited virus-induced signaling of JAK and STAT resulting in increased viral replication, cardiomyopathy, and mortality compared to controls. Inhibition of SOCS in cardiac myocytes increased myocyte resistance to the acute cardiac injury of enteroviral infection. It was suggested that inhibition of SOCS could augment the host-cell antiviral system and might prevent viral-mediated end-organ damage during the early stages of infection.
Sources: Literature
COVID-19 research v0.242 PTPN2 Sarah Leigh gene: PTPN2 was added
gene: PTPN2 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: PTPN2 was set to Unknown
Publications for gene: PTPN2 were set to 19825843; https://doi.org/10.1101/499988
Phenotypes for gene: PTPN2 were set to primary immunodeficiency
Review for gene: PTPN2 was set to RED
Added comment: https://doi.org/10.1101/499988 reports: genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci).
Sources: Literature
Early onset or syndromic epilepsy v2.56 STARD7 Rebecca Foulger Phenotypes for gene: STARD7 were changed from Epilepsy, familial adult myoclonic, 2, 607876 to Epilepsy, familial adult myoclonic, 2, 607876; Familial adult myoclonic epilepsy-2; FAME-2
Early onset or syndromic epilepsy v2.55 STARD7 Rebecca Foulger Classified gene: STARD7 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.55 STARD7 Rebecca Foulger Added comment: Comment on list classification: Added as Amber awaiting clinical review as to whether gene and/or a new STR should be Green. In 158 affected individuals from 22 unrelated families with familial adult myoclonic epilepsy-2, Corbett et al. (2019, PMID:31664034) identified a heterozygous 5-bp repeat expansion (ATTTC)n in intron 1 of the STARD7 gene. Affected individuals had variable expansion of an endogenous (ATTTT)n repeat in addition to the insertion of an abnormal (ATTTC)n repeat.
Early onset or syndromic epilepsy v2.55 STARD7 Rebecca Foulger Gene: stard7 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.54 STARD7 Rebecca Foulger gene: STARD7 was added
gene: STARD7 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: STARD7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: STARD7 were set to 11701600; 24114805; 31664034
Phenotypes for gene: STARD7 were set to Epilepsy, familial adult myoclonic, 2, 607876
Added comment: PMID:31664034. Corbett et al., 2019. In 158 affected individuals from 22 unrelated families with MIM:607876, Corbett et al. (2019) identified a heterozygous 5-bp repeat expansion, (ATTTC)n, in the STARD7 gene. The cohort included 2 families who had previously been identified as having an ins/del mutation in the ADRA2B gene (Guerrini et al., 2001 PMID:11701600, and De Fusco et al., 2014, PMID:24114805), suggesting the the ADRA2B allele is not causative.

OMIM disorder 'Epilepsy, familial adult myoclonic, 2, 607876' (previously associated with ADRA2B) is now associated with the STARD7 gene.
Sources: Literature, Other
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger commented on gene: ADRA2B: Added 'for-review' tag to alert GLH to downgraded rating.
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger Classified gene: ADRA2B as Red List (low evidence)
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger Added comment: Comment on list classification: Downgraded rating from Amber to Red following PMID:31664034 (2019) publication that finds an alternative cause for epilepsy in the earlier reported patients, suggesting the the ADRA2B allele is not causative. MIM:607876 is now associated with a repeat expansion in STARD7, and not ADRA2B.
Early onset or syndromic epilepsy v2.53 ADRA2B Rebecca Foulger Gene: adra2b has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v2.52 ADRA2B Rebecca Foulger Publications for gene: ADRA2B were set to 11701600
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger commented on gene: ADRA2B: PMID:18231815: Direct sequencing of the ADRA2B gene in pedigrees from southern Italy that were described as having familial adult myoclonic epilepsy by Madia et al. (2008) did not reveal any pathogenic mutations.
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger commented on gene: ADRA2B: PMID:31664034. Corbett et al., 2019. In 158 affected individuals from 22 unrelated families with MIM:607876, Corbett et al. (2019) identified a heterozygous 5-bp repeat expansion, (ATTTC)n, in the STARD7 gene. The cohort included 2 families who had previously been identified as having an ins/del mutation in the ADRA2B gene (Guerrini et al., 2001 PMID:11701600, and De Fusco et al., 2014, PMID:24114805), suggesting the the ADRA2B allele is not causative.
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger Added comment: Comment on phenotypes: OMIM disorder 'Epilepsy, familial adult myoclonic, 2, 607876' is now associated with the STARD7 gene. Therefore removed MIM:607876 from the phenotype field of ADRA2B.
Early onset or syndromic epilepsy v2.51 ADRA2B Rebecca Foulger Phenotypes for gene: ADRA2B were changed from Epilepsy, myoclonic, familial adult, 2, 607876 to Cortical myoclonus and epilepsy
Cholestasis v1.8 TMEM67 Ivone Leong Tag for-review tag was added to gene: TMEM67.
Cholestasis v1.8 CC2D2A Ivone Leong Phenotypes for gene: CC2D2A were changed from COACH syndrome 216360; Meckel syndrome 6 612284; Joubert syndrome 9 612285 to COACH syndrome 216360; Meckel syndrome 6 612284; Joubert syndrome 9 612285; Congenital hepatic fibrosis; Ciliopathy
Cholestasis v1.7 CC2D2A Ivone Leong Publications for gene: CC2D2A were set to 27959436; 19574260; 18950740
Cholestasis v1.6 CC2D2A Ivone Leong Tag for-review tag was added to gene: CC2D2A.
Cholestasis v1.6 RPGRIP1L Ivone Leong Tag for-review tag was added to gene: RPGRIP1L.
Cholestasis v1.6 RPGRIP1L Ivone Leong Phenotypes for gene: RPGRIP1L were changed from Meckel syndrome 5 (611561); Joubert syndrome 7 (611560); COACH syndrome (216360) to Meckel syndrome 5 (611561); Joubert syndrome 7 (611560); COACH syndrome (216360); Congenital hepatic fibrosis
Cholestasis v1.5 RPGRIP1L Ivone Leong Publications for gene: RPGRIP1L were set to 17558409; 19574260
Cholestasis v1.4 CC2D2A Miranda Durkie reviewed gene: CC2D2A: Rating: RED; Mode of pathogenicity: ; Publications: 28680603; Phenotypes: ; Mode of inheritance:
Cholestasis v1.4 RPGRIP1L Miranda Durkie reviewed gene: RPGRIP1L: Rating: RED; Mode of pathogenicity: ; Publications: 28680603; Phenotypes: ; Mode of inheritance:
Cholestasis v1.4 TMEM67 Miranda Durkie reviewed gene: TMEM67: Rating: RED; Mode of pathogenicity: ; Publications: 28680603; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v2.171 CD247 Ivone Leong Classified gene: CD247 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.171 CD247 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green after discussion with the Genomics England Clinical Team. An additional case was found (PMID: 26542031). Therefore, there is enough evidence to promote this gene to Green status.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.171 CD247 Ivone Leong Gene: cd247 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.170 SEC61A1 Ivone Leong Tag watchlist was removed from gene: SEC61A1.
Tag for-review tag was added to gene: SEC61A1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.170 SEC61A1 Ivone Leong Classified gene: SEC61A1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.170 SEC61A1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber after discussion with the Genomics England Clinical Team. As there are only 2 families described it was decided that this gene should be rated as Amber. Also added for-review tag.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.170 SEC61A1 Ivone Leong Gene: sec61a1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.169 SEC61A1 Ivone Leong Tag watchlist tag was added to gene: SEC61A1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.169 TNFRSF13B Ivone Leong reviewed gene: TNFRSF13B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.169 OAS1 Rebecca Foulger Classified gene: OAS1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.169 OAS1 Rebecca Foulger Added comment: Comment on list classification: Upgraded rating from Amber to Green following advice from Helen Brittain (Genomics England Clinical Team): There appear to be three unrelated families with variants and hypogammaglobulinaemia. I think this is a relevant phenotype for immune dysfunction.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.169 OAS1 Rebecca Foulger Gene: oas1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 MYO5B Rebecca Foulger changed review comment from: Added 'for-review' tag to highlight Red review from Zornitza (lack of published information) vs multiple Green GLH reviews.; to: In agreement with Helen Brittain (Genomics England Clinical Team), added 'for-review' tag to highlight Red review from Zornitza (lack of published information) vs multiple Green GLH reviews.
Rare multisystem ciliopathy disorders v1.125 EXOC3L2 Rebecca Foulger Classified gene: EXOC3L2 as Amber List (moderate evidence)
Rare multisystem ciliopathy disorders v1.125 EXOC3L2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber following review of EXOC3L2 on the CAKUT gene panel, and on advice from Helen Brittain (Genomics England Clinical Team).
Rare multisystem ciliopathy disorders v1.125 EXOC3L2 Rebecca Foulger Gene: exoc3l2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.112 DHCR7 Rebecca Foulger Classified gene: DHCR7 as Green List (high evidence)
CAKUT v1.112 DHCR7 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green on advice from Helen Brittain (Genomics England Clinical Team). Helen notes that it meets the inclusion criteria (renal malformations as part of a wider syndromic phenotype). There are other post-natally relevant renal malformations (unilateral agenesis, hydronephrosis and cysts). It is also a gene that we have a biochemical test for, so VUSs would be easier to re-categorise than some genes.
CAKUT v1.112 DHCR7 Rebecca Foulger Gene: dhcr7 has been classified as Green List (High Evidence).
CAKUT v1.111 EXOC3L2 Rebecca Foulger Tag watchlist tag was added to gene: EXOC3L2.
CAKUT v1.111 EXOC3L2 Rebecca Foulger Classified gene: EXOC3L2 as Amber List (moderate evidence)
CAKUT v1.111 EXOC3L2 Rebecca Foulger Added comment: Comment on list classification: Agreed by Helen Brittain (Genomics England clinical team) that Amber rating is appropriate here: only one case that didn't lead to fetal demise. Added 'watchlist' tag awaiting further cases.
CAKUT v1.111 EXOC3L2 Rebecca Foulger Gene: exoc3l2 has been classified as Amber List (Moderate Evidence).
Parkinson Disease and Complex Parkinsonism v1.68 PTRHD1 Helen Brittain Marked gene: PTRHD1 as ready
Parkinson Disease and Complex Parkinsonism v1.68 PTRHD1 Helen Brittain Added comment: Comment when marking as ready: Considered to have sufficient cases with a relevant phenotype for a green rating.
Parkinson Disease and Complex Parkinsonism v1.68 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.68 PTRHD1 Helen Brittain Classified gene: PTRHD1 as Green List (high evidence)
Parkinson Disease and Complex Parkinsonism v1.68 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Parkinson Disease and Complex Parkinsonism v1.67 PTRHD1 Helen Brittain gene: PTRHD1 was added
gene: PTRHD1 was added to Parkinson Disease and Complex Parkinsonism. Sources: Other
Mode of inheritance for gene: PTRHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTRHD1 were set to 30398675; 27134041; 29143421; 27753167
Phenotypes for gene: PTRHD1 were set to Intellectual disability; Parkinsonism
Penetrance for gene: PTRHD1 were set to Complete
Review for gene: PTRHD1 was set to GREEN
Added comment: Please see review in ID panel by Konstantinos Varvagiannis: https://panelapp.genomicsengland.co.uk/panels/285/gene/PTRHD1/

In addition: Personal correspondence about a new diagnosis from within the 100,000 genomes project data. A child presenting with learning difficulties, autism, shuffling gait, calf wasting and normal CK has been detected as having homozygous LOF variants in PTRHD1. Reported as class V via NHS diagnostic lab. In view of this additional case and phenotypic overlap (Intellectual disability and Parkinsonian features), I am adding this gene to the panel as green.
Sources: Other
Intellectual disability v3.65 PTRHD1 Helen Brittain Marked gene: PTRHD1 as ready
Intellectual disability v3.65 PTRHD1 Helen Brittain Added comment: Comment when marking as ready: Further case from personal correspondence. Considered sufficient for a green rating.
Intellectual disability v3.65 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Intellectual disability v3.65 PTRHD1 Helen Brittain Phenotypes for gene: PTRHD1 were changed from Intellectual disability; Parkinsonism, Intellectual disability; Parkinsonism to Intellectual disability; Parkinsonism
Intellectual disability v3.64 PTRHD1 Helen Brittain Classified gene: PTRHD1 as Green List (high evidence)
Intellectual disability v3.64 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Intellectual disability v3.63 PTRHD1 Helen Brittain Tag watchlist was removed from gene: PTRHD1.
Intellectual disability v3.63 PTRHD1 Helen Brittain Classified gene: PTRHD1 as Green List (high evidence)
Intellectual disability v3.63 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Intellectual disability v3.63 PTRHD1 Helen Brittain Classified gene: PTRHD1 as Green List (high evidence)
Intellectual disability v3.63 PTRHD1 Helen Brittain Gene: ptrhd1 has been classified as Green List (High Evidence).
Intellectual disability v3.62 PTRHD1 Helen Brittain reviewed gene: PTRHD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Amelogenesis imperfecta v2.5 AMELX Eleanor Williams Phenotypes for gene: AMELX were changed from Amelogenesis imperfecta, type 1E, 301200; Amelogenesis Imperfecta, Type IE, 301200; X-linked hypoplastic amelogenesis imperfecta; hypomaturation AI with variable hypoplastic foci; smooth hypoplastic AI to Amelogenesis imperfecta, type 1E, 301200; iX-linked hypoplastic amelogenesis imperfecta; hypomaturation AI with variable hypoplastic foci; smooth hypoplastic AI
Paediatric disorders - additional genes v1.51 ITGA8 Rebecca Foulger Classified gene: ITGA8 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.51 ITGA8 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber awaiting GLH review. Additional phenotypes were reported in the fetuses and sibling (who died perinatally) from PMID:24439109 (clubbed feet, facial dysmorphism, pulmonary hypoplasia, bilateral cryptorchidism) although renal agenesis is the primary phenotype and only 2 families from one paper.
Paediatric disorders - additional genes v1.51 ITGA8 Rebecca Foulger Gene: itga8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.73 ITGA8 Rebecca Foulger Deleted their comment
Paediatric disorders - additional genes v1.50 TBX18 Rebecca Foulger Classified gene: TBX18 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.50 TBX18 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber awaiting GLH review. Three unrelated CAKUT cases in PMID:26235987 (2015) but as Helen Brittain notes, isolated CAKUT phenotype is less relevant for the Paediatric disorders panel.
Paediatric disorders - additional genes v1.50 TBX18 Rebecca Foulger Gene: tbx18 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.49 TBX18 Rebecca Foulger Publications for gene: TBX18 were set to
Paediatric disorders - additional genes v1.49 TBX18 Rebecca Foulger Phenotypes for gene: TBX18 were changed from CAKUT to CAKUT; Congenital anomalies of kidney and urinary tract 2, 143400
CAKUT v1.110 TBX18 Rebecca Foulger Phenotypes for gene: TBX18 were changed from to CAKUT; Renal cysts and diabetes; glomerulocystic kidney disease; hypomagneseamia; Congenital anomalies of kidney and urinary tract 2, 143400
CAKUT v1.109 TBX18 Rebecca Foulger Publications for gene: TBX18 were set to
Paediatric disorders - additional genes v1.48 LRIG2 Rebecca Foulger Classified gene: LRIG2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.48 LRIG2 Rebecca Foulger Gene: lrig2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.47 LRIG2 Rebecca Foulger Classified gene: LRIG2 as Green List (high evidence)
Paediatric disorders - additional genes v1.47 LRIG2 Rebecca Foulger Added comment: Comment on list classification: Three unrelated cases reported in PMID:23313374 (Stuart et al., 2013), although in one of the families siblings with the same homozygous variant report differing phenotypes. There is also an animal model. The facial phenotype that occurs alongside the urinary tract phenotype is an abnormal facial expression upon smiling rather than a congenital structural phenotype. Therefore have kept Amber for now awaiting clinical review.
Paediatric disorders - additional genes v1.47 LRIG2 Rebecca Foulger Gene: lrig2 has been classified as Green List (High Evidence).
CAKUT v1.108 LRIG2 Rebecca Foulger Publications for gene: LRIG2 were set to Stuart HM, Roberts NA, Bergu B, Daly SB, Urquhart JE, Bhaskar S, Dickerson J, Mermerkaya M, Silay MS, Lewis MA, Olondriz BO, Gener B, Beetz C, Varga RE, Gülpınar O, Süer E, Yalçınkaya F, Gücük A, Yue WW, Erdogan F, Berry A, Hanley NA, McKenzie EA, Hilton EN, Woolf AS, Newman WG. LRIG2 mutations cause urofacial syndrome. Am J Hum Genet 92:259-264, 2013.
Paediatric disorders - additional genes v1.46 LRIG2 Rebecca Foulger commented on gene: LRIG2: PMID:23313374. Stuart et al., 2013 performed exome sequencing in affected siblings from a consanguineous Turkish family with urofacial syndrome. A 1bp deletion variant resulting in premature termination (Glu140AspfsTer6) was found in an 8 year old girl, but also in her 5 year old brother who exhibited the facial features but not CAKUT phenotype. The variant was found in heterozygosity in the unaffected first-cousin parents.

In a second Turkish family with urofacial syndrome, two affected sisters were homozygous for a nonsense LRIG2 variant (R709X). A third case comes from a 5year old Spanish girl compound het for a 1bp deletion (Ser697HisfsTer11) and 371bp insertion variant in LRIG2. Her unaffected parents were each heterozygous for one of the variants.

Facial phenotypes of Urofacial syndrome include grimacing on smiling.
Paediatric disorders - additional genes v1.46 LRIG2 Rebecca Foulger Publications for gene: LRIG2 were set to Stuart HM, Roberts NA, Bergu B, Daly SB, Urquhart JE, Bhaskar S, Dickerson J, Mermerkaya M, Silay MS, Lewis MA, Olondriz BO, Gener B, Beetz C, Varga RE, G lp nar O, S er E, Yal nkaya F, G c k A, Yue WW, Erdogan F, Berry A, Hanley NA, McKenzie EA, Hilton EN, Woolf AS, Newman WG. LRIG2 mutations cause urofacial syndrome. Am J Hum Genet 92:259-264, 2013.
Paediatric disorders - additional genes v1.45 LRIG2 Rebecca Foulger Phenotypes for gene: LRIG2 were changed from CAKUT; Congenital bladder disease: dyssynergic, high pressure bladder.; Urofacial syndrome to CAKUT; Urofacial syndrome 2, 615112; Congenital bladder disease: dyssynergic, high pressure bladder.; Urofacial syndrome
Fetal anomalies v1.73 ITGA8 Rebecca Foulger Classified gene: ITGA8 as Amber List (moderate evidence)
Fetal anomalies v1.73 ITGA8 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber awaiting GLH review. Additional phenotypes were reported in the fetuses and sibling (who died perinatally) from PMID:24439109 (clubbed feet, facial dysmorphism, pulmonary hypoplasia, bilateral cryptorchidism) although renal agenesis is the primary phenotype and only 2 families from one paper.
Fetal anomalies v1.73 ITGA8 Rebecca Foulger Gene: itga8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.72 ITGA8 Rebecca Foulger changed review comment from: PMID:24439109, Humbert et al. (2014). In 3 fetuses of Roma Gypsy descent with bilateral renal hypodysplasia/aplasia-1, Humbert et al identified a homozygous T-to-C transition in intron 27 of the ITGA8 gene (c.2982+2T-C) leading to the skipping of exon 28 and an in-frame 34 amino acide deletion. 1 unaffected mother was heterozygous for the variant. All fetuses had bilateral renal agenesis and anhydramnios, resulting in death in utero.

The authors also identified 2 siblings from West African with bilateral renal hypodysplasia/aplasia-1 and compound het variants in ITGA8 (Glu541AlafsTer12 and G407R). The missense variant was found once in the Exome Variant Server (1 in 13,005). One of the siblings was a fetus that aborted at gestational week 24 due to bilateral renal agenesis and anhydramnios. The second sibling died in the perinatal period.; to: PMID:24439109, Humbert et al. (2014). In 3 fetuses of Roma Gypsy descent with bilateral renal hypodysplasia/aplasia-1, Humbert et al identified a homozygous T-to-C transition in intron 27 of the ITGA8 gene (c.2982+2T-C) leading to the skipping of exon 28 and an in-frame 34 amino acide deletion. 1 unaffected mother was heterozygous for the variant. All fetuses had bilateral renal agenesis and anhydramnios, resulting in death in utero.

The authors also identified 2 siblings from West African with bilateral renal hypodysplasia/aplasia-1 and compound het variants in ITGA8 (Glu541AlafsTer12 and G407R). The missense variant was found once in the Exome Variant Server (1 in 13,005). One of the siblings was a fetus that aborted at gestational week 24 due to bilateral renal agenesis and anhydramnios. The second sibling died in the perinatal period and presented with BRA and bilateral cryptorchidism.
Fetal anomalies v1.72 ITGA8 Rebecca Foulger Phenotypes for gene: ITGA8 were changed from RENAL HYPODYSPLASIA/APLASIA 1; Renal hypodysplasia/aplasia 1, 191830 to bilateral renal agenesis; anhydramnios; RENAL HYPODYSPLASIA/APLASIA 1; Renal hypodysplasia/aplasia 1, 191830
Fetal anomalies v1.71 ITGA8 Rebecca Foulger changed review comment from: PMID:24439109, Humbert et al. (2014). In 3 fetuses of Roma Gypsy descent with bilateral renal hypodysplasia/aplasia-1, Humbert et al identified a homozygous T-to-C transition in intron 27 of the ITGA8 gene (c.2982+2T-C) leading to the skipping of exon 28 and an in-frame 34 amino acide deletion. 1 unaffected mother was heterozygous for the varinat. All fetuses had bilateral renal agenesis and anhydramnios, resulting in death in utero.

The authors also identified 2 siblings from West African with bilateral renal hypodysplasia/aplasia-1 and compound het variants in ITGA8 (Glu541AlafsTer12 and G407R). The missense variant was found once in the Exome Variant Server (1 in 13,005). One of the siblings was a fetus that aborted at gestational week 24 due to bilateral renal agenesis and anhydramnios. The second sibling died in the perinatal period.; to: PMID:24439109, Humbert et al. (2014). In 3 fetuses of Roma Gypsy descent with bilateral renal hypodysplasia/aplasia-1, Humbert et al identified a homozygous T-to-C transition in intron 27 of the ITGA8 gene (c.2982+2T-C) leading to the skipping of exon 28 and an in-frame 34 amino acide deletion. 1 unaffected mother was heterozygous for the variant. All fetuses had bilateral renal agenesis and anhydramnios, resulting in death in utero.

The authors also identified 2 siblings from West African with bilateral renal hypodysplasia/aplasia-1 and compound het variants in ITGA8 (Glu541AlafsTer12 and G407R). The missense variant was found once in the Exome Variant Server (1 in 13,005). One of the siblings was a fetus that aborted at gestational week 24 due to bilateral renal agenesis and anhydramnios. The second sibling died in the perinatal period.
COVID-19 research v0.241 CASP3 Catherine Snow Classified gene: CASP3 as Green List (high evidence)
COVID-19 research v0.241 CASP3 Catherine Snow Gene: casp3 has been classified as Green List (High Evidence).
COVID-19 research v0.240 CASP3 Catherine Snow gene: CASP3 was added
gene: CASP3 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: CASP3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CASP3 were set to 32200494; 24903211; 21160486; 23894522
Phenotypes for gene: CASP3 were set to Kawasaki disease
Added comment: Number of SNPs identified in CASP3 associated with risk of Kawaski Disease. Summarised in PMID:32200494
Sources: Literature
COVID-19 research v0.239 BLK Catherine Snow changed review comment from: Number of SNPs identified in BLK associated with risk of Kawaski Disease
Sources: Literature; to: Number of SNPs identified in BLK associated with risk of Kawaski Disease. Summarised in PMID:32200494
Sources: Literature
COVID-19 research v0.239 BLK Catherine Snow Publications for gene: BLK were set to 22446961; 26182267; 24023612; 25645453
COVID-19 research v0.238 BLK Catherine Snow Classified gene: BLK as Green List (high evidence)
COVID-19 research v0.238 BLK Catherine Snow Gene: blk has been classified as Green List (High Evidence).
COVID-19 research v0.237 BLK Catherine Snow gene: BLK was added
gene: BLK was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: BLK was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BLK were set to 22446961; 26182267; 24023612; 25645453
Phenotypes for gene: BLK were set to Kawasaki disease
Review for gene: BLK was set to GREEN
Added comment: Number of SNPs identified in BLK associated with risk of Kawaski Disease
Sources: Literature
Fetal anomalies v1.71 ITGA8 Rebecca Foulger Classified gene: ITGA8 as Amber List (moderate evidence)
Fetal anomalies v1.71 ITGA8 Rebecca Foulger Added comment: Comment on list classification: Relevant phenotype (renal agenesis) but currently insufficient evidence (2 unrelated cases from PMID:24439109, and 'probable' rating in Gene2Phenotype) for diagnostic-grade rating.
Fetal anomalies v1.71 ITGA8 Rebecca Foulger Gene: itga8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.70 ITGA8 Rebecca Foulger Phenotypes for gene: ITGA8 were changed from RENAL HYPODYSPLASIA/APLASIA 1 to RENAL HYPODYSPLASIA/APLASIA 1; Renal hypodysplasia/aplasia 1, 191830
Fetal anomalies v1.70 ITGA8 Rebecca Foulger Publications for gene: ITGA8 were set to
Fetal anomalies v1.69 ITGA8 Rebecca Foulger commented on gene: ITGA8: PMID:24439109, Humbert et al. (2014). In 3 fetuses of Roma Gypsy descent with bilateral renal hypodysplasia/aplasia-1, Humbert et al identified a homozygous T-to-C transition in intron 27 of the ITGA8 gene (c.2982+2T-C) leading to the skipping of exon 28 and an in-frame 34 amino acide deletion. 1 unaffected mother was heterozygous for the varinat. All fetuses had bilateral renal agenesis and anhydramnios, resulting in death in utero.

The authors also identified 2 siblings from West African with bilateral renal hypodysplasia/aplasia-1 and compound het variants in ITGA8 (Glu541AlafsTer12 and G407R). The missense variant was found once in the Exome Variant Server (1 in 13,005). One of the siblings was a fetus that aborted at gestational week 24 due to bilateral renal agenesis and anhydramnios. The second sibling died in the perinatal period.
Paediatric disorders - additional genes v1.44 GATA3 Rebecca Foulger Classified gene: GATA3 as Green List (high evidence)
Paediatric disorders - additional genes v1.44 GATA3 Rebecca Foulger Gene: gata3 has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v1.43 GATA3 Rebecca Foulger Classified gene: GATA3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.43 GATA3 Rebecca Foulger Added comment: Comment on list classification: Updated from Amber to Green awaiting GLH review. GATA3 HDR syndrome includes hypoparathyroidism and sensorineural deafness in addition to renal dysplasia.
Paediatric disorders - additional genes v1.43 GATA3 Rebecca Foulger Gene: gata3 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.42 GATA3 Rebecca Foulger commented on gene: GATA3: PMID:11389161. Muroya et al., 2001 report 9 Japanese families with HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal dysplasia). Heterozygous gross deletions were reported by FISH in 4 families. Sequence analysis showed heterozygous novel variants in 3 families. 2 families had no GATA3 abnormalities detected.
Paediatric disorders - additional genes v1.42 GATA3 Rebecca Foulger commented on gene: GATA3: GATA3 has an Amber rating on Clefting panel v2.3.
Paediatric disorders - additional genes v1.42 REN Rebecca Foulger Classified gene: REN as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.42 REN Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber awaiting GLH review as to whether renal phenotypes are sufficient for inclusion on the Paediatric disorders panel.
Paediatric disorders - additional genes v1.42 REN Rebecca Foulger Gene: ren has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.41 REN Rebecca Foulger commented on gene: REN: PMID:31736371. He et al., performed a study to identify the potentially pathogenic gene variants that contribute to the AR renal tubular dysgenesis (RTD) in the aborted fetus. WES was performed on an aborted fetus and his parents. Compound heterozygous variants (c.963T>A, p.Y321X and c.492+1G>A splicing site mutation) were identified in the fetus, one inherited from each parent.
Paediatric disorders - additional genes v1.41 REN Rebecca Foulger Publications for gene: REN were set to
Fetal anomalies v1.69 REN Rebecca Foulger Publications for gene: REN were set to
Fetal anomalies v1.68 REN Rebecca Foulger commented on gene: REN: PMID:31736371. He et al., performed a study to identify the potentially pathogenic gene variants that contribute to the AR renal tubular dysgenesis (RTD) in an aborted fetus. WES was performed on the fetus and his parents. Compound heterozygous variants (c.963T>A, p.Y321X and c.492+1G>A splicing site mutation) were identified in the fetus, one inherited from each parent.
Paediatric disorders - additional genes v1.40 REN Rebecca Foulger Added comment: Comment on mode of inheritance: Hyperuricemic nephropathy, familial juvenile 2, 613092 has AD inheritance, and Renal tubular dysgenesis, 267430 has AR inheritance.
Paediatric disorders - additional genes v1.40 REN Rebecca Foulger Mode of inheritance for gene: REN was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paediatric disorders - additional genes v1.39 REN Rebecca Foulger Phenotypes for gene: REN were changed from CAKUT; [Hyperproreninemia]; Renal Tubular Dysgenesis to CAKUT; [Hyperproreninemia]; Hyperuricemic nephropathy, familial juvenile 2, 613092; Renal tubular dysgenesis, 267430
Paediatric disorders - additional genes v1.38 GREB1L Rebecca Foulger Classified gene: GREB1L as Green List (high evidence)
Paediatric disorders - additional genes v1.38 GREB1L Rebecca Foulger Gene: greb1l has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v1.37 GREB1L Rebecca Foulger Classified gene: GREB1L as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.37 GREB1L Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green awaiting GLH review: although the predominant phenotype is renal defects, inner ear malformations are also included in the phenotypic spectrum (PMID:29955957).
Paediatric disorders - additional genes v1.37 GREB1L Rebecca Foulger Gene: greb1l has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.36 GREB1L Rebecca Foulger Phenotypes for gene: GREB1L were changed from CAKUT; Renal hypodysplasia/aplasia 3, 617805 to CAKUT; Renal hypodysplasia/aplasia 3, 617805; inner ear malformations
Paediatric disorders - additional genes v1.36 GREB1L Rebecca Foulger Publications for gene: GREB1L were set to 29100091; 29220675; 29261186
Paediatric disorders - additional genes v1.35 GREB1L Rebecca Foulger commented on gene: GREB1L: PMID:29955957. Schrauwen et al., 2018 performed trio-based WES sequencing in young unrelated subjects with inner ear malformations, and identified novel de novo LOF variants in GREB1L (Glu1410fs and Arg328*) in 2 affected subjects with absent cochleae and eighth cranial nerve malformations.
Paediatric disorders - additional genes v1.35 GREB1L Rebecca Foulger changed review comment from: PMID:29100091. Tomasi et al., 2017. WES or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L.
Fetal cases with bilateral kidney agenesis include p.Gln528Argfs*12 (also present in their alive brother with unilateral kidney agenesis) and splice variant c.4369−1G>C.; to: PMID:29100091. Tomasi et al., 2017. WES or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L. Family histories and phenotypes suggest incomplete penetrance.
Paediatric disorders - additional genes v1.35 GREB1L Rebecca Foulger Publications for gene: GREB1L were set to 29100091; 29220675
Paediatric disorders - additional genes v1.34 GREB1L Rebecca Foulger commented on gene: GREB1L: PMID:29100091. Tomasi et al., 2017. WES or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L.
Fetal cases with bilateral kidney agenesis include p.Gln528Argfs*12 (also present in their alive brother with unilateral kidney agenesis) and splice variant c.4369−1G>C.
Paediatric disorders - additional genes v1.34 GREB1L Rebecca Foulger commented on gene: GREB1L: PMID:29261186 (Boissel et al., 2018) performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies. In 2 cases who presented with renal agenesis, de novo variants in GREB1L were identified (p.A968V and p.S98X).
Paediatric disorders - additional genes v1.34 CHRNA3 Rebecca Foulger Phenotypes for gene: CHRNA3 were changed from CAKUT; dysautonomia; functional lower urinary tract obstruction and secondary CAKUT to CAKUT; dysautonomia; Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT, 191800
Paediatric disorders - additional genes v1.33 CHRNA3 Rebecca Foulger Classified gene: CHRNA3 as Green List (high evidence)
Paediatric disorders - additional genes v1.33 CHRNA3 Rebecca Foulger Added comment: Comment on list classification: Updated gene from Amber to Green, awaiting GLH review. CAKUT is secondary to bladder obstruction, and therefore additional congenital defects may present (PMID:31708116).
Paediatric disorders - additional genes v1.33 CHRNA3 Rebecca Foulger Gene: chrna3 has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v1.32 CHRNA3 Rebecca Foulger changed review comment from: PMID:31708116 (Mann et al., 2019) identify 3 different biallelic variants in CHRNA2 in 5 individuals from 3 unrelated families with functional lower urinary tract obstruction and secondary CAKUT. All 3 variants impair acetylcholine signaling. The truncating variants p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. The third variant is an essential splice site variant. None of the variants were present in gnomAD.; to: PMID:31708116 (Mann et al., 2019) identify 3 different biallelic variants in CHRNA3 in 5 individuals from 3 unrelated families with functional lower urinary tract obstruction and secondary CAKUT. All 3 variants impair acetylcholine signaling. The truncating variants p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. The third variant is an essential splice site variant. None of the variants were present in gnomAD.
Paediatric disorders - additional genes v1.32 AGTR1 Rebecca Foulger Classified gene: AGTR1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.32 AGTR1 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber for now. Plenty of literature suggesting links between AGTR1 polymorphisms and disease risk for e.g. pulmonary arterial hypertension (e.g. PMID:25603901) but key congenital disorder seems to be renal dysgenesis (PMID:16116425).
Paediatric disorders - additional genes v1.32 AGTR1 Rebecca Foulger Gene: agtr1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.31 AGTR1 Rebecca Foulger commented on gene: AGTR1: PMID:16116425. Gribouval et al. 2005 studied 9 families (11 indivs) with AR renal tubular dysgenesis, and found variants in REN, AGT, ACE or AGTR1.
Paediatric disorders - additional genes v1.31 ANOS1 Rebecca Foulger Classified gene: ANOS1 as Green List (high evidence)
Paediatric disorders - additional genes v1.31 ANOS1 Rebecca Foulger Gene: anos1 has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v1.30 ANOS1 Rebecca Foulger Classified gene: ANOS1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.30 ANOS1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green, awaiting GLH review. Sufficient cases to support Kallman syndrome association, which can present with phenotypes beyond renal, some of which could be detected at birth.
Paediatric disorders - additional genes v1.30 ANOS1 Rebecca Foulger Gene: anos1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.29 ANOS1 Rebecca Foulger commented on gene: ANOS1: PMID:16423815. Trarbach et al 2005 report 12 Kallmann syndrome (KS) patients. Two ANOS1 variants (referred to as KAL-1 gene) were found in 2 KS patients (Arg191X, and del1956C leading to a premature stop codon at 617). A patient with a KAL-1 microdeletion was also reported. Renal agenesis and bimanual synkinesis were observed in these cases.
Paediatric disorders - additional genes v1.29 ANOS1 Rebecca Foulger Publications for gene: ANOS1 were set to 1518845
Paediatric disorders - additional genes v1.28 ANOS1 Rebecca Foulger Phenotypes for gene: ANOS1 were changed from CAKUT; Kallman syndrome; Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) to CAKUT; Kallman syndrome; Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1), 308700
Paediatric disorders - additional genes v1.27 AGT Rebecca Foulger Classified gene: AGT as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.27 AGT Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber for now: renal tubulogenesis is key phenotype and therefore CAKUT may be isolated.
Paediatric disorders - additional genes v1.27 AGT Rebecca Foulger Gene: agt has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.68 ACTG2 Rebecca Foulger Publications for gene: ACTG2 were set to 25998219; 30712878
Paediatric disorders - additional genes v1.26 ACTG2 Rebecca Foulger Classified gene: ACTG2 as Green List (high evidence)
Paediatric disorders - additional genes v1.26 ACTG2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on papers demonstrating a role in MMIHS (e.g. PMID:27481187, 25998219), thereby broadening phenotype from isolated CAKUT.
Paediatric disorders - additional genes v1.26 ACTG2 Rebecca Foulger Gene: actg2 has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v1.25 ACTG2 Rebecca Foulger changed review comment from: PMID:27481187 Moreno et al., 201. In 3 individuals with MMIHS and in 1 with chronic intestinal pseudo-obstruction (CIPO) they identified a heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile).; to: PMID:27481187 Moreno et al., 2016. In 3 individuals with MMIHS and in 1 with chronic intestinal pseudo-obstruction (CIPO) they identified a heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile).
Paediatric disorders - additional genes v1.25 ACTG2 Rebecca Foulger commented on gene: ACTG2: PMID:27481187 Moreno et al., 201. In 3 individuals with MMIHS and in 1 with chronic intestinal pseudo-obstruction (CIPO) they identified a heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile).
Paediatric disorders - additional genes v1.25 ACTG2 Rebecca Foulger Publications for gene: ACTG2 were set to 25998219
Paediatric disorders - additional genes v1.24 ACTG2 Rebecca Foulger changed review comment from: PMID:25998219. Tuzovic et al identify a heterozygous de novo missense variant in ACTG2 (p.Arg257His) in 2 siblings with MMIHS. 2 additional missense variants in ACTG2 (p.Arg257Cys and p.Arg178His) were identified in 2 additional MMHIS patients. All patients had evidence of fetal megacystis. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. Note that in OMIM, MMHIS (MIM:249210) is associated with MYLK.; to: PMID:25998219. Tuzovic et al identify a heterozygous de novo missense variant in ACTG2 (p.Arg257His) in 2 siblings with MMIHS. 2 additional missense variants in ACTG2 (p.Arg257Cys and p.Arg178His) were identified in 2 additional MMIHS patients. All patients had evidence of fetal megacystis. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. Note that in OMIM, MMIHS (MIM:249210) is associated with MYLK.
Paediatric disorders - additional genes v1.24 ACE Rebecca Foulger Classified gene: ACE as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.24 ACE Rebecca Foulger Added comment: Comment on list classification: Key papers report renal tubular dysgenesis. In absence of additional morphological features, keep Amber awaiting GLH review.
Paediatric disorders - additional genes v1.24 ACE Rebecca Foulger Gene: ace has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.23 ACE Rebecca Foulger commented on gene: ACE: PMID:30058238 (Bhowmik et al., 2018) report a 32-week old fetus with severe early onset oligohydramnios. A similarly affected sibling was reported from a previous pregnancy. Exome sequencing revealed a homozygous 3' splice-site variant in intron 17 of ACE gene, which confirmed AR renal tubular dysgenesis. It also facilitated prenatal diagnosis in a subsequent pregnancy.
Paediatric disorders - additional genes v1.23 ACE Rebecca Foulger commented on gene: ACE: PMID:16116425. Gribouval et al. 2005 studied 9 families (11 indivs) with AR renal tubular dysgenesis, and found variants in REN, AGT, ACE or AGTR1.
CAKUT v1.107 ACE Rebecca Foulger Publications for gene: ACE were set to
COVID-19 research v0.235 Eleanor Williams Panel name changed from Viral susceptibility to COVID-19 research
List of related panels changed from to Viral susceptibility
COVID-19 research v0.234 ANPEP Eleanor Williams gene: ANPEP was added
gene: ANPEP was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: ANPEP was set to Unknown
Publications for gene: ANPEP were set to 28643204
Added comment: PMID: 28643204 - de Wilde et al 2018 - in a review of known coronavirus entry receptors APN/ANPEP is listed as a entry receptor for several Alphacoronaviruses (Table 1). Sars-cov-2 is a Betacoronavirus.
Sources: Literature
COVID-19 research v0.233 DPP4 Eleanor Williams Publications for gene: DPP4 were set to 23486063; 24554656; 24599590; 25589660; 26124093; https://doi.org/10.1101/2020.04.30.071274
COVID-19 research v0.232 DPP4 Eleanor Williams commented on gene: DPP4: PMID: 31883094 - Leist et al 2020 - describe the generation of the 288-330+/+ MERS-CoV mouse model in which mice were made susceptible to MERS-CoV by modifying two amino acids on mDPP4 (A288 and T330).
COVID-19 research v0.232 DPP4 Eleanor Williams commented on gene: DPP4
COVID-19 research v0.232 ACE2 Eleanor Williams changed review comment from: PMID: 32133153 Cao et al 2020 - Analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations. Their findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations.; to: PMID: 32133153 Cao et al 2020 - Analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations. Their findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations. East Asian populations have much higher AFs in the eQTL variants associated with higher ACE2 expression in tissues.
COVID-19 research v0.232 ACE2 Eleanor Williams Publications for gene: ACE2 were set to 14647384; 15897467; 16007097; 32142651; 32015507
COVID-19 research v0.231 ACE2 Eleanor Williams commented on gene: ACE2: PMID: 32133153 Cao et al 2020 - Analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations. Their findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations.
COVID-19 research v0.231 HSPA5 Eleanor Williams gene: HSPA5 was added
gene: HSPA5 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: HSPA5 was set to Unknown
Publications for gene: HSPA5 were set to 3216948
Review for gene: HSPA5 was set to RED
Added comment: PMID:3216948 - Ibrahim et al 2020 - predict that HSPA5 (GRP78) might bind with COVID-19 spike
Sources: Literature
COVID-19 research v0.230 ACE2 Eleanor Williams commented on gene: ACE2: PMID: 32249956 Hussain et al 2020 - show through molecular modelling that ACE2 alleles, rs73635825 (S19P) and rs143936283 (E329G) showed noticeable variations in their intermolecular interactions with the viral spike protein of SARS-CoV-2
COVID-19 research v0.230 TMPRSS2 Eleanor Williams Publications for gene: TMPRSS2 were set to 31488196; 32142651; 24227843; 25904605; 24600012; 24522916; 32327758
COVID-19 research v0.229 TMPRSS2 Eleanor Williams Deleted their review
COVID-19 research v0.229 TMPRSS2 Eleanor Williams Deleted their comment
COVID-19 research v0.229 ITPKC Catherine Snow Publications for gene: ITPKC were set to 18084290; 20045869
COVID-19 research v0.228 ITPKC Catherine Snow Classified gene: ITPKC as Green List (high evidence)
COVID-19 research v0.228 ITPKC Catherine Snow Gene: itpkc has been classified as Green List (High Evidence).
COVID-19 research v0.227 FCGR2A Catherine Snow edited their review of gene: FCGR2A: Added comment: Has been identified as a risk loci for Kawasaki disease.; Changed publications: 19494086, 12752683, 16185324, 22446962
COVID-19 research v0.227 ORAI1 Catherine Snow reviewed gene: ORAI1: Rating: ; Mode of pathogenicity: None; Publications: 30853710, 26789410; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.227 TMPRSS2 Eleanor Williams Added comment: Comment on publications: Adding pubmed:32327758 - using single cell RNA-sequencing they confirmed the expression of ACE2 in multiple tissues shown in previous studies with added information on tissues not previously investigated, including nasal epithelium and cornea and its co-expression with TMPRSS2
COVID-19 research v0.227 TMPRSS2 Eleanor Williams Publications for gene: TMPRSS2 were set to 31488196; 32142651; 24227843; 25904605; 24600012; 24522916
COVID-19 research v0.226 SCN5A Eleanor Williams changed review comment from: PMID: 32380288 Giudicessi et al 2020 - discuss the potential of p.Ser1103Tyr-SCN5A to exacerbate outcome-related health disparities in the COVID-19 pandemic.; to: PMID: 32380288 Giudicessi et al 2020 - discuss the potential of p.Ser1103Tyr-SCN5A to exacerbate outcome-related health disparities in the COVID-19 pandemic.

Keeping red for now, as this paper is speculation - no real data.
COVID-19 research v0.226 SCN5A Eleanor Williams Publications for gene: SCN5A were set to
COVID-19 research v0.225 SCN5A Eleanor Williams reviewed gene: SCN5A: Rating: ; Mode of pathogenicity: None; Publications: 32380288; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.225 APOE Eleanor Williams Classified gene: APOE as Amber List (moderate evidence)
COVID-19 research v0.225 APOE Eleanor Williams Added comment: Comment on list classification: Rating amber as one study reported showing that a variant (ApoE e4 allele) is associated with hospitalization with COVID-19.
COVID-19 research v0.225 APOE Eleanor Williams Gene: apoe has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.224 APOE Eleanor Williams gene: APOE was added
gene: APOE was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: APOE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APOE were set to https://doi.org/10.1101/2020.05.07.20094409
Phenotypes for gene: APOE were set to dementia
Added comment: Preprint: https://doi.org/10.1101/2020.05.07.20094409 Kuo et al 2020 - Using UK biobank data they found that the ApoE e4 allele ( rs429358) increases risks of being hospitalized with COVID-19, independent of pre-existing dementia, cardiovascular disease, and type-2 diabetes.
ApoE e4 allele frequency is higher in people of African ancestry than in Europeans, and
preliminary results suggest that ApoE e4 prevalence makes a modest contribution to the
excess incidence of COVID-19 in Blacks.
Sources: Literature
Osteogenesis imperfecta v2.6 MESD Eleanor Williams Tag for-review tag was added to gene: MESD.
Osteogenesis imperfecta v2.6 MESD Eleanor Williams changed review comment from: Gene suggested by Alistair Pagnamenta.

Associated with Osteogenesis imperfecta, type XX, #618644 (AR) in OMIM.

PMID: 31564437 Moosa et al 2019. Report 5 independent consanguineous families with a progressively deforming type of OI. Using WES and prioritising homozygous variants, they found all patients were homozygous for a mutation in the third and final exon of MESD. Parents were heterozygous. Variants were not common polymorphisms. 4 different truncation or frameshift variants were found. In mice, homozygous loss-of-function Mesd mutations cause embryonic lethality during gastrulation (PubMed: 11247670). In functional studies the MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking.
Sources: Literature; to: Gene suggested by Alistair Pagnamenta.

Associated with Osteogenesis imperfecta, type XX, #618644 (AR) in OMIM.

PMID: 31564437 Moosa et al 2019. Report 5 independent consanguineous families with a progressively deforming type of OI. Using WES and prioritising homozygous variants, they found all patients were homozygous for a mutation in the third and final exon of MESD. Parents were heterozygous. Variants were not common polymorphisms. 4 different truncation or frameshift variants were found. In mice, homozygous loss-of-function Mesd mutations cause embryonic lethality during gastrulation (PubMed: 11247670). In functional studies the MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking.

Alistair Pagnamenta notes that there is a lack of sibling data.
Osteogenesis imperfecta v2.6 MESD Eleanor Williams Classified gene: MESD as Green List (high evidence)
Osteogenesis imperfecta v2.6 MESD Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. More than three families reported, with plausible disease causing variants.
Osteogenesis imperfecta v2.6 MESD Eleanor Williams Gene: mesd has been classified as Green List (High Evidence).
Osteogenesis imperfecta v2.5 MESD Eleanor Williams Phenotypes for gene: MESD were changed from to Osteogenesis imperfecta, type XX, 618644
Osteogenesis imperfecta v2.4 MESD Eleanor Williams gene: MESD was added
gene: MESD was added to Osteogenesis imperfecta. Sources: Literature
Mode of inheritance for gene: MESD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MESD were set to 31564437
Added comment: Gene suggested by Alistair Pagnamenta.

Associated with Osteogenesis imperfecta, type XX, #618644 (AR) in OMIM.

PMID: 31564437 Moosa et al 2019. Report 5 independent consanguineous families with a progressively deforming type of OI. Using WES and prioritising homozygous variants, they found all patients were homozygous for a mutation in the third and final exon of MESD. Parents were heterozygous. Variants were not common polymorphisms. 4 different truncation or frameshift variants were found. In mice, homozygous loss-of-function Mesd mutations cause embryonic lethality during gastrulation (PubMed: 11247670). In functional studies the MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking.
Sources: Literature
Fetal anomalies v1.67 GREB1L Rebecca Foulger commented on gene: GREB1L: Added 'for-review' tag: Gene has been added and assessed by Curation team but not yet reviewed by clinical team.
Fetal anomalies v1.67 GREB1L Rebecca Foulger Tag for-review tag was added to gene: GREB1L.
Fetal anomalies v1.67 GREB1L Rebecca Foulger Classified gene: GREB1L as Green List (high evidence)
Fetal anomalies v1.67 GREB1L Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green following curation of PMID:29100091 which presents additional fetal cases of renal agenesis and GREB1L variants. Sufficient evidence for association of GREB1L with kidney agenesis, and phenotype can present fetally.
Fetal anomalies v1.67 GREB1L Rebecca Foulger Gene: greb1l has been classified as Green List (High Evidence).
Fetal anomalies v1.66 GREB1L Rebecca Foulger Publications for gene: GREB1L were set to 29261186
Fetal anomalies v1.65 GREB1L Rebecca Foulger commented on gene: GREB1L: PMID:29100091. Tomasi et al., 2017. WES or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L.
Fetal cases with bilateral kidney agenesis include p.Gln528Argfs*12 (also present in their alive brother with unilateral kidney agenesis) and splice variant c.4369−1G>C.
Fetal anomalies v1.65 GREB1L Rebecca Foulger Classified gene: GREB1L as Amber List (moderate evidence)
Fetal anomalies v1.65 GREB1L Rebecca Foulger Added comment: Comment on list classification: Added to panel and set rating to Amber. Not yet associated with a disorder in Gene2Phenotype, but 2 fetal cases presented in PMID:29261186. Renal agenesis phenotype is relevant to the panel. Therefore Amber awaiting further cases.
Fetal anomalies v1.65 GREB1L Rebecca Foulger Gene: greb1l has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.64 GREB1L Rebecca Foulger gene: GREB1L was added
gene: GREB1L was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: GREB1L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GREB1L were set to 29261186
Phenotypes for gene: GREB1L were set to Renal hypodysplasia/aplasia 3, 617805; renal agenesis
Added comment: Added to Fetal panel based on PMID:29261186 (Boissel et al., 2018) who performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies. In 2 cases presenting with renal agenesis, de novo variants in GREB1L were identified (p.A968V and p.S98X).
Sources: Literature
Paediatric disorders - additional genes v1.23 CHRNA3 Rebecca Foulger changed review comment from: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.; to: Added 'for-review' tag: Requires GLH review as to whether phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.23 CHRNA3 Rebecca Foulger Phenotypes for gene: CHRNA3 were changed from CAKUT; dysautonomia to CAKUT; dysautonomia; functional lower urinary tract obstruction and secondary CAKUT
Paediatric disorders - additional genes v1.22 CHRNA3 Rebecca Foulger commented on gene: CHRNA3: PMID:31708116 (Mann et al., 2019) identify 3 different biallelic variants in CHRNA2 in 5 individuals from 3 unrelated families with functional lower urinary tract obstruction and secondary CAKUT. All 3 variants impair acetylcholine signaling. The truncating variants p.Thr337Asnfs∗81 and p.Ser340∗ led to impaired plasma membrane localization of CHRNA3. The third variant is an essential splice site variant. None of the variants were present in gnomAD.
Paediatric disorders - additional genes v1.22 ANOS1 Rebecca Foulger changed review comment from: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.; to: Added 'for-review' tag: Requires GLH review as to whether phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.22 ANOS1 Rebecca Foulger changed review comment from: Sufficient cases of variants in ANOS1 to support association with Kallmann syndrome (MIM:308700). KS phenotypes are present at birth and can include renal agenesis, and micropenis. Cases are often reported at puberty with lack of sexual development.; to: Sufficient cases of variants in ANOS1 to support association with Kallmann syndrome (MIM:308700). KS phenotypes are present at birth and can include renal agenesis, and micropenis. Cases are often reported at puberty with lack of sexual development.
Paediatric disorders - additional genes v1.22 ANOS1 Rebecca Foulger Publications for gene: ANOS1 were set to
Paediatric disorders - additional genes v1.21 ANOS1 Rebecca Foulger commented on gene: ANOS1: Sufficient cases of variants in ANOS1 to support association with Kallmann syndrome (MIM:308700). KS phenotypes are present at birth and can include renal agenesis, and micropenis. Cases are often reported at puberty with lack of sexual development.
Paediatric disorders - additional genes v1.21 AGT Rebecca Foulger commented on gene: AGT: PMID:16116425. Gribouval et al. 2005 studied 9 families (11 indivs) with AR renal tubular dysgenesis, and found variants in REN, AGT, ACE or AGTR1.
Paediatric disorders - additional genes v1.21 AGT Rebecca Foulger changed review comment from: Added to Paediatric disorders - additional genes panel, based on Green rating on CAKUT panel V1.106. Note that AGT is on V14.137 Paediatric panel already but with Red rating.; to: Added to Paediatric disorders - additional genes panel, based on Green rating on CAKUT panel V1.106. Note that AGT is on V14.137 Paediatric disorders panel already but with Red rating.
Paediatric disorders - additional genes v1.21 AGT Rebecca Foulger Phenotypes for gene: AGT were changed from CAKUT; {Hypertension, essential, susceptibility to}, 145500{Preeclampsia, susceptibility to}Renal tubular dysgenesis, 267430; Renal Tubular Dysgenesis to Renal tubular dysgenesis, 267430; CAKUT
Paediatric disorders - additional genes v1.20 AGT Rebecca Foulger Publications for gene: AGT were set to
Paediatric disorders - additional genes v1.19 ACTG2 Rebecca Foulger changed review comment from: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.; to: Added 'for-review' tag: Requires GLH review for inclusion on Paediatric disorders panel: whether CAKUT phenotype presents alongside additional congenital malformations.
Fetal anomalies v1.63 ACTG2 Rebecca Foulger Mode of pathogenicity for gene: ACTG2 was changed from to Other
Paediatric disorders - additional genes v1.19 ACTG2 Rebecca Foulger commented on gene: ACTG2: PMID:25998219. Tuzovic et al identify a heterozygous de novo missense variant in ACTG2 (p.Arg257His) in 2 siblings with MMIHS. 2 additional missense variants in ACTG2 (p.Arg257Cys and p.Arg178His) were identified in 2 additional MMHIS patients. All patients had evidence of fetal megacystis. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. Note that in OMIM, MMHIS (MIM:249210) is associated with MYLK.
Fetal anomalies v1.62 ACTG2 Rebecca Foulger Phenotypes for gene: ACTG2 were changed from Visceral myopathy 155310 to Visceral myopathy 155310; Fetal Megacystis
Fetal anomalies v1.61 ACTG2 Rebecca Foulger Publications for gene: ACTG2 were set to
Paediatric disorders - additional genes v1.19 ACTG2 Rebecca Foulger Phenotypes for gene: ACTG2 were changed from CAKUT; Megacystis-microcolon intestinal hypoperistalsis syndrome; visceral myopathy; Berdon syndrome to CAKUT; Megacystis-microcolon intestinal hypoperistalsis syndrome; Visceral myopathy, 155310; Berdon syndrome
Paediatric disorders - additional genes v1.18 ACE Rebecca Foulger Publications for gene: ACE were set to 16116425; 22095942
Paediatric disorders - additional genes v1.17 ACE Rebecca Foulger changed review comment from: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.; to: Added 'for-review' tag: Requires GLH review for inclusion on Paediatric disorders panel: whether CAKUT phenotype presents alongside additional congenital malformations.
Fetal anomalies v1.60 ACE Rebecca Foulger commented on gene: ACE: PMID:30058238 (Bhowmik et al., 2018) report a 32-week old fetus with severe early onset oligohydramnios. A similarly affected sibling was reported from a previous pregnancy. Exome sequencing revealed a homozygous 3' splice-site variant in intron 17 of ACE gene, which confirmed AR renal tubular dysgenesis. It also facilitated prenatal diagnosis in a subsequent pregnancy.
Fetal anomalies v1.60 ACE Rebecca Foulger Publications for gene: ACE were set to
Paediatric disorders - additional genes v1.17 ACE Rebecca Foulger Publications for gene: ACE were set to
Fetal anomalies v1.59 GJB2 Rebecca Foulger commented on gene: GJB2: Note that GJB2 is no longer present on the DD panel of Gene2Phenotype. All GJB2 phenotypes (May 2020) are associated with the Gene2Phenotype skin panel. Red rating is still appropriate for this Fetal panel.
COVID-19 research v0.223 DDX58 Sarah Leigh Classified gene: DDX58 as Amber List (moderate evidence)
COVID-19 research v0.223 DDX58 Sarah Leigh Added comment: Comment on list classification: Wild type DDX58 confers detection and eradication of replicating viral genomes, variants in this gene could therefore interfere with this mechanism.
COVID-19 research v0.223 DDX58 Sarah Leigh Gene: ddx58 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.222 DDX58 Sarah Leigh Publications for gene: DDX58 were set to 21939710; 16625202
COVID-19 research v0.221 DDX58 Sarah Leigh gene: DDX58 was added
gene: DDX58 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: DDX58 was set to Unknown
Publications for gene: DDX58 were set to 21939710; 16625202
Added comment: PMID 21939710 found DDX5 (formerly known as RIGI) was essential for virus-induced expression of IRF3 and concluded that DDX5 is essential for detection and eradication of replicating viral genomes. PMID 16625202 reported that DDX58 is essential for the production of interferons in response to certain RNA viruses including paramyxoviruses, influenza virus, and Japanese encephalitis virus.
Sources: Literature
Paediatric disorders - additional genes v1.16 TBX18 Rebecca Foulger Classified gene: TBX18 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.16 TBX18 Rebecca Foulger Gene: tbx18 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.15 REN Rebecca Foulger Classified gene: REN as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.15 REN Rebecca Foulger Gene: ren has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.14 LRIG2 Rebecca Foulger Classified gene: LRIG2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.14 LRIG2 Rebecca Foulger Gene: lrig2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.13 ITGA8 Rebecca Foulger Classified gene: ITGA8 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.13 ITGA8 Rebecca Foulger Gene: itga8 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.12 GREB1L Rebecca Foulger Classified gene: GREB1L as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.12 GREB1L Rebecca Foulger Gene: greb1l has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.11 GATA3 Rebecca Foulger Classified gene: GATA3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.11 GATA3 Rebecca Foulger Gene: gata3 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.10 CHRNA3 Rebecca Foulger Classified gene: CHRNA3 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.10 CHRNA3 Rebecca Foulger Gene: chrna3 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.9 ANOS1 Rebecca Foulger Classified gene: ANOS1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.9 ANOS1 Rebecca Foulger Gene: anos1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.8 AGTR1 Rebecca Foulger Classified gene: AGTR1 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.8 AGTR1 Rebecca Foulger Gene: agtr1 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.7 AGT Rebecca Foulger Classified gene: AGT as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.7 AGT Rebecca Foulger Gene: agt has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.6 ACTG2 Rebecca Foulger Classified gene: ACTG2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.6 ACTG2 Rebecca Foulger Gene: actg2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v1.5 ACE Rebecca Foulger Classified gene: ACE as Amber List (moderate evidence)
Paediatric disorders - additional genes v1.5 ACE Rebecca Foulger Gene: ace has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.220 DPP4 Sarah Leigh Publications for gene: DPP4 were set to 23486063; 24554656; 24599590; 25589660; 26124093
COVID-19 research v0.219 DPP4 Sarah Leigh Classified gene: DPP4 as Amber List (moderate evidence)
COVID-19 research v0.219 DPP4 Sarah Leigh Gene: dpp4 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.218 DPP4 Sarah Leigh gene: DPP4 was added
gene: DPP4 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: DPP4 was set to Unknown
Publications for gene: DPP4 were set to 23486063; 24554656; 24599590; 25589660; 26124093
Review for gene: DPP4 was set to AMBER
Added comment: DPP4 is a functional receptor for human coronavirus-Erasmus Medical Center (hCoV-EMC), also known as Middle East respiratory syndrome coronavirus (MERS-CoV). Blades 4 and 5 of the 8-blade beta-propeller region of DPP4 confer binding and susceptibility to MERS-CoV (PMID 24554656). Rhodants are not susceptible to MERS-CoV, however, a mouse models expressing human DPP4 became infected with MERS-CoV (PMID 24599590; 25589660; 26124093).
Sources: Literature
Paediatric disorders - additional genes v1.4 TBX18 Rebecca Foulger Tag for-review tag was added to gene: TBX18.
Paediatric disorders - additional genes v1.4 TBX18 Rebecca Foulger commented on gene: TBX18: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 GREB1L Rebecca Foulger Tag for-review tag was added to gene: GREB1L.
Paediatric disorders - additional genes v1.4 GREB1L Rebecca Foulger commented on gene: GREB1L: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 REN Rebecca Foulger Tag for-review tag was added to gene: REN.
Paediatric disorders - additional genes v1.4 REN Rebecca Foulger commented on gene: REN: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 LRIG2 Rebecca Foulger Tag for-review tag was added to gene: LRIG2.
Paediatric disorders - additional genes v1.4 LRIG2 Rebecca Foulger commented on gene: LRIG2: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 ITGA8 Rebecca Foulger Tag for-review tag was added to gene: ITGA8.
Paediatric disorders - additional genes v1.4 ITGA8 Rebecca Foulger commented on gene: ITGA8: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 GATA3 Rebecca Foulger Tag for-review tag was added to gene: GATA3.
Paediatric disorders - additional genes v1.4 GATA3 Rebecca Foulger commented on gene: GATA3: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 CHRNA3 Rebecca Foulger Tag for-review tag was added to gene: CHRNA3.
Paediatric disorders - additional genes v1.4 CHRNA3 Rebecca Foulger commented on gene: CHRNA3: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 ANOS1 Rebecca Foulger Tag for-review tag was added to gene: ANOS1.
Paediatric disorders - additional genes v1.4 ANOS1 Rebecca Foulger commented on gene: ANOS1: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 AGTR1 Rebecca Foulger Tag for-review tag was added to gene: AGTR1.
Paediatric disorders - additional genes v1.4 AGTR1 Rebecca Foulger commented on gene: AGTR1: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 AGT Rebecca Foulger Tag for-review tag was added to gene: AGT.
Paediatric disorders - additional genes v1.4 AGT Rebecca Foulger commented on gene: AGT: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 ACTG2 Rebecca Foulger commented on gene: ACTG2: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 ACTG2 Rebecca Foulger Tag for-review tag was added to gene: ACTG2.
Paediatric disorders - additional genes v1.4 ACE Rebecca Foulger commented on gene: ACE: Added 'for-review' tag: Requires GLH review as to whether CAKUT phenotype is sufficient for inclusion on Paediatric disorders panel.
Paediatric disorders - additional genes v1.4 ACE Rebecca Foulger Tag for-review tag was added to gene: ACE.
Paediatric disorders - additional genes v1.4 AGT Rebecca Foulger commented on gene: AGT
Paediatric disorders - additional genes v1.4 TBX18 Rebecca Foulger commented on gene: TBX18
Paediatric disorders - additional genes v1.4 LRIG2 Rebecca Foulger commented on gene: LRIG2
Paediatric disorders - additional genes v1.4 ITGA8 Rebecca Foulger commented on gene: ITGA8
Paediatric disorders - additional genes v1.4 GATA3 Rebecca Foulger commented on gene: GATA3
Paediatric disorders - additional genes v1.4 REN Rebecca Foulger commented on gene: REN
Paediatric disorders - additional genes v1.4 GREB1L Rebecca Foulger commented on gene: GREB1L
Paediatric disorders - additional genes v1.4 CHRNA3 Rebecca Foulger commented on gene: CHRNA3
Paediatric disorders - additional genes v1.4 ANOS1 Rebecca Foulger commented on gene: ANOS1
Paediatric disorders - additional genes v1.4 AGTR1 Rebecca Foulger commented on gene: AGTR1
Paediatric disorders - additional genes v1.4 ACTG2 Rebecca Foulger commented on gene: ACTG2
Paediatric disorders - additional genes v1.4 ACE Rebecca Foulger commented on gene: ACE
Paediatric disorders - additional genes v1.3 AGT Rebecca Foulger gene: AGT was added
gene: AGT was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: AGT was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: AGT were set to CAKUT; {Hypertension, essential, susceptibility to}, 145500{Preeclampsia, susceptibility to}Renal tubular dysgenesis, 267430; Renal Tubular Dysgenesis
Paediatric disorders - additional genes v1.3 TBX18 Rebecca Foulger gene: TBX18 was added
gene: TBX18 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: TBX18 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TBX18 were set to CAKUT
Paediatric disorders - additional genes v1.3 LRIG2 Rebecca Foulger gene: LRIG2 was added
gene: LRIG2 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: LRIG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRIG2 were set to Stuart HM, Roberts NA, Bergu B, Daly SB, Urquhart JE, Bhaskar S, Dickerson J, Mermerkaya M, Silay MS, Lewis MA, Olondriz BO, Gener B, Beetz C, Varga RE, G lp nar O, S er E, Yal nkaya F, G c k A, Yue WW, Erdogan F, Berry A, Hanley NA, McKenzie EA, Hilton EN, Woolf AS, Newman WG. LRIG2 mutations cause urofacial syndrome. Am J Hum Genet 92:259-264, 2013.
Phenotypes for gene: LRIG2 were set to CAKUT; Congenital bladder disease: dyssynergic, high pressure bladder.; Urofacial syndrome
Paediatric disorders - additional genes v1.3 ITGA8 Rebecca Foulger gene: ITGA8 was added
gene: ITGA8 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: ITGA8 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ITGA8 were set to CAKUT; Renal hypodysplasia/aplasia 1, 191830
Paediatric disorders - additional genes v1.3 GATA3 Rebecca Foulger gene: GATA3 was added
gene: GATA3 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: GATA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GATA3 were set to CAKUT; Hypoparathyroidism, sensorineural deafness, and renal dysplasia, 146255; Hypoparathyroidism, Sensorineural Deafness, and Renal Disease
Paediatric disorders - additional genes v1.3 REN Rebecca Foulger gene: REN was added
gene: REN was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: REN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: REN were set to CAKUT; [Hyperproreninemia]; Renal Tubular Dysgenesis
Paediatric disorders - additional genes v1.3 GREB1L Rebecca Foulger gene: GREB1L was added
gene: GREB1L was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: GREB1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GREB1L were set to 29100091; 29220675
Phenotypes for gene: GREB1L were set to CAKUT; Renal hypodysplasia/aplasia 3, 617805
Paediatric disorders - additional genes v1.3 CHRNA3 Rebecca Foulger gene: CHRNA3 was added
gene: CHRNA3 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: CHRNA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHRNA3 were set to 31708116
Phenotypes for gene: CHRNA3 were set to CAKUT; dysautonomia
Paediatric disorders - additional genes v1.3 ANOS1 Rebecca Foulger gene: ANOS1 was added
gene: ANOS1 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: ANOS1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: ANOS1 were set to CAKUT; Kallman syndrome; Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1)
Paediatric disorders - additional genes v1.3 AGTR1 Rebecca Foulger gene: AGTR1 was added
gene: AGTR1 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: AGTR1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: AGTR1 were set to CAKUT; Hypertension, essential, 145500; Renal Tubular Dysgenesis; Renal tubular dysgenesis, 267430
Paediatric disorders - additional genes v1.3 ACTG2 Rebecca Foulger gene: ACTG2 was added
gene: ACTG2 was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: ACTG2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTG2 were set to 25998219
Phenotypes for gene: ACTG2 were set to CAKUT; Megacystis-microcolon intestinal hypoperistalsis syndrome; visceral myopathy; Berdon syndrome
Paediatric disorders - additional genes v1.3 ACE Rebecca Foulger gene: ACE was added
gene: ACE was added to Paediatric disorders - additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: ACE was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ACE were set to CAKUT; Renal Tubular Dysgenesis
COVID-19 research v0.217 MX1 Sarah Leigh gene: MX1 was added
gene: MX1 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: MX1 was set to Unknown
Publications for gene: MX1 were set to 3162334; 14872030; 21935451; https://doi.org/10.1101/2020.05.04.075911
Review for gene: MX1 was set to AMBER
Added comment: MX1 is an interferon-induced protein with antiviral activity (PMID 3162334).
PMID 14872030 c.-88G>T was more frequent in 40 unrelated Japanese patients with subacute sclerosing panencephalitisis (associated with CNS infection with measles virus), than in 90 controls (0.42 in patients vs 0.29 in controls). Variant c.-88G>T results increased MX1 expression, the authors suggest that MX1 may paradoxically enable persistence of the virus in the CNS by attenuating viral gene expression and preventing complete immunologic clearance.
PMID 21935451 concluded that genetic variation in the interferon response pathway is associated with risk for symptomatic West Nile viru infection and disease progression.
Preprint https://doi.org/10.1101/2020.05.04.075911 Reports that rs35074065 of TMPRSS2 results in increased expression of the nearby gene MX1.
Sources: Literature
COVID-19 research v0.216 BST2 Rebecca Foulger Classified gene: BST2 as Red List (low evidence)
COVID-19 research v0.216 BST2 Rebecca Foulger Added comment: Comment on list classification: Added to panel as a Red gene: present in latest release of UniProt COVID portal. Plays a role in tethering viruses to the host cell to block viral release. Recent research (PMID:31199522) shows interaction with SARS-CoV spike protein, which inhibits BST2 function and allows viral release.
COVID-19 research v0.216 BST2 Rebecca Foulger Gene: bst2 has been classified as Red List (Low Evidence).
COVID-19 research v0.215 BST2 Rebecca Foulger commented on gene: BST2: PMID:31199522. Wang et al., 2019 show that SARS-CoV spike (S) glycoprotein antagonises the BST2 tethering of SARS-CoV via BST2 downregulation. The authors show colocalization BST2 and SARS-CoV S protein.
COVID-19 research v0.215 BST2 Rebecca Foulger gene: BST2 was added
gene: BST2 was added to Viral susceptibility. Sources: Literature,Other
Mode of inheritance for gene: BST2 was set to Unknown
Publications for gene: BST2 were set to 31199522
Added comment: BST2 is present in the UniProt COVID portal (11th May 2020 Release): https://covid-19.uniprot.org/uniprotkb/Q10589. BST2 is an IFN-induced antiviral host restriction factor which physically blocks the release of viruses by directly tethering nascent virions to the membranes of infected cells.
Sources: Literature, Other
COVID-19 research v0.214 TMPRSS2 Sarah Leigh changed review comment from: Preprint https://doi.org/10.1101/2020.05.04.075911 reports rs35074065 of TMPRSS2 results in the overexpression of both TMPRSS2 and a nearby gene MX1. rs35074065 overlaps with a transcription factor binding site of an activator (IRF1) and a repressor (IRF2). IRF1 activator can bind to variant delC allele, but IRF2 repressor fails to bind. Thus, in an individual carrying the delC allele, there is only activation, but no repression. On viral entry, IRF1 mediated upregulation of MX1 leads to neutrophil infiltration and processing of 614G mutated Spike protein by neutrophil Elastase. The simultaneous processing of 614G spike protein by TMPRSS2 and Elastase serine proteases facilitates the entry of the 614G subtype into host cells. Thus, SARS-CoV-2, particularly the 614G subtype, has spread more easily and with higher frequency to Europe and North America where the delC allele regulating expression of TMPRSS2 and MX1 host proteins is common, but not to East Asia where this allele is rare.; to: Preprint https://doi.org/10.1101/2020.05.04.075911 reports rs35074065 of TMPRSS2 results in the overexpression of both TMPRSS2 and a nearby gene MX1. rs35074065 overlaps with a transcription factor binding site of an activator (IRF1) and a repressor (IRF2). IRF1 activator can bind to variant delC allele, but IRF2 repressor fails to bind. Thus, in an individual carrying the delC allele of rs35074065, there is only activation, but no repression. On viral entry, IRF1 mediated upregulation of MX1 leads to neutrophil infiltration and processing of 614G variant viral Spike protein by neutrophil Elastase. The simultaneous processing of 614G spike protein by TMPRSS2 and Elastase serine proteases facilitates the entry of the 614G subtype into host cells. Thus, SARS-CoV-2, particularly the 614G subtype, has spread more easily and with higher frequency to Europe and North America where the delC allele regulating expression of TMPRSS2 and MX1 host proteins is common, but not to East Asia where this allele is rare.
COVID-19 research v0.214 KPNA2 Rebecca Foulger Classified gene: KPNA2 as Red List (low evidence)
COVID-19 research v0.214 KPNA2 Rebecca Foulger Added comment: Comment on list classification: Added KPNA2 to the panel as a Red gene. Present in the latest UniProt COVID portal release based on functional data that show an interaction with SARS-COVID viral ORF6 protein.
COVID-19 research v0.214 KPNA2 Rebecca Foulger Gene: kpna2 has been classified as Red List (Low Evidence).
COVID-19 research v0.213 KPNA2 Rebecca Foulger changed review comment from: KPNA2 present in the UniProt COVID portal (11th May 2020 Release): https://covid-19.uniprot.org/uniprotkb/P52292. KPNA2 acts as a nuclear import factor. KPNA2 is retained in ER/Golgi membranes upon interaction with SARS-COV virus ORF6 protein, and therefore KPNA2 is unable to transport STAT1 into the nucleus, therby blocking the expression of STAT1-activated genes that establish an antiviral state (PMID:17596301).
Sources: Literature, Other; to: KPNA2 is present in the UniProt COVID portal (11th May 2020 Release): https://covid-19.uniprot.org/uniprotkb/P52292. KPNA2 acts as a nuclear import factor. KPNA2 is retained in ER/Golgi membranes upon interaction with SARS-COV virus ORF6 protein, and therefore KPNA2 is unable to transport STAT1 into the nucleus, therby blocking the expression of STAT1-activated genes that establish an antiviral state (PMID:17596301).
Sources: Literature, Other
COVID-19 research v0.213 KPNA2 Rebecca Foulger gene: KPNA2 was added
gene: KPNA2 was added to Viral susceptibility. Sources: Literature,Other
Mode of inheritance for gene: KPNA2 was set to Unknown
Publications for gene: KPNA2 were set to 17596301
Added comment: KPNA2 present in the UniProt COVID portal (11th May 2020 Release): https://covid-19.uniprot.org/uniprotkb/P52292. KPNA2 acts as a nuclear import factor. KPNA2 is retained in ER/Golgi membranes upon interaction with SARS-COV virus ORF6 protein, and therefore KPNA2 is unable to transport STAT1 into the nucleus, therby blocking the expression of STAT1-activated genes that establish an antiviral state (PMID:17596301).
Sources: Literature, Other
COVID-19 research v0.212 SH3BP2 Catherine Snow Classified gene: SH3BP2 as Red List (low evidence)
COVID-19 research v0.212 SH3BP2 Catherine Snow Added comment: Comment on list classification: Demoting gene based on expert review
COVID-19 research v0.212 SH3BP2 Catherine Snow Gene: sh3bp2 has been classified as Red List (Low Evidence).
COVID-19 research v0.211 FURIN Rebecca Foulger Publications for gene: FURIN were set to
COVID-19 research v0.210 FURIN Rebecca Foulger Classified gene: FURIN as Amber List (moderate evidence)
COVID-19 research v0.210 FURIN Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber: Although no SNP studies, or potential variants identified yet, recent papers (e.g. PMID:32362314) and preprints have identified a role for Furin protease activity in SARS-CoV-2 entry into human cells. Therefore changes to Furin sequence could potentially alter viral susceptibility.
COVID-19 research v0.210 FURIN Rebecca Foulger Gene: furin has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.209 FURIN Rebecca Foulger commented on gene: FURIN: PMID:32362314. Hoffmann et al., 2020 report that Furin cleaves the SARS-CoV-2 spike protein at the S1/S2 site, and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. Therefore furin may be a potential target for therapuetic intervention.
COVID-19 research v0.209 FURIN Rebecca Foulger commented on gene: FURIN: PMID:25974265. Hardes et al., 2015. Furing is required for H7N1 and H5N1 influenza virus infection, probably by cleaving hemagglutinin. Therefore inhibition of Furin is a potential strategy for short-term treatment of acute infectious diseases, including avian influenza.
Monogenic hearing loss v2.18 SLC52A3 Eleanor Williams Tag for-review tag was added to gene: SLC52A3.
Monogenic hearing loss v2.18 SLC52A2 Eleanor Williams Tag for-review tag was added to gene: SLC52A2.
COVID-19 research v0.209 FURIN Rebecca Foulger commented on gene: FURIN
Hypophosphataemia or rickets v2.5 CLCN5 Ivone Leong Publications for gene: CLCN5 were set to 28383812; 9187673
COVID-19 research v0.209 CD14 Catherine Snow Classified gene: CD14 as Green List (high evidence)
COVID-19 research v0.209 CD14 Catherine Snow Added comment: Comment on list classification: Upgrade to Green based on expert review from Sophie Hambleton
COVID-19 research v0.209 CD14 Catherine Snow Gene: cd14 has been classified as Green List (High Evidence).
COVID-19 research v0.208 ABO Catherine Snow Classified gene: ABO as Green List (high evidence)
COVID-19 research v0.208 ABO Catherine Snow Added comment: Comment on list classification: Upgrade to Green based on expert review
COVID-19 research v0.208 ABO Catherine Snow Gene: abo has been classified as Green List (High Evidence).
Ectodermal dysplasia v1.6 KREMEN1 Catherine Snow Classified gene: KREMEN1 as Amber List (moderate evidence)
Ectodermal dysplasia v1.6 KREMEN1 Catherine Snow Added comment: Comment on list classification: Changed rating to Amber as additional family with ED identified in literature by external reviewer.
Ectodermal dysplasia v1.6 KREMEN1 Catherine Snow Gene: kremen1 has been classified as Amber List (Moderate Evidence).
Ectodermal dysplasia v1.5 KREMEN1 Catherine Snow Publications for gene: KREMEN1 were set to 27049303
COVID-19 research v0.207 SELPLG Sarah Leigh commented on gene: SELPLG: PMID: 30833724 identifies SELPLG (refered to as PSGL1 in the literature) as an HIV restriction factor, SELPLG is induced by interferon-γ in activated CD4+ T cells to inhibit HIV-1 reverse transcription and potently block viral infectivity by incorporating in progeny virions.
Preprint https://doi.org/10.1101/2020.05.01.073387 report that virion incorporation of SELPLG on SARS-CoV and SARS-CoV-2 pseudovirions blocks S protein-mediated virus attachment and infection of target cells, Suggesting that SELPLG-imprinted non-infectious viral particles could serve as a live attenuated vaccine for SARS-CoV-2 infection.
COVID-19 research v0.207 SELPLG Sarah Leigh gene: SELPLG was added
gene: SELPLG was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: SELPLG was set to Unknown
Publications for gene: SELPLG were set to 19543284; 30833724; doi.org/10.1101/2020.05.01.073387
Review for gene: SELPLG was set to RED
Added comment: In PMID 19543284 SELPLG (refered to as PSGL1 in the literature) is a receptor for 5 of 8 the Enterovirus-71 (EV71) strains. EV71 interaction and viral replication could be inhibited by monoclonal antibodies to SELPLG. The authors concluded that SELPLG-positive leukocytes are involved in the cell tropism and pathogenesis of hand, foot and mouth disease and other EV71-mediated diseases.
Sources: Literature
COVID-19 research v0.206 ACE2 Sarah Leigh changed review comment from: In preprint https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection. The authors speculated that modulation levels of ACE2 and natriuretic peptides may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection.; to: Preprint: https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection. The authors speculated that modulation levels of ACE2 and natriuretic peptides may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection.

Preprint: https://doi.org/10.1101/2020.05.03.074781 uses mCSM-PPI212 mutation effect predictor for protein-protein complex affinity, primarily validated against published experimental ACE2 variant SARS-CoV S-protein affinities to analysis variants from gnomAD. p.Gly326Glu, predicted to enhances ACE2 binding affinity for SARS-CoV-2 S, therefore a potential risk factor for COVID-19. p.Glu37Lys, p.Gly352Val and p.Asp355Asn predicted to reduce ACE2 affinity for SARS-CoV-2 S, therefore potentially protective against COVID-19.
Catecholaminergic polymorphic VT v2.4 CALM3 Eleanor Williams Phenotypes for gene: CALM3 were changed from to ?Ventricular tachycardia, catecholaminergic polymorphic 6, 618782; Long QT syndrome 16,618782
Long QT syndrome v2.6 CALM3 Eleanor Williams Phenotypes for gene: CALM3 were changed from to ?Ventricular tachycardia, catecholaminergic polymorphic 6, 618782; Long QT syndrome 16,618782
Mitochondrial disorders v2.6 QRSL1 Eleanor Williams Phenotypes for gene: QRSL1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis) to Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 40, 618835
COVID-19 research v0.206 CCL5 Sarah Leigh Classified gene: CCL5 as Green List (high evidence)
COVID-19 research v0.206 CCL5 Sarah Leigh Added comment: Comment on list classification: Based on expert review by Sophie Hambleton (Newcastle University)
COVID-19 research v0.206 CCL5 Sarah Leigh Gene: ccl5 has been classified as Green List (High Evidence).
Possible mitochondrial disorder, nuclear genes v1.15 QRSL1 Eleanor Williams Phenotypes for gene: QRSL1 were changed from Mitochondrial cardiomyopathy to Mitochondrial cardiomyopathy; Combined oxidative phosphorylation deficiency 40, 618835
Likely inborn error of metabolism v2.8 QRSL1 Eleanor Williams Phenotypes for gene: QRSL1 were changed from Multiple respiratory chain complex deficiencies (disorders of protein synthesis) to Multiple respiratory chain complex deficiencies (disorders of protein synthesis); Combined oxidative phosphorylation deficiency 40, 618835
Intellectual disability v3.62 TMX2 Eleanor Williams Phenotypes for gene: TMX2 were changed from Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration; Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, 618730
Intellectual disability v3.61 SMARCD1 Eleanor Williams Phenotypes for gene: SMARCD1 were changed from Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot to Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Abnormality of the hand; Abnormality of the foot; Coffin-Siris syndrome 11, 618779
Hereditary spastic paraplegia v1.215 PCYT2 Eleanor Williams Phenotypes for gene: PCYT2 were changed from Complex hereditary spastic paraplegia; Spastic paraplegia 82, autosomal recessive #618770 to Complex hereditary spastic paraplegia; Spastic paraplegia 82, autosomal recessive, 618770
Early onset or syndromic epilepsy v2.50 PCYT2 Eleanor Williams Phenotypes for gene: PCYT2 were changed from Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Cerebral atrophy; Cerebellar atrophy to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Cerebral atrophy; Cerebellar atrophy; Spastic paraplegia 82, autosomal recessive, 618770
Hereditary spastic paraplegia v1.214 PCYT2 Eleanor Williams Phenotypes for gene: PCYT2 were changed from Complex hereditary spastic paraplegia to Complex hereditary spastic paraplegia; Spastic paraplegia 82, autosomal recessive #618770
COVID-19 research v0.205 ACE2 Sarah Leigh changed review comment from: In preprint https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection.; to: In preprint https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection. The authors speculated that modulation levels of ACE2 and natriuretic peptides may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection.
COVID-19 research v0.205 ACE2 Sarah Leigh commented on gene: ACE2
Intellectual disability v3.60 NKAP Eleanor Williams Phenotypes for gene: NKAP were changed from Global developmental delay; Intellectual disability to Global developmental delay; Intellectual disability; Intellectual developmental disorder, X-linked, syndromic, Hackman-Di Donato type #301039
Intellectual disability v3.59 DLG4 Eleanor Williams Phenotypes for gene: DLG4 were changed from Intellectual disability; Marfanoid habitus to Intellectual disability; Marfanoid habitus; Intellectual developmental disorder 62 #618793
Fetal anomalies v1.59 SUZ12 Eleanor Williams Phenotypes for gene: SUZ12 were changed from Weaver-like overgrowth syndrome to Weaver-like overgrowth syndrome; Imagawa-Matsumoto syndrome #618786
Kabuki syndrome v1.4 PQBP1 Rebecca Foulger Phenotypes for gene: PQBP1 were changed from intellectual disability; long triangular face; bulbous nose; hypoplastic malar region; micrognathia; partial agenesis of corpus callosum; spasticity; contractures to Kabuki-like syndrome; intellectual disability; long triangular face; bulbous nose; hypoplastic malar region; micrognathia; partial agenesis of corpus callosum; spasticity; contractures
Kabuki syndrome v1.3 PQBP1 Rebecca Foulger Classified gene: PQBP1 as Red List (low evidence)
Kabuki syndrome v1.3 PQBP1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Red. Gene was added to the panel and rated Red by Cristina Dias. 1 individual in PMID:30244542 with PQBP1 hemizygous variant and Kabuki-like dysmorphic facial features. Therefore Red rating appropriate awaiting further cases that expand the phenotypic spectrum of PQBP1 disorders.
Kabuki syndrome v1.3 PQBP1 Rebecca Foulger Gene: pqbp1 has been classified as Red List (Low Evidence).
Kabuki syndrome v1.2 PQBP1 Rebecca Foulger commented on gene: PQBP1
COVID-19 research v0.205 CCL5 Sarah Leigh reviewed gene: CCL5: Rating: ; Mode of pathogenicity: None; Publications: https://doi.org/10.1101/2020.05.02.20084673; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.205 CCR5 Sarah Leigh edited their review of gene: CCR5: Added comment: Preprint https://doi.org/10.1101/2020.05.02.20084673 reports 10 terminally-ill, critical COVID-19 patients with profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Treatment with CCR5 blocking antibody leronlimab, results in complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. From single-cell RNA-sequencing, this effect appears to be a result of reduced transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes.; Changed publications: https://doi.org/10.1101/2020.05.02.20084673
COVID-19 research v0.205 IL6 Sarah Leigh Classified gene: IL6 as Green List (high evidence)
COVID-19 research v0.205 IL6 Sarah Leigh Gene: il6 has been classified as Green List (High Evidence).
COVID-19 research v0.204 IL6 Sarah Leigh edited their review of gene: IL6: Added comment: Preprint https://doi.org/10.1101/2020.05.02.20084673 reports 10 terminally-ill, critical COVID-19 patients with profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Treatment with CCR5 blocking antibody leronlimab, results in complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. From single-cell RNA-sequencing, this effect appears to be a result of reduced transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes.; Changed publications: https://doi.org/10.1101/2020.05.02.20084673
Intellectual disability v3.58 CDK8 Eleanor Williams Phenotypes for gene: CDK8 were changed from Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of cardiovascular system morphology; Hearing impairment; Abnormality of vision; Anorectal anomaly; Seizures to Generalized hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of cardiovascular system morphology; Hearing impairment; Abnormality of vision; Anorectal anomaly; Seizures; Intellectual developmental disorder with hypotonia and behavioral abnormalities #618748
Congenital myopathy v2.5 FXR1 Eleanor Williams Phenotypes for gene: FXR1 were changed from Congenital multi-minicore myopathy to Congenital multi-minicore myopathy; ?Myopathy, congenital proximal, with minicore lesions #618823; ?Myopathy, congenital, with respiratory insufficiency and bone fractures #618822
Hereditary spastic paraplegia, childhood onset v2.12 PCYT2 Rebecca Foulger Tag for-review tag was added to gene: PCYT2.
Hereditary spastic paraplegia, childhood onset v2.12 PCYT2 Rebecca Foulger Classified gene: PCYT2 as Green List (high evidence)
Hereditary spastic paraplegia, childhood onset v2.12 PCYT2 Rebecca Foulger Added comment: Comment on list classification: Added to panel based on sufficient cases in PMID:31637422 with HSP phenotype. Updated rating to Green following confirmation from Helen Brittain, Genomics England Clinical Team, that phenotype is appropriate for the panel. Added 'for-review' tag so that GLHs can confirm that gene is indeed required for childhood onset panel (as Helen notes: one patient had onset at 16 and mild delay of motor skills).
Hereditary spastic paraplegia, childhood onset v2.12 PCYT2 Rebecca Foulger Gene: pcyt2 has been classified as Green List (High Evidence).
Hereditary spastic paraplegia, childhood onset v2.11 PCYT2 Rebecca Foulger gene: PCYT2 was added
gene: PCYT2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Spastic paraplegia 82, autosomal recessive, 618770
Added comment: PMID:31637422. In 5 patients from 4 unrelated families with autosomal recessive spastic paraplegia-82 (MIM:618770), Vaz et al. (2019) identified homozygous or compound heterozygous mutations in the PCYT2 gene. The variants segregated with the disorder in all families. Functional studies showed reduced (not absent) PYCT2 activity.
Sources: Literature
Hereditary spastic paraplegia, adult onset v1.7 PCYT2 Rebecca Foulger Classified gene: PCYT2 as Green List (high evidence)
Hereditary spastic paraplegia, adult onset v1.7 PCYT2 Rebecca Foulger Added comment: Comment on list classification: Added to panel as Green for now based on sufficient cases with HSP phenotype in PMID:31637422. Added 'for-review' tag as suggested by Helen Brittain, Genomics England Clinical Team, as this gene requires additional review by GLH as to appropriateness for adult panel.
Hereditary spastic paraplegia, adult onset v1.7 PCYT2 Rebecca Foulger Gene: pcyt2 has been classified as Green List (High Evidence).
Hereditary spastic paraplegia, adult onset v1.6 PCYT2 Rebecca Foulger Tag for-review tag was added to gene: PCYT2.
Hereditary spastic paraplegia, adult onset v1.6 PCYT2 Rebecca Foulger gene: PCYT2 was added
gene: PCYT2 was added to Hereditary spastic paraplegia - adult onset. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Spastic paraplegia 82, autosomal recessive, 618770
Added comment: PMID:31637422. In 5 patients from 4 unrelated families with autosomal recessive spastic paraplegia-82 (MIM:618770), Vaz et al. (2019) identified homozygous or compound heterozygous mutations in the PCYT2 gene. The variants segregated with the disorder in all families. Functional studies showed reduced (not absent) PYCT2 activity.
Sources: Literature
Early onset or syndromic epilepsy v2.49 PCYT2 Rebecca Foulger Classified gene: PCYT2 as Green List (high evidence)
Early onset or syndromic epilepsy v2.49 PCYT2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green. Gene was added to panel and rated Green by Konstantinos Varvagiannis. Green rating confirmed by Genomics England Clinical Team.
Early onset or syndromic epilepsy v2.49 PCYT2 Rebecca Foulger Gene: pcyt2 has been classified as Green List (High Evidence).
Intellectual disability v3.57 PCYT2 Rebecca Foulger Phenotypes for gene: PCYT2 were changed from Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy to Spastic paraplegia 82, autosomal recessive, 618770; Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy
COVID-19 research v0.204 TMPRSS2 Sarah Leigh reviewed gene: TMPRSS2: Rating: ; Mode of pathogenicity: None; Publications: https://doi.org/10.1101/2020.05.04.075911; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.56 EXT2 Rebecca Foulger Classified gene: EXT2 as Green List (high evidence)
Intellectual disability v3.56 EXT2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green. Sufficient cases to support causation of MIM:616682, of which ID is a prominent phenotype. Note that I have updated the Mode of Inheritance from AD to AR to match MIM:616682 (and the Genetic epilepsy syndromes panel, #402).
Intellectual disability v3.56 EXT2 Rebecca Foulger Gene: ext2 has been classified as Green List (High Evidence).
Intellectual disability v3.55 EXT2 Rebecca Foulger changed review comment from: PMID:30288735. In 2 siblings with MIM:616682, Gentile et al identified compound het missense variants in EXT2, which segregated with the disorder (D227N and Y608C). The D227N vairant contributes to exostosis (inherited from the mother who had a family history of exostosis).; to: PMID:30288735. In 2 siblings with MIM:616682, Gentile et al identified compound het missense variants in EXT2, which segregated with the disorder (D227N and Y608C). The D227N variant contributes to exostosis (inherited from the mother who had a family history of exostosis).
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:30288735. In 2 siblings with MIM:616682, Gentile et al identified compound het missense variants in EXT2, which segregated with the disorder (D227N and Y608C). The D227N vairant contributes to exostosis (inherited from the mother who had a family history of exostosis).
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:30997052. In a 14 year old girl, Gupta et al. (2019) identified compound het missense variants in the EXT2 gene (V373D and T672M), which segregated with the disorder in the family. The patient also carried a maternal heterozygous variant (R454C) in NDST1. She had developmental delay, autism and epilepsy amongst her phenotypes.
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:30075207. In 2 brothers, born of consanguineous Syrian parents, with MIM:616682 El-Bazzal et al. (2019) identified a homozygous missense mutation in the EXT2 gene (p.Ser4Leu). Psychomotor delay was noted for both at the age of 3 months.
Intellectual disability v3.55 EXT2 Rebecca Foulger commented on gene: EXT2: PMID:26246518: In 4 siblings, born of consanguineous parents in the Old Order Mennonite community, with seizures, scoliosis, and macrocephaly/microcephaly syndrome (MIM:616682), Farhan et al. (2015) identified homozygosity for 2 missense mutations in EXT2 (M87R and R95C). All siblings had moderate ID and a seizure disorder.
Intellectual disability v3.55 EXT2 Rebecca Foulger Phenotypes for gene: EXT2 were changed from Seizures, scoliosis, and macrocephaly syndrome, 616682 to Seizures, scoliosis, and macrocephaly syndrome, 616682; autosomal recessive EXT2-related syndrome
Intellectual disability v3.54 EXT2 Rebecca Foulger Deleted their comment
Intellectual disability v3.54 EXT2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from MONOALLELIC to BIALLELIC. EXT2 is associated with 2 different disorders: Seizures, scoliosis, and macrocephaly syndrome, 616682 (AR) and Exostoses, multiple, type 2, 133701 (AD). MIM:616682 is relevant to this panel.
Intellectual disability v3.54 EXT2 Rebecca Foulger Mode of inheritance for gene: EXT2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.53 EXT2 Rebecca Foulger Publications for gene: EXT2 were set to 25529582; 26246518; 30997052; 30288735
Intellectual disability v3.52 EXT2 Rebecca Foulger Phenotypes for gene: EXT2 were changed from Exostoses, multiple, type 2, 133701 to Seizures, scoliosis, and macrocephaly syndrome, 616682
Intellectual disability v3.51 EXT2 Rebecca Foulger Publications for gene: EXT2 were set to 25529582
Intellectual disability v3.51 EXT2 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from MONOALLELIC to BIALLELIC. EXT2 is associated with 2 different disorders: Seizures, scoliosis, and macrocephaly syndrome, 616682 (AR) and Exostoses, multiple, type 2, 133701 (AD). MIM:616682 is relevant to this panel.
Intellectual disability v3.51 EXT2 Rebecca Foulger Mode of inheritance for gene: EXT2 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.50 EXT2 Rebecca Foulger Mode of inheritance for gene: EXT2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.49 EXT2 Rebecca Foulger Publications for gene: EXT2 were set to
Intellectual disability v3.48 WASF1 Rebecca Foulger Phenotypes for gene: WASF1 were changed from ID associated with autistic features, seizures, and developmental delay; intellectual disability to Neurodevelopmental disorder with absent language and variable seizures, 618707; ID associated with autistic features, seizures, and developmental delay; intellectual disability
Intellectual disability v3.47 POU3F3 Rebecca Foulger Phenotypes for gene: POU3F3 were changed from Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior to Snijders Blok-Fisher syndrome, 618604; Generalized hypotonia; Delayed speech and language development; Global developmental delay; Intellectual disability; Autistic behavior
Intellectual disability v3.46 POLR2A Rebecca Foulger Phenotypes for gene: POLR2A were changed from Global developmental delay; Generalized hypotonia; Feeding difficulties to Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, 618603; Global developmental delay; Generalized hypotonia; Feeding difficulties
CAKUT v1.106 GPC3 Ivone Leong Classified gene: GPC3 as Green List (high evidence)
CAKUT v1.106 GPC3 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. Based on the review and literature there is enough evidence to support a gene-disease association. Therefore, this gene has been given Green status.
CAKUT v1.106 GPC3 Ivone Leong Gene: gpc3 has been classified as Green List (High Evidence).
CAKUT v1.105 GPC3 Ivone Leong Publications for gene: GPC3 were set to
Intellectual disability v3.45 PHF21A Rebecca Foulger Added comment: Comment on phenotypes: Potocki-Shaffer syndrome (MIM:601224) is a contiguous gene deletion syndrome involving genes on chromosome 11p11.2.
Intellectual disability v3.45 PHF21A Rebecca Foulger Phenotypes for gene: PHF21A were changed from Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, 618725 to Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, 618725
Intellectual disability v3.44 PHF21A Rebecca Foulger Phenotypes for gene: PHF21A were changed from Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability to Potocki-Shaffer syndrome, 601224; PSS; Intellectual disability; Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, 618725
Intellectual disability v3.43 MSL3 Rebecca Foulger Phenotypes for gene: MSL3 were changed from Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; no OMIM number to Muscular hypotonia; Feeding difficulties; Neurodevelopmental delay; Intellectual disability; Basilicata-Akhtar syndrome, 301032
CAKUT v1.104 HOXA13 Ivone Leong Classified gene: HOXA13 as Green List (high evidence)
CAKUT v1.104 HOXA13 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. Based on the review and available literature there is enough evidence to support a gene-disease association. Therefore, this gene has been given a Green status.
CAKUT v1.104 HOXA13 Ivone Leong Gene: hoxa13 has been classified as Green List (High Evidence).
CAKUT v1.103 HOXA13 Ivone Leong Publications for gene: HOXA13 were set to
CAKUT v1.102 LIFR Ivone Leong Classified gene: LIFR as Green List (high evidence)
CAKUT v1.102 LIFR Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. Based on the review and the evidence there is enough evidence to support a gene-disease association. Therefore, this gene has been given Green status.
CAKUT v1.102 LIFR Ivone Leong Gene: lifr has been classified as Green List (High Evidence).
Monogenic hearing loss v2.18 SLC52A2 Eleanor Williams Tag treatable tag was added to gene: SLC52A2.
Monogenic hearing loss v2.18 SLC52A2 Eleanor Williams Classified gene: SLC52A2 as Green List (high evidence)
Monogenic hearing loss v2.18 SLC52A2 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. More than 3 cases reported in patients with Brown-Vialetto-Van Laere syndrome 2 and variants in this gene. Expert reviewer reports that hearing loss may be the first presentation.
Monogenic hearing loss v2.18 SLC52A2 Eleanor Williams Gene: slc52a2 has been classified as Green List (High Evidence).
Monogenic hearing loss v2.17 SLC52A2 Eleanor Williams Phenotypes for gene: SLC52A2 were changed from to Brown-Vialetto-Van Laere syndrome 2 #614707
Monogenic hearing loss v2.16 SLC52A2 Eleanor Williams Publications for gene: SLC52A2 were set to
Monogenic hearing loss v2.15 SLC52A2 Eleanor Williams Mode of inheritance for gene: SLC52A2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.14 SLC52A2 Eleanor Williams edited their review of gene: SLC52A2: Changed publications: 22740598, 22864630, 23243084, 24253200; Changed phenotypes: Brown-Vialetto-Van Laere syndrome 2 #614707
Monogenic hearing loss v2.14 SLC52A2 Eleanor Williams edited their review of gene: SLC52A2: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.14 SLC52A2 Eleanor Williams commented on gene: SLC52A2: Associated with Brown-Vialetto-Van Laere syndrome 2 #614707 (AR) in OMIM. Early childhood onset of sensorineural deafness is a feature along with bulbar dysfunction, and severe diffuse muscle weakness and wasting of the upper and lower limbs and axial muscles, resulting in respiratory insufficiency.

Numerous cases have been reported with variants in the SLC52A2 gene and Brown-Vialetto-Van Laere syndrome 2:

PMID: 22740598 Johnson et al 2012 - used linkage and exome sequencing to identify a novel mutation (p.G306R (c.916G>A)) in SLC52A2 in an extended Lebanese Brown-Vialetto-Van Laere kindred. The same homozygous mutation was identified in one additional subject from the UK, from 44 screened.

PMID: 22864630 Haack et al 2012 - exome sequencing of a single case with Brown-Vialetto-Van Laere syndrome showed compound heterozygosity for two pathogenic mutations in the SLC52A2 gene. Overexpression studies confirmed that the gene products of both mutant alleles have reduced riboflavin transport activities.

PMID: 23243084 Ciccolella et al 2013 - 1 case of a severe BVVL patient with two novel compound heterozygous mutations in SLC52A2 (c.155C>T, p.S52F and c.1255G>A, p.G419S). Functional studies show that these variants impair the gene expression of the corresponding transporter, resulting in a significant reduction of riboflavin transport.

PMID: 24253200 Foley et al 2014 - using exome and sanger sequencing identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy, hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression.
Hypophosphataemia or rickets v2.4 CLCN5 Martina Owens changed review comment from: Variants in this gene cause Dent disease - Oudet et al 1997 (PMID: 9187673) - family with four brothers presenting low molecular weight proteinuria, dramatic hypercalciuria and hypophosphataemic rickets. Morimoto et al 1998 (PMID: 9596078) - all patients had low molecular weight proteinuria (LMWP). LMWP is the pathognomonic finding of Dent disease, therfore possible that these patients will be tested using the Proteinuric renal disease panel. 60% patients with Dent disease have variant in this gene (NB. 15% of Dent patients have variants in the OCRL gene and this gene should be considerd for addition to the Proteinuric renal disease panel).; to: Variants in this gene cause Dent disease - Oudet et al 1997 (PMID: 9187673) - family with four brothers presenting low molecular weight proteinuria, dramatic hypercalciuria and hypophosphataemic rickets. Morimoto et al 1998 (PMID: 9596078) - all patients had low molecular weight proteinuria (LMWP). LMWP is the pathognomonic finding of Dent disease, therfore possible that these patients will be tested using the Proteinuric renal disease panel. 60% patients with Dent disease have variant in this gene (NB. 15% of Dent patients have variants in the OCRL gene and this gene should be considered for addition to the Proteinuric renal disease panel).
CAKUT v1.101 LRP4 Ivone Leong Classified gene: LRP4 as Green List (high evidence)
CAKUT v1.101 LRP4 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. LRP4 is associated with a relevant phenotype in OMIM and Gene2Phenotype, with Gene2Phenotype listing renal agenesis and renal hypoplasia as a phenotype. There are >3 unrelated cases of patients with LRP4 variants who have renal hypoplasia or renal agenesis as a feature. There is also a mouse model. Therefore there is enough evidence to support a gene-disease association for this gene to be Green.
CAKUT v1.101 LRP4 Ivone Leong Gene: lrp4 has been classified as Green List (High Evidence).
CAKUT v1.100 LRP4 Ivone Leong Publications for gene: LRP4 were set to
Monogenic hearing loss v2.14 SLC52A3 Eleanor Williams Phenotypes for gene: SLC52A3 were changed from to Brown-Vialetto-Van Laere syndrome 1 #211530
Monogenic hearing loss v2.13 SLC52A3 Eleanor Williams Publications for gene: SLC52A3 were set to
Monogenic hearing loss v2.12 SLC52A3 Eleanor Williams edited their review of gene: SLC52A3: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.12 SLC52A3 Eleanor Williams Tag treatable tag was added to gene: SLC52A3.
Monogenic hearing loss v2.12 SLC52A3 Eleanor Williams Mode of inheritance for gene: SLC52A3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Monogenic hearing loss v2.11 SLC52A3 Eleanor Williams Classified gene: SLC52A3 as Green List (high evidence)
Monogenic hearing loss v2.11 SLC52A3 Eleanor Williams Added comment: Comment on list classification: More than 3 cases reported with variants in SLC52A3 in patients Brown-Vialetto-van Laere syndrome. Sensorineural deafness is a feature of this syndrome and often presents first.
Monogenic hearing loss v2.11 SLC52A3 Eleanor Williams Gene: slc52a3 has been classified as Green List (High Evidence).
Monogenic hearing loss v2.10 SLC52A3 Eleanor Williams commented on gene: SLC52A3: Associated with Brown-Vialetto-Van Laere syndrome 1 #211530 (AR) in OMIM, a form of progressive bulbar palsy with sensorineural deafness.

Multiple cases of variants in this gene have been found in patients with Brown-Vialetto-Van Laere syndrome 1:

PMID: 20206331 Green et al 2010 - identified homozygous or compound heterozygous variants in C20orf54 (SLC52A3) in individuals with Brown-Vialetto-Van Laere syndrome from 7 families of European, Pakistani and Arabic ancestry. Nonsense and missense variants were found. Used homozgyosity mapping in the first family and then candidate gene analysis. They also report that 58 cases have been documented in the literature, with the age at onset ranged from infancy to early in the third decade, with the majority presenting in the second decade. Hearing loss preceded the onset of neurological signs in most cases. C20ORF54 is thought to play a role in riboflavin transport.

PMID: 20920669 Johnson et al 2010 - performed exome sequencing in patients with Brown-Vialetto-van Laere syndrome. In one patient in common with Green et al 2010 they found compound heterozygous variants in C20orf54 (patient 2008-410) rather than the homozygous variant Green et al reported (case 4). The results were confirmed by Sanger sequence and the parents were found to each have 1 heterozygous variant. They also report an additional family (DZ) from Eastern Turkey with a homozygous variant in affected individuals.
Intellectual disability v3.42 CNOT3 Rebecca Foulger commented on gene: CNOT3
Intellectual disability v3.42 CNOT3 Rebecca Foulger Mode of inheritance for gene: CNOT3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v3.41 CNOT3 Rebecca Foulger Publications for gene: CNOT3 were set to 25529582; 28135719
Intellectual disability v3.40 CNOT3 Rebecca Foulger Phenotypes for gene: CNOT3 were changed from CNOT3 syndrome; intellectual disability, global developmental delay to CNOT3 syndrome; intellectual disability, global developmental delay; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, 618672
Early onset or syndromic epilepsy v2.48 WASF1 Rebecca Foulger Phenotypes for gene: WASF1 were changed from ID associated with autistic features, seizures, and developmental delay; Intellectual disability to Neurodevelopmental disorder with absent language and variable seizures, 618707
COVID-19 research v0.204 ACE2 Rebecca Foulger commented on gene: ACE2: Added 'treatable' tag based on preprint http://biorxiv.org/cgi/content/short/2020.05.07.082230 which suggests that a modified ACE2 peptide could act as a treatment to block the viral receptor forming a complex with ACE2.
COVID-19 research v0.204 ACE2 Rebecca Foulger Tag treatable tag was added to gene: ACE2.
Laterality disorders and isomerism v1.5 NODAL Zornitza Stark reviewed gene: NODAL: Rating: RED; Mode of pathogenicity: None; Publications: 9354794, 19064609; Phenotypes: Heterotaxy, visceral, 5 (MIM#270100); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
CAKUT v1.99 LRP4 Ivone Leong Phenotypes for gene: LRP4 were changed from Cenani-Lenz syndactyly syndrome, MIM# 212780 to Cenani-Lenz syndactyly syndrome, 212780
CAKUT v1.98 LIFR Ivone Leong Publications for gene: LIFR were set to PMID: 28334964
CAKUT v1.97 KMT2D Ivone Leong Classified gene: KMT2D as Green List (high evidence)
CAKUT v1.97 KMT2D Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on the evidence and review there is enough evidence to support a gene-disease association; therefore, this gene has been given Green status.
CAKUT v1.97 KMT2D Ivone Leong Gene: kmt2d has been classified as Green List (High Evidence).
CAKUT v1.96 KMT2D Ivone Leong Phenotypes for gene: KMT2D were changed from Kabuki syndrome 1, MIM# 147920 to Kabuki syndrome 1, 147920
CAKUT v1.95 KDM6A Ivone Leong Classified gene: KDM6A as Green List (high evidence)
CAKUT v1.95 KDM6A Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. Based on the evidence and review there is enough evidence to support a gene-disease association; therefore, this gene has been given Green status.
CAKUT v1.95 KDM6A Ivone Leong Gene: kdm6a has been classified as Green List (High Evidence).
CAKUT v1.94 KDM6A Ivone Leong Mode of inheritance for gene: KDM6A was changed from Other to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
CAKUT v1.93 KDM6A Ivone Leong Phenotypes for gene: KDM6A were changed from Kabuki syndrome 2, MIM# 300867 to Kabuki syndrome 2, 300867
CAKUT v1.92 JAG1 Ivone Leong Classified gene: JAG1 as Green List (high evidence)
CAKUT v1.92 JAG1 Ivone Leong Gene: jag1 has been classified as Green List (High Evidence).
CAKUT v1.91 JAG1 Ivone Leong Classified gene: JAG1 as No list
CAKUT v1.91 JAG1 Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer (Chirag Patel (Genetic Health Queensland)). JAG1 is associated with a relevant disease in OMIM and Gene2Phenotype.

Renal structural involvement for cases of Alagille syndrome caused by variants in the JAG1 gene is well known. Based on the expert review and literature evidence there is enough evidence to support a gene-disease assocation. Therefore this gene has been given Green status.
CAKUT v1.91 JAG1 Ivone Leong Gene: jag1 has been removed from the panel.
CAKUT v1.90 JAG1 Ivone Leong Publications for gene: JAG1 were set to 22105858
Monogenic hearing loss v2.10 SLC52A3 Eleanor Williams gene: SLC52A3 was added
gene: SLC52A3 was added to Hearing loss. Sources: Expert list
Mode of inheritance for gene: SLC52A3 was set to Unknown
Added comment: Gene suggested for panel by Dr Julia Rankin (Royal Devon and Exeter NHS Foundation Trust). Sensorineural deafness is the presenting feature in cases presenting after infancy with other neurology a year or 2 later – treatment with Riboflavin can be effective.
Sources: Expert list
Monogenic hearing loss v2.9 SLC52A2 Eleanor Williams changed review comment from: Gene suggested for panel by Dr Julia Rankin (Royal Devon and Exeter NHS Foundation Trust)
Sources: Expert list; to: Gene suggested for panel by Dr Julia Rankin (Royal Devon and Exeter NHS Foundation Trust). Sensorineural deafness is the presenting feature in cases presenting after infancy with other neurology a year or 2 later – treatment with Riboflavin can be effective.
Sources: Expert list
Monogenic hearing loss v2.9 SLC52A2 Eleanor Williams gene: SLC52A2 was added
gene: SLC52A2 was added to Hearing loss. Sources: Expert list
Mode of inheritance for gene: SLC52A2 was set to Unknown
Added comment: Gene suggested for panel by Dr Julia Rankin (Royal Devon and Exeter NHS Foundation Trust)
Sources: Expert list
CAKUT v1.89 JAG1 Ivone Leong Phenotypes for gene: JAG1 were changed from Alagille syndrome 1; OMIM #118450 to Alagille syndrome 1 118450
CAKUT v1.88 JAG1 Ivone Leong Publications for gene: JAG1 were set to PMID: 22105858
CAKUT v1.87 HOXA13 Ivone Leong Phenotypes for gene: HOXA13 were changed from Hand-foot-uterus syndrome, MIM# 140000 to Hand-foot-uterus syndrome, 140000
Fetal anomalies v1.58 EXOC3L2 Rebecca Foulger Phenotypes for gene: EXOC3L2 were changed from Dandy-Walker malformation to Dandy-Walker malformation; Meckel-Gruber-like syndrome
CAKUT v1.86 GREB1L Ivone Leong Classified gene: GREB1L as Green List (high evidence)
CAKUT v1.86 GREB1L Ivone Leong Added comment: Comment on list classification: New gene added by expert reviewer. GREB1L is associated with a relevant phenotype in OMIM (there are >3 cases described there). Based on the expert reviews and literature there is enough to support gene-disease association, therefore this gene has been given a Green status.
CAKUT v1.86 GREB1L Ivone Leong Gene: greb1l has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 MYO5B Rebecca Foulger commented on gene: MYO5B
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 MYO5B Rebecca Foulger Tag for-review tag was added to gene: MYO5B.
CAKUT v1.85 GREB1L Ivone Leong Phenotypes for gene: GREB1L were changed from Renal hypodysplasia/aplasia 3, MIM# 617805 to Renal hypodysplasia/aplasia 3, 617805
CAKUT v1.84 GREB1L Ivone Leong Publications for gene: GREB1L were set to 29100091
COVID-19 research v0.204 SNORA31 Abdelazeem Elhabyan reviewed gene: SNORA31: Rating: ; Mode of pathogenicity: None; Publications: 31806906; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.204 TICAM1 Abdelazeem Elhabyan reviewed gene: TICAM1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22105173,26513235; Phenotypes: Herpes simplex encephalitis predisposition; Mode of inheritance: Other
Early onset or syndromic epilepsy v2.47 NR4A2 Konstantinos Varvagiannis gene: NR4A2 was added
gene: NR4A2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NR4A2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NR4A2 were set to https://doi.org/10.1038/s41436-020-0815-4; 31428396
Phenotypes for gene: NR4A2 were set to Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility
Penetrance for gene: NR4A2 were set to unknown
Review for gene: NR4A2 was set to GREEN
Added comment: Seizures have been reported in at least 6 unrelated individuals with NR4A2 variants (not including cases with contiguous gene deletions spanning also this gene). Please consider inclusion with amber or green rating.
---
Singh et al (2020 - https://doi.org/10.1038/s41436-020-0815-4) provide details on the phenotype of 9 unrelated individuals with NR4A2 pathogenic variants (in almost all cases de novo).

Features included hypotonia (in 6/9), DD (9/9), varying levels of ID (mild to severe in 8/8 for whom this information was available), seizures (6/9 - variable epilepsy phenotypes), behavioral problems (5/9 - with autism reported for one). Less frequent features incl. hypermobility (in 3), ataxia/movement disorder (in 3).

8 total pLoF and missense variants were identified as de novo events following trio exome sequencing with Sanger validation (7/8 variants). For 1(/8) individual with a stopgain variant, a single parental sample was available. A 9th individual was found to harbor a ~3.7 Mb 2q deletion spanning also other genes (which might also contribute to his phenotype of epilepsy).

Only the effect of a variant affecting the splice-acceptor site was studied (c.865-1_865delGCinsAAAAAGGAGT - NM_006186.3) with RT-PCR demonstrating an out-of-frame skipping of exon 4. Another variant (NM_006186.3:c.325dup) found in a subject with DD, ID and epilepsy had also previously been reported in another individual with similar phenotype of epilepsy and ID (Ramos et al - PMID: 31428396 - the variant was de novo with other causes for his phenotype excluded).

As discussed by Singh et al, NR4A2 encodes a steroid-thyroid-retinoid receptor which acts as a nuclear receptor transcription factor. The authors summarize previous reports on NR4A2 haploinsufficiency (NR4A2 has a pLI of 1 and HI score of 1.28% - Z-score is 2.24).

The authors comment on mouse models suggesting a role of NR4A2 for dopaminergic neurons, and provide plausible explanations for the phenotype of ID/seizures.

Previous reviews for the ID panel:
--
In a study of 457 autism families (Feliciano et al. - doi.org/10.1101/516625) the authors provide phenotypic information on a further individual with ASD and ID. This subject (SP0041645 - SPARK cohort) harbored a de novo frameshift variant (p.G231fs using ENST00000409572.1 as reference). Table 2 includes also the individual previously reported by Iossifov et al. who also presented with ASD and ID (11172.p1 - SSC cohort - PMID and details discussed below).
--
Recent publications provide several lines of evidence that pathogenic NR4A2 variants cause DD/ID and/or autism spectrum disorder (ASD).

Lévy et al. (PMID: 29770430) summarize the phenotype of 2q24.1 microdeletions spanning either only NR4A2 [2 new patients as well as an individual reported by Reuter et al (PMID: 28544326)] or both NR4A2 and GPD2 (1 patient from this study as well as 2 further from Leppa et al. (PMID: 27569545) and Barge-Schaapveld et al. (PMID: 23554088)]. All these CNVs had occurred as de novo events. Common features included - among others - language impairment (6/6), ID (6/6), ASD (3/4) or abnormal behaviour (4/4).

As the authors note, NR4A2 belongs to a subfamily of highly conserved transcription factors. The gene is involved in several developmental processes, among others in neuronal development. Previous studies have also shown high expression in human fetal brain as well as a role in the development of language-related brain regions.

The absence of CNVs in general population encompassing NR4A2 (and presence of such CNVs spanning GDP2) as well as the minimal deletions confined to NR4A2 suggest that happloinsufficiency of NR4A2 is responsible for the DD/ID/ASD phenotypes. This is also supported by the HI index of 1.28 as well as pLI of 0.99.

Guo et al. (PMID: 30504930) report on a patient with de novo frameshift variant (p.P201Rfs*82) and provide a summary of individuals with de novo missense variants (schematic overview in suppl. fig. S4) previously reported in larger DD/ID/ASD cohorts, namely :

- The DDD study (PMID: 28135719) : subjects DDD4K.00386 (R312Q - https://decipher.sanger.ac.uk/ddd/research-variant/1e7622c3a0ba1b506c5808ccea46e759#overview) and DDD4K.04161 (R289P - https://decipher.sanger.ac.uk/ddd/research-variant/673e8e570d28dd0c5797ddafb22e53eb#overview)

- By Lelieveld et al. (PMID: 27479843) : patient with ID and V307G

- By Iossifov et al. (PMID: 25363768) : subject with ASD and Y275H.

[All these appear to cluster in a region of missense constraint : https://decipher.sanger.ac.uk/gene/NR4A2#overview/protein-info].

NR4A2 is not associated with any phenotype in OMIM, nor in G2P.

The gene is included in gene panels for intellectual disability offered by diagnostic laboratories (incl. Radboudumc).

As a result, it could be considered for inclusion in this panel possibly as green (or amber).
Sources: Literature, Radboud University Medical Center, Nijmegen
Sources: Literature
Intellectual disability v3.39 NR4A2 Konstantinos Varvagiannis edited their review of gene: NR4A2: Added comment: Singh et al (2020 - https://doi.org/10.1038/s41436-020-0815-4) provide details on the phenotype of 9 unrelated individuals with NR4A2 pathogenic variants (in almost all cases de novo).

Features included hypotonia (in 6/9), DD (9/9), varying levels of ID (mild to severe in 8/8 for whom this information was available), seizures (6/9 - variable epilepsy phenotypes), behavioral problems (5/9 - with autism reported for one). Less frequent features incl. hypermobility (in 3), ataxia/movement disorder (in 3).

8 total pLoF and missense variants were identified as de novo events following trio exome sequencing with Sanger validation (7/8 variants). For 1(/8) individual with a stopgain variant, a single parental sample was available. A 9th individual was found to harbor a ~3.7 Mb 2q deletion spanning also other genes (which might also contribute to his phenotype of epilepsy).

Only the effect of a variant affecting the splice-acceptor site was studied (c.865-1_865delGCinsAAAAAGGAGT - NM_006186.3) with RT-PCR demonstrating an out-of-frame skipping of exon 4. Another variant (NM_006186.3:c.325dup) found in a subject with DD, ID and epilepsy had also previously been reported in another individual with similar phenotype of epilepsy and ID (Ramos et al - PMID: 31428396 - the variant was de novo with other causes for his phenotype excluded).

As discussed by Singh et al, NR4A2 encodes a steroid-thyroid-retinoid receptor which acts as a nuclear receptor transcription factor. The authors summarize previous reports on NR4A2 haploinsufficiency (NR4A2 has a pLI of 1 and HI score of 1.28% - Z-score is 2.24).

The authors comment on mouse models suggesting a role of NR4A2 for dopaminergic neurons, and provide plausible explanations for the phenotype of ID/seizures.; Changed publications: https://doi.org/10.1038/s41436-020-0815-4, 31428396, 29770430, 30504930, 28544326, 27569545, 23554088, 28135719, 27479843, 25363768; Changed phenotypes: Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility
Early onset or syndromic epilepsy v2.47 CUL3 Konstantinos Varvagiannis gene: CUL3 was added
gene: CUL3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CUL3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CUL3 were set to 32341456
Phenotypes for gene: CUL3 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE - MIM #614496
Penetrance for gene: CUL3 were set to unknown
Review for gene: CUL3 was set to AMBER
Added comment: Epilepsy has been reported in at least 2 relevant individuals in the literature.
--
Nakashima et al (2020 - PMID:32341456) provide clinical details on 3 unrelated individuals with de novo CUL3 variants.

Features included DD, variable degrees of ID (P1: severe, P3: mild, P2: NA although he displayed motor and severe speech and language delay and had severe learning difficulties). Two out of three had intractable seizures (onset 2 - 6 months). One presented with congenital heart defects (ASD, PV stenosis) and another submucosal palatoschisis/bifid uvula. There were no facial dysmorphisms reported.

CUL3 encodes Cullin-3, a core piece of the E3 ubiquitin ligase complex, thus playing a role in the ubiquitin-proteasome system. [ https://ghr.nlm.nih.gov/gene/CUL3 ]. Germline variants in some other Cullin family genes (eg. CUL4B, CUL7) cause disorders with ID as a feature.

The 3 individuals reported by Nakashima had variable previous investigations (karyotype, CMA, metabolic testing) which were non-diagnostic. Singleton or trio exome sequencing identified 2 frameshift and 1 missense variant (NM_003590.4:c.854T>C / p.Val285Ala), further confirmed with Sanger sequencing. De novo occurrence was confirmed by analysis of microsatellite markers in an individual with singleton ES.

While the frameshift variants were presumed to lead to NMD (not studied), studies in HEK293T cells suggested that the Val285Ala reduced binding ability with KEAP1, possibly leading to instability of the Cullin-RING ligase (CRL) complex and impairment of the ubiquitin-proteasome system.

In OMIM, the phenotype associated with heterozygous CUL3 mutations is Pseudohypoaldosteronism type IIE (PHA2E - # 614496). As OMIM and Nakashima et al comment, PHA2E-associated variants are clustered around exon 9, most lead to skipping of exon 9 and produce an in-frame deletion of 57 aa in the cullin homology domain. Few (probably 3) missense variants in exon 9 have also been reported. Individuals with PHA2E do not display DD/ID and conversely individuals with NDD did not display features of PHA2E.

Nakashima et al summarize the phenotypes associated with 12 further de novo CUL3 variants in the literature with most pLOF ones detected in individuals with autism and/or developmental disorders and in few cases with congenital heart disease. Few additional missense variants and a stoploss one have been reported in individuals with NDD and one in SCZ.

Heterozygous Cul3 (/tissue-specific) deletion in mice resulted in autism-like behavior. Cul3 deficient mice also demonstrated NMDAR hypofunction and decreased spine density. [PMIDs cited : 31455858, 31780330]

Overall haploinsufficiency is favored as the underlying mechanism of variants associated with NDD. Nakashima et al comment that the pathogenesis of missense variants remains unknown and/or that a dominant-negative effect on CRL may be possible.

Studies on larger cohorts reporting on individuals with relevant phenotypes due to de novo CUL3 variants (eg. DDD study - PMID: 28135719, Lelieveld et al - PMID: 27479843), are better summarized in denovo-db (after filtering for coding variants):

http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=cul3
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Please consider inclusion in other panels if appropriate (e.g. for ASD).
Sources: Literature
Intellectual disability v3.39 CUL3 Konstantinos Varvagiannis reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 32341456; Phenotypes: Global developmental delay, Intellectual disability, Seizures, Abnormality of cardiovascular system morphology, Abnormality of the palate, Pseudohypoaldosteronism, type IIE - MIM #614496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.204 ITGAM Sophie Hambleton edited their review of gene: ITGAM: Changed rating: AMBER
COVID-19 research v0.204 IL18 Sophie Hambleton edited their review of gene: IL18: Added comment: IL-18 is important in the pathogenesis of HLH (PMID:29326099) and the newly described autoinflammatory state IL18PAP-MAS (PMID: 31874111). Elevated IL-18 levels were detected in patients with COVID although not differentiating severe from mild/moderate disease (MedRxiv preprint https://doi.org/10.1101/2020.03.02.20029975). It is plausible that genetically determined differences in the activity of IL-18 might influence risk of severe COVID-19; Changed rating: AMBER
COVID-19 research v0.204 IL6 Sophie Hambleton reviewed gene: IL6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.204 IFNL3 Sophie Hambleton reviewed gene: IFNL3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.204 CD14 Sophie Hambleton reviewed gene: CD14: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.204 CCL5 Sophie Hambleton reviewed gene: CCL5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v3.11 ATP1A2 Rebecca Foulger Classified gene: ATP1A2 as Amber List (moderate evidence)
Arthrogryposis v3.11 ATP1A2 Rebecca Foulger Added comment: Comment on list classification: Rated as Amber: 2 unrelated families in PMID:30690204 with arthrogryposis amongst their postnatal phenotypes. Further cases required for diagnostic rating.
Arthrogryposis v3.11 ATP1A2 Rebecca Foulger Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.204 ABO Sophie Hambleton reviewed gene: ABO: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v3.10 ATP1A2 Rebecca Foulger gene: ATP1A2 was added
gene: ATP1A2 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: ATP1A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP1A2 were set to 30690204
Phenotypes for gene: ATP1A2 were set to arthrogryposis, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency
Added comment: Added to panel based on PMID:30690204 (Monteiro et al., 2020) who describe 3 newborns from 2 unrelated families who died neontally, presenting in utero with fetal hydrops, seizures and polyhydramnios. At birth they had arthrogryposis, microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic LOF variants in ATP1A2 were found upon WES.
Sources: Literature
Fetal hydrops v1.22 PSAT1 Rebecca Foulger Classified gene: PSAT1 as Red List (low evidence)
Fetal hydrops v1.22 PSAT1 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Amber by Zornitza Stark. Fetal cases in Neu-Laxova syndrome (MIM:616038) in PMID:25152457 and 31903955 but not necessarily hydrops. Therefore rated Red awaiting further cases with hydrops.
Fetal hydrops v1.22 PSAT1 Rebecca Foulger Gene: psat1 has been classified as Red List (Low Evidence).
Fetal anomalies v1.57 PSAT1 Rebecca Foulger Classified gene: PSAT1 as Green List (high evidence)
Fetal anomalies v1.57 PSAT1 Rebecca Foulger Added comment: Comment on list classification: Rated 'probable' for Neu-Laxova syndrome in Gene2Phenotype, but there are sufficient cases from the literature to support causation (6 families in PMID:25152457 and 1 Chinese family in PMID:31903955). Therefore updated rating from Amber to Green: Fetally-relevant phenotype and sufficient evidence.
Fetal anomalies v1.57 PSAT1 Rebecca Foulger Gene: psat1 has been classified as Green List (High Evidence).
Fetal anomalies v1.56 PSAT1 Rebecca Foulger Phenotypes for gene: PSAT1 were changed from NEU-LAXOVA SYNDROME; PHOSPHOSERINE AMINOTRANSFERASE DEFICIENCY to Neu-Laxova syndrome 2, 616038; NEU-LAXOVA SYNDROME; PHOSPHOSERINE AMINOTRANSFERASE DEFICIENCY
Fetal anomalies v1.55 PSAT1 Rebecca Foulger Publications for gene: PSAT1 were set to
Fetal anomalies v1.54 PSAT1 Rebecca Foulger commented on gene: PSAT1: PMID:31903955 (Ni et al., 2019) report Chinese Neu-Laxova syndrome (NLS) patients from 2 families. Compound het PSAT1 variants R342W and Y70N were found in the proband from family 1. (PHGDH variants were identified in family 2).
Fetal anomalies v1.54 PSAT1 Rebecca Foulger commented on gene: PSAT1: PMID:25152457. Acuna-Hidalgo et al., 2014 report a rare AR disorder with severe malformations leading to prenatal or early postnatal lethality (Neu-Laxova syndrome). They identified variants in PHGDH, PSAT1 and PSPH in individuals with NLS, including 6 families with 3 different missense and frameshift PSAT1 variants which segregated with the disease.
Intellectual disability v3.39 ATP1A2 Rebecca Foulger Phenotypes for gene: ATP1A2 were changed from Migraine, familial hemiplegic, 2 602481 to Migraine, familial hemiplegic, 2 602481; Alternating hemiplegia of childhood 1, 104290
Fetal hydrops v1.21 ATP1A2 Rebecca Foulger Classified gene: ATP1A2 as Amber List (moderate evidence)
Fetal hydrops v1.21 ATP1A2 Rebecca Foulger Added comment: Comment on list classification: Added to panel by Zornitza Stark. Not yet associated with a disorder in Gene2Phenotype. 2 families with Fetal hydrops reported in PMID:30690204 (3 individuals). Therefore phenotype is relevant to panel, and rated Amber awaiting further cases.
Fetal hydrops v1.21 ATP1A2 Rebecca Foulger Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Fetal hydrops v1.20 ATP1A2 Rebecca Foulger commented on gene: ATP1A2
Fetal anomalies v1.54 ATP1A2 Rebecca Foulger Classified gene: ATP1A2 as Amber List (moderate evidence)
Fetal anomalies v1.54 ATP1A2 Rebecca Foulger Added comment: Comment on list classification: Added to panel with Amber review by Zornitza Stark. Not yet associated with a disorder in Gene2Phenotype. 2 families reported in PMID:30690204 with a fetally-relevant phenotype (including fetal hydrops). Therefore rated Amber awaiting further cases.
Fetal anomalies v1.54 ATP1A2 Rebecca Foulger Gene: atp1a2 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.53 ATP1A2 Rebecca Foulger commented on gene: ATP1A2
COVID-19 research v0.204 HAVCR2 Sarah Leigh Classified gene: HAVCR2 as Green List (high evidence)
COVID-19 research v0.204 HAVCR2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in at least 20 families. PMID 30374066 haplotype analysis identified at least 12 distinct chromosome backgrounds within 7 families homozygous for rs184868814, suggestive of recurrant occurrence.
COVID-19 research v0.204 HAVCR2 Sarah Leigh Gene: havcr2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 HAVCR2 Sarah Leigh Classified gene: HAVCR2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 HAVCR2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in at least 20 families. PMID 30374066 haplotype analysis identified at least 12 distinct chromosome backgrounds within 7 families homozygous for rs184868814, suggestive of recurrant occurrence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.168 HAVCR2 Sarah Leigh Gene: havcr2 has been classified as Green List (High Evidence).
Cystic kidney disease v2.17 SEC61A1 Rebecca Foulger Phenotypes for gene: SEC61A1 were changed from interstitial nephritis; chronic kidney disease; cystic kidney disease; Hyperuricemic nephropathy, familial juvenile, 4, 617056 to glomerulocystic kidney disease; interstitial nephritis; chronic kidney disease; cystic kidney disease; Hyperuricemic nephropathy, familial juvenile, 4, 617056
Cystic kidney disease v2.16 SEC61A1 Rebecca Foulger Phenotypes for gene: SEC61A1 were changed from interstitial nephritis; chronic kidney disease; cystic kidney disease; ator) Hyperuricemic nephropathy, familial juvenile, 4, 617056 to interstitial nephritis; chronic kidney disease; cystic kidney disease; Hyperuricemic nephropathy, familial juvenile, 4, 617056
Cystic kidney disease v2.15 SEC61A1 Rebecca Foulger Phenotypes for gene: SEC61A1 were changed from interstitial nephritis; chronic kidney disease; cystic kidney disease to interstitial nephritis; chronic kidney disease; cystic kidney disease; ator) Hyperuricemic nephropathy, familial juvenile, 4, 617056
Cystic kidney disease v2.14 SEC61A1 Rebecca Foulger Mode of inheritance for gene: SEC61A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cystic kidney disease v2.13 SEC61A1 Rebecca Foulger Classified gene: SEC61A1 as Amber List (moderate evidence)
Cystic kidney disease v2.13 SEC61A1 Rebecca Foulger Gene: sec61a1 has been classified as Amber List (Moderate Evidence).
Cystic kidney disease v2.12 ALG8 Rebecca Foulger Publications for gene: ALG8 were set to 30135240
Cystic kidney disease v2.11 ALG8 Rebecca Foulger Phenotypes for gene: ALG8 were changed from cystic liver disease; cystic kidney disease to cystic liver disease; cystic kidney disease; Polycystic liver disease 3 with or without kidney cysts, 617874
Cystic kidney disease v2.10 ALG8 Rebecca Foulger Mode of inheritance for gene: ALG8 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cystic kidney disease v2.9 ALG8 Rebecca Foulger Classified gene: ALG8 as Green List (high evidence)
Cystic kidney disease v2.9 ALG8 Rebecca Foulger Gene: alg8 has been classified as Green List (High Evidence).
Cystic kidney disease v2.8 ALG9 Rebecca Foulger Classified gene: ALG9 as Green List (high evidence)
Cystic kidney disease v2.8 ALG9 Rebecca Foulger Gene: alg9 has been classified as Green List (High Evidence).
Cystic kidney disease v2.7 ALG9 Rebecca Foulger Phenotypes for gene: ALG9 were changed from cystic liver disease; cystic kidney disease to cystic liver disease; cystic kidney disease; Gillessen-Kaesbach-Nishimura syndrome, 263210
Cystic kidney disease v2.6 ALG9 Rebecca Foulger Publications for gene: ALG9 were set to 31395617
Cystic kidney disease v2.5 ALG9 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI to match review by Eleanor Williams.
Cystic kidney disease v2.5 ALG9 Rebecca Foulger Mode of inheritance for gene: ALG9 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Fetal anomalies v1.53 ALG9 Rebecca Foulger Phenotypes for gene: ALG9 were changed from AR lethal skeletal dysplasia; ALG9-CDG; Congenital disorder of glycosylation, type Il, 608776; NIHF; hydops fetalis to Gillessen-Kaesbach-Nishimura syndrome, 263210; AR lethal skeletal dysplasia; ALG9-CDG; Congenital disorder of glycosylation, type Il, 608776; NIHF; hydops fetalis
Primary immunodeficiency or monogenic inflammatory bowel disease v2.167 HAVCR2 Sarah Leigh Phenotypes for gene: HAVCR2 were changed from Tim-3 deficiency; T-cell lymphoma, subcutaneous panniculitis-like, HLH; T-cell lymphoma, subcutaneous panniculitis-like, 618398; Autoinflammatory Disorders to T-cell lymphoma, subcutaneous panniculitis-like, 618398; Tim-3 deficiency; Autoinflammatory Disorders
Severe familial anorexia v1.3 Eleanor Williams List of related panels changed from to
Juvenile dermatomyositis v1.3 Eleanor Williams List of related panels changed from to
Intellectual disability v3.38 ALG9 Rebecca Foulger Classified gene: ALG9 as Green List (high evidence)
Intellectual disability v3.38 ALG9 Rebecca Foulger Added comment: Comment on list classification: As highlighted by Zornitza Stark, since the last curation review, a number of papers have been published on the ALG9 phenotype, including PMID:26453364 and PMID:28932688 who review the literature and report additional cases. At least 6-7 (of 10/11) patients have developmental delay. Therefore sufficient cases to support causation and have updated rating from Red to Green.
Intellectual disability v3.38 ALG9 Rebecca Foulger Gene: alg9 has been classified as Green List (High Evidence).
COVID-19 research v0.203 ICOSLG Sarah Leigh edited their review of gene: ICOSLG: Changed rating: RED
PHACE(S) syndrome v1.2 Eleanor Williams List of related panels changed from to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.166 ICOSLG Sarah Leigh Classified gene: ICOSLG as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.166 ICOSLG Sarah Leigh Gene: icoslg has been classified as Red List (Low Evidence).
Familial Neural Tube Defects v1.6 Eleanor Williams List of related panels changed from to
Intellectual disability v3.37 ALG9 Rebecca Foulger Phenotypes for gene: ALG9 were changed from Congenital disorder of glycosylation, type Il 608776; Gillessen-Kaesbach-Nishimura syndrome 263210 to Developmental delay; Congenital disorder of glycosylation, type Il 608776; Gillessen-Kaesbach-Nishimura syndrome 263210
COVID-19 research v0.203 ICOSLG Sarah Leigh reviewed gene: ICOSLG: Rating: AMBER; Mode of pathogenicity: None; Publications: 30498080, 31532372; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.36 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants (including the 4 new patients reported by PMID:26453364). They also report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had seizures and developmental delay. She had a homozygous variant in ALG9: p.Tyr287Cys.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.165 ICOSLG Sarah Leigh Classified gene: ICOSLG as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.165 ICOSLG Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. One homozygous variant reported in one case of Combined Immunodeficiency. Supportive functional evidence was presented. This variant in this French Canadian case has been reported twice in PMID 30498080 & 31532372.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.165 ICOSLG Sarah Leigh Gene: icoslg has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.203 ZNF341 Sophie Hambleton reviewed gene: ZNF341: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: immunodeficiency, recurrent infections, eczema, skeletal abnormalities, hyper-IgE, mucocutaneous candidiasis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.36 ALG9 Rebecca Foulger changed review comment from: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. 6/10 patients had developmental disability including the index patient (IV:5), a6 year old girl with global DD, skeletal dysplasia, epilepsy, facial dysmorphisms amongst her phenotypes. The three affected cousins had similar phenotypes.; to: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. 6/10 patients had developmental disability including the index patient (IV:5), a 6 year old girl with global DD, skeletal dysplasia, epilepsy, facial dysmorphisms amongst her phenotypes. The three affected cousins had similar phenotypes.
Fetal anomalies v1.52 ALG9 Rebecca Foulger changed review comment from: Comment on list classification: ALG9 congenital disorder of glycosylation disorder has a broad phenotype and can include non-immune hydrops/NIHF (PMID:26453364 and 31420886). Although the NIHF phenotype is not consistent, even within families carrying the same variant, there are additional prenatal phenotypes reported in the literature for ALG9 cases: 3 fetally-lethal cases of skeletal dysplasia in PMID:25966638, and an individual with multiple malformations detected prenatally in PMID:28932688. Overall: fetally-relevant phenotype and sufficient cases for inclusion on panel and have therefore increased rating from Amber to Green.; to: Comment on list classification: ALG9 congenital disorder of glycosylation has a broad phenotype and can include non-immune hydrops/NIHF (PMID:26453364 and 31420886). Although the NIHF phenotype is not consistent, even within families carrying the same variant, there are additional prenatal phenotypes reported in the literature for ALG9 cases: 3 fetally-lethal cases of skeletal dysplasia in PMID:25966638, and an individual with multiple malformations detected prenatally in PMID:28932688. Overall: fetally-relevant phenotype and sufficient cases for inclusion on panel and have therefore increased rating from Amber to Green.
Fetal anomalies v1.52 ALG9 Rebecca Foulger Classified gene: ALG9 as Green List (high evidence)
Fetal anomalies v1.52 ALG9 Rebecca Foulger Added comment: Comment on list classification: ALG9 congenital disorder of glycosylation disorder has a broad phenotype and can include non-immune hydrops/NIHF (PMID:26453364 and 31420886). Although the NIHF phenotype is not consistent, even within families carrying the same variant, there are additional prenatal phenotypes reported in the literature for ALG9 cases: 3 fetally-lethal cases of skeletal dysplasia in PMID:25966638, and an individual with multiple malformations detected prenatally in PMID:28932688. Overall: fetally-relevant phenotype and sufficient cases for inclusion on panel and have therefore increased rating from Amber to Green.
Fetal anomalies v1.52 ALG9 Rebecca Foulger Gene: alg9 has been classified as Green List (High Evidence).
COVID-19 research v0.203 XRCC2 Sophie Hambleton reviewed gene: XRCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.164 ICOSLG Sarah Leigh Publications for gene: ICOSLG were set to 32086639; 32048120; 30498080; 31532372
COVID-19 research v0.203 WRAP53 Sophie Hambleton reviewed gene: WRAP53: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.203 UBE2T Sophie Hambleton reviewed gene: UBE2T: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.203 TRIM22 Sophie Hambleton reviewed gene: TRIM22: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: very early onset inflammatory bowel disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.51 ALG9 Rebecca Foulger Deleted their comment
COVID-19 research v0.203 IFITM3 Sophie Hambleton reviewed gene: IFITM3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.51 ALG9 Rebecca Foulger Tag for-review was removed from gene: ALG9.
Fetal anomalies v1.51 ALG9 Rebecca Foulger Phenotypes for gene: ALG9 were changed from ALG9-CDG; Congenital disorder of glycosylation, type Il, 608776; NIHF; hydops fetalis to AR lethal skeletal dysplasia; ALG9-CDG; Congenital disorder of glycosylation, type Il, 608776; NIHF; hydops fetalis
COVID-19 research v0.203 PIK3CG Sophie Hambleton reviewed gene: PIK3CG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.50 ALG9 Rebecca Foulger Publications for gene: ALG9 were set to 26453364; 31420886
COVID-19 research v0.203 TP53 Sophie Hambleton reviewed gene: TP53: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Fetal anomalies v1.49 ALG9 Rebecca Foulger changed review comment from: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants. In addition to summarising the 3 patients from Tham et al (PMID:25966638) who died in utero
, they report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had a homozygous variant in ALG9: p.Tyr287Cys.; to: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants. In addition to summarising the 3 patients from Tham et al (PMID:25966638) who died in utero, they report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had a homozygous variant in ALG9: p.Tyr287Cys.
Fetal anomalies v1.49 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:28932688. Davis et al., 2017 review the literature for ALG9:CDG cases. They summarise 10 patients from 6 different families with one of four ALG9 variants. In addition to summarising the 3 patients from Tham et al (PMID:25966638) who died in utero
, they report an additional patient with ALG9-CDH with a milder phenotype. Prenatally, dysmorphic features, renal cysts and cardiac malformations were detected. She had a homozygous variant in ALG9: p.Tyr287Cys.
COVID-19 research v0.203 CDC42 Sophie Hambleton reviewed gene: CDC42: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Haemophagocytic lymphohistiocytosis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.49 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:25966638 (Tham et al) performed fetal autopsy on 3 affected fetuses who died in utero from 2 unrelated families (from Turkey and Iraq) with Gillessen-Kaesbach-Nishimura syndrome (AR lethal skeletal dysplasia). All patients were homozygous for a splicing variant in ALG9 (NM_024740.2: c.1173+2T>A).
COVID-19 research v0.203 TOP2B Sophie Hambleton reviewed gene: TOP2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31409799; Phenotypes: hypogammglobulinaemia, B cell deficiency, Hoffman syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.203 TNFSF11 Sophie Hambleton reviewed gene: TNFSF11: Rating: GREEN; Mode of pathogenicity: None; Publications: 17632511; Phenotypes: osteopetrosis, osteoclast-poor; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.36 ALG9 Rebecca Foulger Publications for gene: ALG9 were set to 15945070; 15148656
Primary immunodeficiency or monogenic inflammatory bowel disease v2.163 ICOSLG Sarah Leigh Publications for gene: ICOSLG were set to 32086639; 32048120; 30498080
Intellectual disability v3.35 ALG9 Rebecca Foulger commented on gene: ALG9
COVID-19 research v0.203 TNFRSF9 Sophie Hambleton reviewed gene: TNFRSF9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: immunodeficiency, autoimmunity, lymphoma, EBV predisposition; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal hydrops v1.20 ALG9 Rebecca Foulger Classified gene: ALG9 as Amber List (moderate evidence)
Fetal hydrops v1.20 ALG9 Rebecca Foulger Added comment: Comment on list classification: ALG9 added to panel and rated Green by Zornitza Stark. Although there are 3 families from the literature with hydrops, and there is evidence linking congenital disorders of glycosylation to NIHF, the phenotype is inconsistent. In PMID:26453364, 1/10 patients was reported with hydrops: 3 cousins did not have Hydrops reported despite harbouring the same p.E530K variant. PMID:31420886 report 3/15 ALG9 families with NIHF. Therefore rated Amber awaiting clinical review.
Fetal hydrops v1.20 ALG9 Rebecca Foulger Gene: alg9 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.203 TMPRSS2 Sophie Hambleton reviewed gene: TMPRSS2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Fetal hydrops v1.19 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. Paitient IV:3/patient4 (a male cousin of the index patient) presented with nonimmune hydrops fetalis diagnosed by fetal US at 28 weeks, and a novel homozygous variant p.E350K in the ALG9 gene.
Fetal hydrops v1.19 ALG9 Rebecca Foulger commented on gene: ALG9
COVID-19 research v0.203 TGFBR2 Sophie Hambleton reviewed gene: TGFBR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 15731757, 16928994, 24577266; Phenotypes: Loeys Dietz syndrome, arterial aneurysms, atopy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.203 TGFBR1 Sophie Hambleton reviewed gene: TGFBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15731757, 16928994, 24577266; Phenotypes: Loeys Dietz syndrome, arterial aneurysms, atopy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.49 ALG9 Rebecca Foulger Tag for-review tag was added to gene: ALG9.
Fetal anomalies v1.49 ALG9 Rebecca Foulger Classified gene: ALG9 as Amber List (moderate evidence)
Fetal anomalies v1.49 ALG9 Rebecca Foulger Added comment: Comment on list classification: Inborn errors of glycosylation can be a cause of non‐immune hydrops fetalis. Although G2P has a 'probable' GDA rating, there is sufficient evidence to link ALG9 to a glycosylation disorder. Approx 20% of cases show non-immune hydrops fetalis (NIHF). In PMID:26453364, 1/10 patients had NIHF: the patient was one of 4 patients within a consanguineous family and hydrops was not reported for the other 3 cousins. 3/15 ALG9 families reported with hydrops in PMID:31420886. Since phenotype is inconsistent, have kept rating as Amber awaiting further clinical review as to whether there are sufficient cases for inclusion on Fetal anomalies panel.
Fetal anomalies v1.49 ALG9 Rebecca Foulger Gene: alg9 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.203 TGFB1 Sophie Hambleton reviewed gene: TGFB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: infantile-onset inflammatory bowel disease, epilepsy, brain atrophy, posterior leukoencephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.48 ALG9 Rebecca Foulger Publications for gene: ALG9 were set to
Fetal anomalies v1.47 ALG9 Rebecca Foulger Phenotypes for gene: ALG9 were changed from ALG9-CDG to ALG9-CDG; Congenital disorder of glycosylation, type Il, 608776; NIHF; hydops fetalis
Fetal anomalies v1.46 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:31420886 Makhamreh et al., 2020 provide a literature review of Nonimmune hydrops fetalis (NIHF) and congenital disorders of glycosylation. 3/15 families had NIHF and ALG9 variants (20%). Full text unavailable at time of curation.
COVID-19 research v0.203 TFRC Sophie Hambleton reviewed gene: TFRC: Rating: GREEN; Mode of pathogenicity: None; Publications: 26642240; Phenotypes: combined immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.203 TCIRG1 Sophie Hambleton reviewed gene: TCIRG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 10888887; Phenotypes: infantile osteopetrosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.46 ALG9 Rebecca Foulger commented on gene: ALG9: PMID:26453364. AlSubhi et al., 2016 summarise 6 patients with ALG9-CDG from the literature and report 4 additional patients from a large consanguineous family. Patient IV:3/patient4 (a male cousin of the index patient) presented with nonimmune hydrops fetalis diagnosed by fetal US at 28 weeks, and a novel homozygous variant p.E350K in the ALG9 gene. Table 2 doesn't list Hydrops in any of the previous patients.
COVID-19 research v0.203 IL2RB Sarah Leigh Classified gene: IL2RB as Green List (high evidence)
COVID-19 research v0.203 IL2RB Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 5 unrelated families (two families with the same variant had shared ethnic heritage PMID 31040185).
COVID-19 research v0.203 IL2RB Sarah Leigh Gene: il2rb has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.162 IL2RB Sarah Leigh Classified gene: IL2RB as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.162 IL2RB Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 5 unrelated families (two families with the same variant had shared ethnic heritage PMID 31040185).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.162 IL2RB Sarah Leigh Gene: il2rb has been classified as Green List (High Evidence).
COVID-19 research v0.202 STN1 Sophie Hambleton reviewed gene: STN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27432940; Phenotypes: syndromic bone marrow failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.202 SRP72 Sophie Hambleton reviewed gene: SRP72: Rating: GREEN; Mode of pathogenicity: None; Publications: 22541560; Phenotypes: aplastic anaemia, myelodysplasia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.202 IL6R Sarah Leigh Classified gene: IL6R as Green List (high evidence)
COVID-19 research v0.202 IL6R Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 3 unrelated cases, together with supportive functional studies.
COVID-19 research v0.202 IL6R Sarah Leigh Gene: il6r has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.161 IL6R Sarah Leigh Classified gene: IL6R as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.161 IL6R Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 3 unrelated cases, together with supportive functional studies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.161 IL6R Sarah Leigh Gene: il6r has been classified as Green List (High Evidence).
COVID-19 research v0.201 SRP54 Sophie Hambleton reviewed gene: SRP54: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: severe congenital neutropenia, Shwachman-Diamond syndrome, exocrine pancreatic insufficiency, autism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dystonia, chorea or related movement disorder, childhood onset v1.4 WDR34 Catherine Snow commented on gene: WDR34
Dystonia, chorea or related movement disorder, childhood onset v1.4 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Skeletal ciliopathies v1.3 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Skeletal ciliopathies v1.3 WDR34 Catherine Snow commented on gene: WDR34
Rare multisystem ciliopathy disorders v1.124 WDR34 Catherine Snow commented on gene: WDR34
Rare multisystem ciliopathy disorders v1.124 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Intellectual disability v3.35 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Intellectual disability v3.35 WDR34 Catherine Snow commented on gene: WDR34
Clefting v2.3 WDR34 Catherine Snow commented on gene: WDR34
Clefting v2.3 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
DDG2P v2.5 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
DDG2P v2.5 WDR34 Catherine Snow commented on gene: WDR34
Fetal anomalies v1.46 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Fetal anomalies v1.46 WDR34 Catherine Snow commented on gene: WDR34
Skeletal dysplasia v2.7 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Skeletal dysplasia v2.7 WDR34 Catherine Snow commented on gene: WDR34
Ductal plate malformation v1.10 WDR34 Catherine Snow commented on gene: WDR34
Ductal plate malformation v1.10 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
COVID-19 research v0.201 SNX10 Sophie Hambleton reviewed gene: SNX10: Rating: GREEN; Mode of pathogenicity: None; Publications: 22499339, 23280965, 28592808; Phenotypes: infantile osteopetrosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb disorders v2.5 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
Limb disorders v2.5 WDR34 Catherine Snow commented on gene: WDR34
Thoracic dystrophies v1.7 WDR34 Catherine Snow commented on gene: WDR34
Thoracic dystrophies v1.7 WDR34 Catherine Snow Tag new-gene-name tag was added to gene: WDR34.
COVID-19 research v0.201 SNORA31 Sophie Hambleton reviewed gene: SNORA31: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: herpes simplex encephalitis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Limb disorders v2.5 WDR60 Catherine Snow commented on gene: WDR60
Limb disorders v2.5 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Thoracic dystrophies v1.7 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Thoracic dystrophies v1.7 WDR60 Catherine Snow commented on gene: WDR60
Primary immunodeficiency or monogenic inflammatory bowel disease v2.160 IL6R Sarah Leigh Phenotypes for gene: IL6R were changed from Hyper-IgE; Eczema; Recurrent infections; Recurrent pyogenic infections, cold abscesses, high circulating IL-6 levels; Combined immunodeficiencies with associated or syndromic features to [Interleukin 6, serum level of, QTL] 614752; [Interleukin-6 receptor, soluble, serum level of, QTL] 614689; Hyper-IgE; Eczema; Recurrent infections; Recurrent pyogenic infections, cold abscesses, high circulating IL-6 levels; Combined immunodeficiencies with associated or syndromic features
Skeletal ciliopathies v1.3 WDR60 Catherine Snow commented on gene: WDR60
Skeletal ciliopathies v1.3 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Renal ciliopathies v1.15 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Renal ciliopathies v1.15 WDR60 Catherine Snow commented on gene: WDR60
Rare multisystem ciliopathy disorders v1.124 WDR60 Catherine Snow commented on gene: WDR60
Rare multisystem ciliopathy disorders v1.124 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Intellectual disability v3.35 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Intellectual disability v3.35 WDR60 Catherine Snow commented on gene: WDR60
Clefting v2.3 WDR60 Catherine Snow commented on gene: WDR60
Clefting v2.3 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
DDG2P v2.5 WDR60 Catherine Snow commented on gene: WDR60
DDG2P v2.5 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Fetal anomalies v1.46 WDR60 Catherine Snow commented on gene: WDR60
Fetal anomalies v1.46 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Unexplained young onset end-stage renal disease v1.10 WDR60 Catherine Snow commented on gene: WDR60
Unexplained young onset end-stage renal disease v1.10 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Skeletal dysplasia v2.7 WDR60 Catherine Snow Tag new-gene-name tag was added to gene: WDR60.
Skeletal dysplasia v2.7 WDR60 Catherine Snow commented on gene: WDR60
Neurological ciliopathies v1.7 WDR63 Catherine Snow Tag new-gene-name tag was added to gene: WDR63.
Neurological ciliopathies v1.7 WDR63 Catherine Snow commented on gene: WDR63
Rare multisystem ciliopathy disorders v1.124 WDR63 Catherine Snow Tag new-gene-name tag was added to gene: WDR63.
Rare multisystem ciliopathy disorders v1.124 WDR63 Catherine Snow commented on gene: WDR63
Rare anaemia v1.4 C15orf41 Catherine Snow commented on gene: C15orf41
Rare anaemia v1.4 C15orf41 Catherine Snow Tag new-gene-name tag was added to gene: C15orf41.
Cytopenias and congenital anaemias v1.73 C15orf41 Catherine Snow Tag new-gene-name tag was added to gene: C15orf41.
Cytopenias and congenital anaemias v1.73 C15orf41 Catherine Snow commented on gene: C15orf41
Renal ciliopathies v1.15 KIAA0556 Catherine Snow Tag new-gene-name tag was added to gene: KIAA0556.
Neurological ciliopathies v1.7 KIAA0556 Catherine Snow Tag new-gene-name tag was added to gene: KIAA0556.
Ophthalmological ciliopathies v1.4 KIAA0556 Catherine Snow Tag new-gene-name tag was added to gene: KIAA0556.
Rare multisystem ciliopathy disorders v1.124 KIAA0556 Catherine Snow Tag new-gene-name tag was added to gene: KIAA0556.
Cerebral vascular malformations v2.4 MRVI1 Catherine Snow Tag new-gene-name tag was added to gene: MRVI1.
Renal ciliopathies v1.15 KIAA0556 Catherine Snow commented on gene: KIAA0556
Neurological ciliopathies v1.7 KIAA0556 Catherine Snow commented on gene: KIAA0556
Ophthalmological ciliopathies v1.4 KIAA0556 Catherine Snow commented on gene: KIAA0556
Rare multisystem ciliopathy disorders v1.124 KIAA0556 Catherine Snow commented on gene: KIAA0556
Cerebral vascular malformations v2.4 MRVI1 Catherine Snow commented on gene: MRVI1
Intellectual disability v3.35 UGDH Konstantinos Varvagiannis gene: UGDH was added
gene: UGDH was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGDH were set to 32001716
Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792
Penetrance for gene: UGDH were set to Complete
Review for gene: UGDH was set to GREEN
Added comment: Hengel et al (2020 - PMID: 32001716) report on 36 individuals with biallelic UGDH pathogenic variants.

The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever.

Affected subjects were tested by exome sequencing and UGDH variants were the only/best candidates for the phenotype following also segregation studies. Many were compound heterozygous or homozygous (~6 families were consanguineous) for missense variants and few were compound heterozygous for missense and pLoF variants. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode.

UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate [OMIM].

Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate).

Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ.

Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors.
Sources: Literature
Early onset or syndromic epilepsy v2.47 UGDH Konstantinos Varvagiannis gene: UGDH was added
gene: UGDH was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: UGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGDH were set to 32001716
Phenotypes for gene: UGDH were set to Epileptic encephalopathy, early infantile, 84 - MIM #618792
Penetrance for gene: UGDH were set to Complete
Review for gene: UGDH was set to GREEN
Added comment: Hengel et al (2020 - PMID: 32001716) report on 36 individuals with biallelic UGDH pathogenic variants.

The phenotype corresponded overall to a developmental epileptic encephalopathy with hypotonia, feeding difficulties, severe global DD, moderate or commonly severe ID in all. Hypotonia and motor disorder (incl. spasticity, dystonia, ataxia, chorea, etc) often occurred prior to the onset of seizures. A single individual did not present seizures and 2 sibs had only seizures in the setting of fever.

Affected subjects were tested by exome sequencing and UGDH variants were the only/best candidates for the phenotype following also segregation studies. Many were compound heterozygous or homozygous (~6 families were consanguineous) for missense variants and few were compound heterozygous for missense and pLoF variants. There were no individuals with biallelic pLoF variants identified. Parental/sib studies were all compatible with AR inheritance mode.

UGDH encodes the enzyme UDP-glucose dehydrogenase which converts UDP-glucose to UDP-glucuronate, the latter being a critical component of the glycosaminoglycans, hyaluronan, chondroitin sulfate, and heparan sulfate [OMIM].

Patient fibroblast and biochemical assays suggested a LoF effect of variants leading to impairment of UGDH stability, oligomerization or enzymatic activity (decreased UGDH-catalyzed reduction of NAD+ to NADH / hyaluronic acid production which requires UDP-glucuronate).

Attempts to model the disorder using an already developped zebrafish model (for a hypomorphic LoF allele) were unsuccessful as fish did not exhibit seizures spontaneously or upon induction with PTZ.

Modelling of the disorder in vitro using patient-derived cerebral organoids demonstrated smaller organoids due to reduced number of proliferating neural progenitors.
Sources: Literature
Fetal hydrops v1.19 AHCY Rebecca Foulger Phenotypes for gene: AHCY were changed from Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; S-adenosylhomocysteine hydrolase deficiency; AHCY deficiency to non-immune hydrops; Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; S-adenosylhomocysteine hydrolase deficiency; AHCY deficiency
Early onset or syndromic epilepsy v2.47 YIF1B Konstantinos Varvagiannis gene: YIF1B was added
gene: YIF1B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Penetrance for gene: YIF1B were set to Complete
Review for gene: YIF1B was set to AMBER
Added comment: AlMuhaizea et al (2020 - PMID: 32006098) report on the phenotype of 6 individuals (from 5 families) with biallelic YIF1B truncating variants.

Affected subjects presented hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID (as evident from best motor/language milestones achieved - Table S1) as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3.

Variable initial investigations were performed including SNP CMA, MECP2, microcephaly / neurotransmitter disorders gene panel testing did not reveal P/LP variants.

YIF1B variants were identified in 3 families within ROH. Following exome sequencing, affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*.

YIF1B encodes an intracellular transmembrane protein.

It has been previously demonstrated that - similarly to other proteins of the Yip family being implicated in intracellular traffic between the Golgi - Yif1B is involved in the anterograde traffic pathway. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). The rat ortholog interacts with serotonin receptor 1 (5-HT1AR) with colocalization of Yif1BB and 5-HT1AR in intermediate compartment vesicles and involvement of the former in intracellular trafficing/modulation of 5-HT1AR transport to dendrites (PMID cited: 18685031).

Available mRNA and protein expression data (Protein Atlas) suggest that the gene is widely expressed in all tissues incl. neuronal cells. Immunochemistry data from the Human Brain Atlas also suggest that YIF1B is found in vesicles and localized to the Golgi apparatus. Immunohistochemistry in normal human brain tissue (cerebral cortex) demonstrated labeling of neuronal cells (Human Protein Atlas).

Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.

Please consider inclusion in other panels that may be relevant (e.g. microcephaly, etc).
Sources: Literature
Intellectual disability v3.35 YIF1B Konstantinos Varvagiannis gene: YIF1B was added
gene: YIF1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: YIF1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YIF1B were set to 32006098
Phenotypes for gene: YIF1B were set to Central hypotonia; Failure to thrive; Microcephaly; Global developmental delay; Intellectual disability; Seizures; Spasticity; Abnormality of movement
Penetrance for gene: YIF1B were set to Complete
Review for gene: YIF1B was set to GREEN
Added comment: AlMuhaizea et al (2020 - PMID: 32006098) report on the phenotype of 6 individuals (from 5 families) with biallelic YIF1B truncating variants.

Affected subjects presented hypotonia, failure to thrive, microcephaly (5/6), severe global DD and ID (as evident from best motor/language milestones achieved - Table S1) as well as features suggestive of a motor disorder (dystonia/spasticity/dyskinesia). Seizures were reported in 2 unrelated individuals (2/6). MRI abnormalities were observed in some with thin CC being a feature in 3.

Variable initial investigations were performed including SNP CMA, MECP2, microcephaly / neurotransmitter disorders gene panel testing did not reveal P/LP variants.

YIF1B variants were identified in 3 families within ROH. Following exome sequencing, affected individuals were found to be homozygous for truncating variants (4/5 families being consanguineous). The following 3 variants were identified (NM_001039672.2) : c.186dupT or p.Ala64fs / c.360_361insACAT or p.Gly121fs / c.598G>T or p.Glu200*.

YIF1B encodes an intracellular transmembrane protein.

It has been previously demonstrated that - similarly to other proteins of the Yip family being implicated in intracellular traffic between the Golgi - Yif1B is involved in the anterograde traffic pathway. Yif1B KO mice demonstrate a disorganized Golgi architecture in pyramidal hippocampal neurons (Alterio et al 2015 - PMID: 26077767). The rat ortholog interacts with serotonin receptor 1 (5-HT1AR) with colocalization of Yif1BB and 5-HT1AR in intermediate compartment vesicles and involvement of the former in intracellular trafficing/modulation of 5-HT1AR transport to dendrites (PMID cited: 18685031).

Available mRNA and protein expression data (Protein Atlas) suggest that the gene is widely expressed in all tissues incl. neuronal cells. Immunochemistry data from the Human Brain Atlas also suggest that YIF1B is found in vesicles and localized to the Golgi apparatus. Immunohistochemistry in normal human brain tissue (cerebral cortex) demonstrated labeling of neuronal cells (Human Protein Atlas).

Functional/network analysis of genes co-regulated with YIF1B based on available RNAseq data, suggest enrichement in in genes important for nervous system development and function.

Please consider inclusion in other panels that may be relevant (e.g. microcephaly, etc).
Sources: Literature
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.4 ISCA-37420-Loss Catherine Snow Mode of inheritance for Region: ISCA-37420-Loss was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.47 SPTBN4 Konstantinos Varvagiannis gene: SPTBN4 was added
gene: SPTBN4 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SPTBN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN4 were set to 28540413; 28940097; 29861105; 31230720; 31857255
Phenotypes for gene: SPTBN4 were set to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness MIM#617519
Penetrance for gene: SPTBN4 were set to Complete
Review for gene: SPTBN4 was set to GREEN
Added comment: Biallelic pathogenic SPTBN4 variants cause Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (MIM #617519).

There are several reports on the phenotype of relevant affected individuals with severe/profound DD/ID in at least 9 individuals :

- Knierim et al (2017 - PMID: 28540413) [1 affected individual]
- Anazi et al (2017 - PMID: 28940097) [1]
- Wang et al (2018 - PMID: 29861105) [6]
- Pehlivan et al (2019 - PMID: 31230720) [1]

A recent article by Häusler et al (2019 - PMID: 31857255) describes the phenotype of 2 sibs, both presenting with motor and speech delay, although the older one had reportedly 'normal' cognitive performance allowing attendance of regular school at the age of 6 years.

Features include congenital hypotonia, severe DD and ID (in most as outlined above, ID was the primary indication for testing on several occasions), poor or absent reflexes and weakness secondary to axonal motor neuropathy, feeding and respiratory difficulties, hearing and visual impairment. Seizures have been reported in at least 4 unrelated individuals (3 by Wang et al / 1 by Pehlivan et al).

Variants in most cases were nonsense/frameshift although biallelic missense variants have also been reported. Sibs in the report by Häusler et al harbored a homozygous splicing variant.

SPTBN4 encodes a member of the beta-spectrin protein family that is expressed in the brain, peripheral nervous system, pancreas, and skeletal muscle.

βIV spectrin links ankyrinG and clustered ion channels (at axon initial segments and nodes of Ranvier) to the axonal cytoskeleton. Pathogenic variants are proposed to disrupt the cytoskeletal machinery controlling proper localization of ion channels and function of axonal domains where ion channels are normally clustered in high density. Among the evidence provided : nerve biopsies from an affected individual displayed reduced nodal Na+ channels and no nodal KCNQ2 K+ channels / Loss of AnkyrinG and βIV spectrin in animal model resulted in loss of KCNQ2- and KCNQ3- subunit containing K+ channels.

Apart from the ID / epilepsy panels please consider inclusion in other relevant ones.
Sources: Literature
Intellectual disability v3.35 SPTBN4 Konstantinos Varvagiannis gene: SPTBN4 was added
gene: SPTBN4 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SPTBN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN4 were set to 28540413; 28940097; 29861105; 31230720; 31857255
Phenotypes for gene: SPTBN4 were set to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness MIM#617519
Penetrance for gene: SPTBN4 were set to Complete
Review for gene: SPTBN4 was set to GREEN
Added comment: Biallelic pathogenic SPTBN4 variants cause Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (MIM #617519).

There are several reports on the phenotype of relevant affected individuals with severe/profound DD/ID in at least 9 individuals :

- Knierim et al (2017 - PMID: 28540413) [1 affected individual]
- Anazi et al (2017 - PMID: 28940097) [1]
- Wang et al (2018 - PMID: 29861105) [6]
- Pehlivan et al (2019 - PMID: 31230720) [1]

A recent article by Häusler et al (2019 - PMID: 31857255) describes the phenotype of 2 sibs, both presenting with motor and speech delay, although the older one had reportedly 'normal' cognitive performance allowing attendance of regular school at the age of 6 years.

Features include congenital hypotonia, severe DD and ID (in most as outlined above, ID was the primary indication for testing on several occasions), poor or absent reflexes and weakness secondary to axonal motor neuropathy, feeding and respiratory difficulties, hearing and visual impairment. Seizures have been reported in at least 4 unrelated individuals (3 by Wang et al / 1 by Pehlivan et al).

Variants in most cases were nonsense/frameshift although biallelic missense variants have also been reported. Sibs in the report by Häusler et al harbored a homozygous splicing variant.

SPTBN4 encodes a member of the beta-spectrin protein family that is expressed in the brain, peripheral nervous system, pancreas, and skeletal muscle.

βIV spectrin links ankyrinG and clustered ion channels (at axon initial segments and nodes of Ranvier) to the axonal cytoskeleton. Pathogenic variants are proposed to disrupt the cytoskeletal machinery controlling proper localization of ion channels and function of axonal domains where ion channels are normally clustered in high density. Among the evidence provided : nerve biopsies from an affected individual displayed reduced nodal Na+ channels and no nodal KCNQ2 K+ channels / Loss of AnkyrinG and βIV spectrin in animal model resulted in loss of KCNQ2- and KCNQ3- subunit containing K+ channels.

Apart from the ID / epilepsy panels please consider inclusion in other relevant ones.
Sources: Literature
Intellectual disability v3.35 TNRC6B Konstantinos Varvagiannis reviewed gene: TNRC6B: Rating: GREEN; Mode of pathogenicity: None; Publications: 32152250, 28135719, 25363768, 27479843, 28959963, 25228304; Phenotypes: Global developmental delay, Intellectual disability, Autistic behavior; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v2.47 CDC42BPB Konstantinos Varvagiannis gene: CDC42BPB was added
gene: CDC42BPB was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CDC42BPB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDC42BPB were set to 32031333
Phenotypes for gene: CDC42BPB were set to Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality
Penetrance for gene: CDC42BPB were set to unknown
Review for gene: CDC42BPB was set to AMBER
Added comment: Chilton et al (2020 - PMID: 32031333) report on 14 individuals with missense and loss-of-function CDC42BPB variants.

Features included hypotonia (8/11), DD (12/13 - the 14th was a fetus), ID (7/13), ASD (8/12), clinical seizures (in 3 - a 4th had abnormal EEG without seizures), behavioral abnormalities. Variable non-specific dysmorphic features were reported in some (sparse hair being the most frequent - 4/8). Additional features were observed in few (=<4) incl. cryptorchidism, ophthalmological issues, constipation, kidney abnormalities, micropenis, etc.

All individuals had non-diagnostic prior genetic testing (incl. CMA, FMR1, MECP2, Angelman/Prader-Willi methylation studies, autism gene panel - suggesting relevance to the current panel) or metabolic testing.

Variants were identified following clinical exome sequencing with Sanger confirmation. Most occurred as de novo events (11/14) while inheritance was not available for few (3/14). Missense variants did not display (particular) clustering.

Almost all variants were absent from gnomAD and were predicted to be deleterious in silico (among others almost all had CADD scores >25).

As the authors comment, CDC42BPB encodes myotonic dystrophy-related Cdc42-binding kinase β (MRCKβ) a serine/threonine protein kinase playing a role in regulation of cytoskeletal reorganization and cell migration in nonmuscle cells (through phosporylation of MLC2).

Previous studies have demonstrated that it is ubiquitously expressed with prenatal brain expression.

The gene appears to be intolerant to pLoF (pLI of 1) as well as to missense variants (Z-score of 3.66).

CDC42BPB is a downstream effector of CDC42. Mutations of the latter cause Takenouchi-Kosaki syndrome with DD/ID and some further overlapping features (with CDC42BPB-associated phenotypes).

Homozygous Cdc42bpb KO in mouse appears to be nonviable (MGI:2136459). Loss of gek in the eyes of Drosophila results in disrupted growth cone targeting to the lamina (gek is the fly CDC42BPB ortholog).
Sources: Literature
Intellectual disability v3.35 CDC42BPB Konstantinos Varvagiannis gene: CDC42BPB was added
gene: CDC42BPB was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDC42BPB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDC42BPB were set to 32031333
Phenotypes for gene: CDC42BPB were set to Central hypotonia; Global developmental delay; Intellectual disability; Seizures; Autistic behavior; Behavioral abnormality
Penetrance for gene: CDC42BPB were set to unknown
Review for gene: CDC42BPB was set to GREEN
Added comment: Chilton et al (2020 - PMID: 32031333) report on 14 individuals with missense and loss-of-function CDC42BPB variants.

Features included hypotonia (8/11), DD (12/13 - the 14th was a fetus), ID (7/13), ASD (8/12), clinical seizures (in 3 - a 4th had abnormal EEG without seizures), behavioral abnormalities. Variable non-specific dysmorphic features were reported in some (sparse hair being the most frequent - 4/8). Additional features were observed in few (=<4) incl. cryptorchidism, ophthalmological issues, constipation, kidney abnormalities, micropenis, etc.

All individuals had non-diagnostic prior genetic testing (incl. CMA, FMR1, MECP2, Angelman/Prader-Willi methylation studies, autism gene panel - suggesting relevance to the current panel) or metabolic testing.

Variants were identified following clinical exome sequencing with Sanger confirmation. Most occurred as de novo events (11/14) while inheritance was not available for few (3/14). Missense variants did not display (particular) clustering.

Almost all variants were absent from gnomAD and were predicted to be deleterious in silico (among others almost all had CADD scores >25).

As the authors comment, CDC42BPB encodes myotonic dystrophy-related Cdc42-binding kinase β (MRCKβ) a serine/threonine protein kinase playing a role in regulation of cytoskeletal reorganization and cell migration in nonmuscle cells (through phosporylation of MLC2).

Previous studies have demonstrated that it is ubiquitously expressed with prenatal brain expression.

The gene appears to be intolerant to pLoF (pLI of 1) as well as to missense variants (Z-score of 3.66).

CDC42BPB is a downstream effector of CDC42. Mutations of the latter cause Takenouchi-Kosaki syndrome with DD/ID and some further overlapping features (with CDC42BPB-associated phenotypes).

Homozygous Cdc42bpb KO in mouse appears to be nonviable (MGI:2136459). Loss of gek in the eyes of Drosophila results in disrupted growth cone targeting to the lamina (gek is the fly CDC42BPB ortholog).

Please consider inclusion with amber / green rating in the ID panel (>=4 relevant individuals / variants) and other panels (e.g. for epilepsy, ASD).
Sources: Literature
COVID-19 research v0.201 IFNL3 Catherine Snow Classified gene: IFNL3 as Amber List (moderate evidence)
COVID-19 research v0.201 IFNL3 Catherine Snow Gene: ifnl3 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.200 IFNL3 Catherine Snow gene: IFNL3 was added
gene: IFNL3 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: IFNL3 was set to Unknown
Review for gene: IFNL3 was set to AMBER
Added comment: IFNL3 was identified in preprint https://doi.org/10.1101/2020.04.26.20080408 "A gene locus that controls expression of ACE2 in virus infection" A GWAS for performed for ACE2 expression in HCV-infected liver tissue from 195 individuals. it was discovered that polymorphisms in the host IFNL region which control expression of IFNL3 and IFNL4 modulate ACE2 expression.
Sources: Literature
COVID-19 research v0.199 IFNL4 Catherine Snow changed review comment from: IFNL4 was identified in preprint "A gene locus that controls expression of ACE2 in virus infection"
A GWAS for performed for ACE2 expression in HCV-infected liver tissue from 195 individuals. it was discovered that polymorphisms in the host IFNL region which control expression of IFNL3 and IFNL4 modulate ACE2 expression.
PMID: 31776283 Investigates the IFNL4 gene - it acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation.
Sources: Literature; to: IFNL4 was identified in preprint https://doi.org/10.1101/2020.04.26.20080408 "A gene locus that controls expression of ACE2 in virus infection" A GWAS for performed for ACE2 expression in HCV-infected liver tissue from 195 individuals. it was discovered that polymorphisms in the host IFNL region which control expression of IFNL3 and IFNL4 modulate ACE2 expression.

PMID: 31776283 Investigates the IFNL4 gene - it acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation.
Sources: Literature
COVID-19 research v0.199 IFNL4 Catherine Snow gene: IFNL4 was added
gene: IFNL4 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: IFNL4 was set to Unknown
Publications for gene: IFNL4 were set to 31776283
Review for gene: IFNL4 was set to AMBER
Added comment: IFNL4 was identified in preprint "A gene locus that controls expression of ACE2 in virus infection"
A GWAS for performed for ACE2 expression in HCV-infected liver tissue from 195 individuals. it was discovered that polymorphisms in the host IFNL region which control expression of IFNL3 and IFNL4 modulate ACE2 expression.
PMID: 31776283 Investigates the IFNL4 gene - it acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.159 FCHO1 Sarah Leigh Classified gene: FCHO1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.159 FCHO1 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. At least 5 biallelic variants reported in at least 5 unrelated cases, together with supportive functional studies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.159 FCHO1 Sarah Leigh Gene: fcho1 has been classified as Green List (High Evidence).
COVID-19 research v0.198 ITPKC Catherine Snow changed review comment from: Adding ITPKC as Kawasaki disease in children linked to coronavirus.

Onouchi et al (PMID:18084290) identified a functional SNP in intron 1 of ITPKC (rs28493229) that was significantly associated with risk of Kawasaki disease and the formation of coronary artery aneurysms in both Japanese and U.S. children. But Chi et al. (2010) did not find a statistically significant association between the ITPKC gene SNP rs28493229 and Kawasaki disease or coronary artery lesions in Taiwanese children.
Sources: Literature, Research; to: Adding ITPKC as a Kawasaki like disease in children linked to coronavirus.

Onouchi et al (PMID:18084290) identified a functional SNP in intron 1 of ITPKC (rs28493229) that was significantly associated with risk of Kawasaki disease and the formation of coronary artery aneurysms in both Japanese and U.S. children. But Chi et al. (2010) did not find a statistically significant association between the ITPKC gene SNP rs28493229 and Kawasaki disease or coronary artery lesions in Taiwanese children.
Sources: Literature, Research
COVID-19 research v0.198 ITPKC Catherine Snow changed review comment from: Adding ITPKC as Kawasaki disease in children linked to coronavirus as becoming more "common".

Onouchi et al (PMID:18084290) identified a functional SNP in intron 1 of ITPKC (rs28493229) that was significantly associated with risk of Kawasaki disease and the formation of coronary artery aneurysms in both Japanese and U.S. children. But Chi et al. (2010) did not find a statistically significant association between the ITPKC gene SNP rs28493229 and Kawasaki disease or coronary artery lesions in Taiwanese children.
Sources: Literature, Research; to: Adding ITPKC as Kawasaki disease in children linked to coronavirus.

Onouchi et al (PMID:18084290) identified a functional SNP in intron 1 of ITPKC (rs28493229) that was significantly associated with risk of Kawasaki disease and the formation of coronary artery aneurysms in both Japanese and U.S. children. But Chi et al. (2010) did not find a statistically significant association between the ITPKC gene SNP rs28493229 and Kawasaki disease or coronary artery lesions in Taiwanese children.
Sources: Literature, Research
COVID-19 research v0.198 ITPKC Catherine Snow changed review comment from: Onouchi et al (PMID:18084290) identified a functional SNP in intron 1 of ITPKC (rs28493229) that was significantly associated with risk of Kawasaki disease and the formation of coronary artery aneurysms in both Japanese and U.S. children. But Chi et al. (2010) did not find a statistically significant association between the ITPKC gene SNP rs28493229 and Kawasaki disease or coronary artery lesions in Taiwanese children.
Sources: Literature, Research; to: Adding ITPKC as Kawasaki disease in children linked to coronavirus as becoming more "common".

Onouchi et al (PMID:18084290) identified a functional SNP in intron 1 of ITPKC (rs28493229) that was significantly associated with risk of Kawasaki disease and the formation of coronary artery aneurysms in both Japanese and U.S. children. But Chi et al. (2010) did not find a statistically significant association between the ITPKC gene SNP rs28493229 and Kawasaki disease or coronary artery lesions in Taiwanese children.
Sources: Literature, Research
COVID-19 research v0.198 ITPKC Catherine Snow Classified gene: ITPKC as Amber List (moderate evidence)
COVID-19 research v0.198 ITPKC Catherine Snow Gene: itpkc has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.198 ITPKC Catherine Snow Classified gene: ITPKC as Amber List (moderate evidence)
COVID-19 research v0.198 ITPKC Catherine Snow Gene: itpkc has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.197 ITPKC Catherine Snow gene: ITPKC was added
gene: ITPKC was added to Viral susceptibility. Sources: Literature,Research
Mode of inheritance for gene: ITPKC was set to Unknown
Publications for gene: ITPKC were set to 18084290; 20045869
Phenotypes for gene: ITPKC were set to Kawasaki disease, susceptibility to, 611775
Review for gene: ITPKC was set to AMBER
Added comment: Onouchi et al (PMID:18084290) identified a functional SNP in intron 1 of ITPKC (rs28493229) that was significantly associated with risk of Kawasaki disease and the formation of coronary artery aneurysms in both Japanese and U.S. children. But Chi et al. (2010) did not find a statistically significant association between the ITPKC gene SNP rs28493229 and Kawasaki disease or coronary artery lesions in Taiwanese children.
Sources: Literature, Research
Primary immunodeficiency or monogenic inflammatory bowel disease v2.158 IL6ST Sarah Leigh Classified gene: IL6ST as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.158 IL6ST Sarah Leigh Added comment: Comment on list classification: Based on expert review and the reporting of additional variants.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.158 IL6ST Sarah Leigh Gene: il6st has been classified as Green List (High Evidence).
Fetal hydrops v1.18 AHCY Rebecca Foulger Classified gene: AHCY as Amber List (moderate evidence)
Fetal hydrops v1.18 AHCY Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber based on additional 2018 paper highlighted by Zornitza Stark (PMID:30121674) which reports an infant with non-immune hydrops. This takes total number of families to two.
Fetal hydrops v1.18 AHCY Rebecca Foulger Gene: ahcy has been classified as Amber List (Moderate Evidence).
Fetal hydrops v1.17 AHCY Rebecca Foulger commented on gene: AHCY: PMID:30121674. Judkins et al., 2018 report an infant with a prenatal diagnosis of non-immune hydrops. The infant was born with phenotypes including hypotonia, poor respiratory effort, chylothorax, encephalopathy, coagulopathy, progressive hepatic failure, and refractory pulmonary hypertension. Life support was withdrawn at 7 days. Novel compound het variants in the AHCY were found. Full text not available.
Fetal hydrops v1.17 AHCY Rebecca Foulger Publications for gene: AHCY were set to 23137060; 20852937
Fetal anomalies v1.46 AHCY Rebecca Foulger Phenotypes for gene: AHCY were changed from S-adenosylhomocysteine hydrolase deficiency; Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752 to Fetal hydrops; S-adenosylhomocysteine hydrolase deficiency; Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752
Fetal anomalies v1.45 AHCY Rebecca Foulger Classified gene: AHCY as Amber List (moderate evidence)
Fetal anomalies v1.45 AHCY Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Amber by Zornitza Stark. Two unrelated families with hydrops reported (PMID:30121674, 20852937). Note that previous reports of AHCY deficiency do not include hydrops (e.g. PMID:15024124). Overall, phenotype is relevant to the panel but currently insufficient evidence for Green rating. Rated Amber awaiting further evidence.
Fetal anomalies v1.45 AHCY Rebecca Foulger Gene: ahcy has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.157 IL6ST Sarah Leigh Added comment: Comment on phenotypes: Eosinophilia;Eczema;Bacterial infections, boiles, eczema, pulmonary abscesses, pneumatoceles, bone fractures, scoliosis, retention of primary teeth, craniosynostosis;Abnormal acute-phase responses;Recurrent infections;Elevated IgE;Combined immunodeficiencies with associated or syndromic features
Primary immunodeficiency or monogenic inflammatory bowel disease v2.157 IL6ST Sarah Leigh Phenotypes for gene: IL6ST were changed from Eosinophilia; Eczema; Bacterial infections, boiles, eczema, pulmonary abscesses, pneumatoceles, bone fractures, scoliosis, retention of primary teeth, craniosynostosis; Abnormal acute-phase responses; Recurrent infections; Elevated IgE; Combined immunodeficiencies with associated or syndromic features to Hyper-IgE recurrent infection syndrome 4, autosomal recessive 618523; Stuve-Wiedemann-like syndrome: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response.; Hyper-IgE syndrome, autosomal dominant
Fetal anomalies v1.44 AHCY Rebecca Foulger commented on gene: AHCY: PMID:20852937. Grubbs et al., 2010 report 2 sisters born with fetal hydrops and compound het for 2 variants in AHCY (p.Arg49Cys and p.Asp86Gly). Phenotypes included severe hypotonia/myopathy, feeding problems, and respiratory failure. The sisters died age 25 days and 122 days.
Fetal anomalies v1.44 AHCY Rebecca Foulger commented on gene: AHCY
COVID-19 research v0.196 IL6ST Sarah Leigh Publications for gene: IL6ST were set to 31235509; 32086639; 30309848; 28747427; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.156 IL6ST Sarah Leigh Publications for gene: IL6ST were set to 31235509; 32086639; 30309848; 28747427; 32048120
Fetal anomalies v1.44 AHCY Rebecca Foulger Phenotypes for gene: AHCY were changed from S-adenosylhomocysteine hydrolase deficiency to S-adenosylhomocysteine hydrolase deficiency; Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752
Retinal disorders v2.13 USP45 Ivone Leong Phenotypes for gene: USP45 were changed from Lebers congenital amaurosis; retinal dystrophy to Lebers congenital amaurosis; retinal dystrophy; ?Leber congenital amaurosis 19, 618513
Hypogonadotropic hypogonadism (GMS) v1.8 NDNF Ivone Leong Classified gene: NDNF as Green List (high evidence)
Hypogonadotropic hypogonadism (GMS) v1.8 NDNF Ivone Leong Added comment: Comment on list classification: Gene added by expert reviewer (Simon Thomas (Wessex)) with suggested Green rating.

The gene is associated with a relevent disease in OMIM and is probably associated with a relevent disease in Gene2Phentoype. There are 3 unrelated cases. Therefore, there is enough evidence to support this gene-disease phenotype.
Hypogonadotropic hypogonadism (GMS) v1.8 NDNF Ivone Leong Gene: ndnf has been classified as Green List (High Evidence).
Hypogonadotropic hypogonadism (GMS) v1.7 NDNF Ivone Leong Phenotypes for gene: NDNF were changed from Congenital hypogonadotropic hypogonadism (CHH) to Congenital hypogonadotropic hypogonadism (CHH); Hypogonadotropic hypogonadism 25 with anosmia, 618841
Hypogonadotropic hypogonadism (GMS) v1.6 NDNF Ivone Leong Publications for gene: NDNF were set to PMID: 31883645
Hypogonadotropic hypogonadism v1.28 KLB Ivone Leong Classified gene: KLB as Green List (high evidence)
Hypogonadotropic hypogonadism v1.28 KLB Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on expert review (Rachel Jones (GSTT))
Hypogonadotropic hypogonadism v1.28 KLB Ivone Leong Gene: klb has been classified as Green List (High Evidence).
DDG2P v2.5 CDK8 Rebecca Foulger Phenotypes for gene: CDK8 were changed from SYNDROMIC INTELLECTUAL DISABILITY 612100 to SYNDROMIC INTELLECTUAL DISABILITY
Retinal disorders v2.12 DRAM2 Ivone Leong Classified gene: DRAM2 as Green List (high evidence)
Retinal disorders v2.12 DRAM2 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green based on expert review.
Retinal disorders v2.12 DRAM2 Ivone Leong Gene: dram2 has been classified as Green List (High Evidence).
Retinal disorders v2.11 DRAM2 Ivone Leong Phenotypes for gene: DRAM2 were changed from to Cone-rod dystrophy 21, 616502; macular dystrophy; cone-dystrophy
Retinal disorders v2.10 DRAM2 Ivone Leong Publications for gene: DRAM2 were set to
Retinal disorders v2.9 DRAM2 Ivone Leong Mode of inheritance for gene: DRAM2 was changed from to BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.195 CD4 Ivone Leong Classified gene: CD4 as Amber List (moderate evidence)
COVID-19 research v0.195 CD4 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on expert review.

"Single individual reported, functional data, emerging gene.
Zornitza Stark (Australian Genomics), 1 May 2020" - review copied from Primary immunodeficiency (Version 2.155).
COVID-19 research v0.195 CD4 Ivone Leong Gene: cd4 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.194 CD4 Ivone Leong Phenotypes for gene: CD4 were changed from Selective CD4 cell deficiency to Selective CD4 cell deficiency; OKT4 epitope deficiency, 613949; Absence of CD4+ T cells; exuberant, relapsing, treatment-refractory warts
COVID-19 research v0.193 CD4 Ivone Leong Publications for gene: CD4 were set to 25611551
COVID-19 research v0.192 CD4 Ivone Leong Mode of inheritance for gene: CD4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.155 CD4 Ivone Leong Classified gene: CD4 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.155 CD4 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on expert review.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.155 CD4 Ivone Leong Gene: cd4 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.154 CD4 Ivone Leong Mode of inheritance for gene: CD4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.43 SMG9 Rebecca Foulger Publications for gene: SMG9 were set to
Fetal anomalies v1.43 SMG9 Rebecca Foulger Phenotypes for gene: SMG9 were changed from SMG9 Multiple Congenital Anomaly Syndrome to SMG9 Multiple Congenital Anomaly Syndrome; Heart and brain malformation syndrome, 616920
Fetal anomalies v1.42 SMG9 Rebecca Foulger Classified gene: SMG9 as Green List (high evidence)
Fetal anomalies v1.42 SMG9 Rebecca Foulger Added comment: Comment on list classification: Rated probable in Gene2Phenotype for SMG9 Multiple Congenital Anomaly Syndrome based on 2 families in PMID:27018474. Additional family now reported in PMID:31390136. Fetally-relevant phenotype (anomalies detected in-utero) and sufficient cases to support causation. Therefore upgraded from Amber to Green.
Fetal anomalies v1.42 SMG9 Rebecca Foulger Gene: smg9 has been classified as Green List (High Evidence).
Fetal anomalies v1.41 SMG9 Rebecca Foulger commented on gene: SMG9: PMID:31390136. Lecoquierre et al., 2019 performed exome sequencing in a patient with syndromic DD and diverse malformations including cleft lip and palate, facial dysmorphia, brain abnormalities, herat defect, growth retardation and severe infections. She carried a homozygous SMG9 variant, p.(Gln393*). Her unaffected parents were both heterozygous. Phenotypes were first noted in-utero: polyhydamnios, lateral cleft lip and palate, and IUGR noted on ultrasound.
COVID-19 research v0.191 CDC42 Ivone Leong Classified gene: CDC42 as Green List (high evidence)
COVID-19 research v0.191 CDC42 Ivone Leong Gene: cdc42 has been classified as Green List (High Evidence).
COVID-19 research v0.190 CDC42 Ivone Leong gene: CDC42 was added
gene: CDC42 was added to Viral susceptibility. Sources: Expert Review
Mode of inheritance for gene: CDC42 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDC42 were set to 31601675; 32303876; 32231661; 31271789
Phenotypes for gene: CDC42 were set to Neonatal-onset cytopaenia with dyshaematopoiesis; autoinflammation; rash; HLH
Review for gene: CDC42 was set to GREEN
Added comment: "PMID 31601675: four unrelated individuals with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. All shared the same de novo CDC42 variant (Chr1:22417990C>T, p.R186C). Another pair of sibs reported in PMID 32303876 with infantile myelofibrosis and myeloproliferation and same variant (parental mosaicism). Yet another individual in PMID 32231661 with different de novo variant, p.Cys81Tyr who in addition developed haematological malignancy and also had syndromic features, including ID. Note other missense variants in this gene cause Takenouchi-Kosaki syndrome, MIM# 616737 Sources: Literature
Zornitza Stark (Australian Genomics), 30 Apr 2020" - review copied from Primary immunodeficiency (Version 2.153)

"Comment on list classification: Gene added by Zornitza Stark (Australian Genomics) with a suggested Green rating based on evidence she has provided. As well as the listed cases there is another paper (PMID: 31271789) describing 4 unrelated cases with de novo variants in CDC42 (p.C188Y, p.R186C, p.*192C*24). The patients predominantly had systemic autoinflammatory disease and development of HLH. Therefore there is enough evidence to rate this gene as Green.
Ivone Leong (Genomics England Curator), 5 May 2020" - review copied from Primary immunodeficiency (Version 2.153)
Sources: Expert Review
Fetal anomalies v1.41 SMG9 Rebecca Foulger commented on gene: SMG9: PMID:27018474. Shaheen et al, 2016 report 2 consanguineous families with different homozygous LOF variants in SMG9 and and a similar set of congenital anomalies including craniofacial dysmorphism, and major brain and heart malformations.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.153 CDC42 Ivone Leong Classified gene: CDC42 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.153 CDC42 Ivone Leong Added comment: Comment on list classification: Gene added by Zornitza Stark (Australian Genomics) with a suggested Green rating based on evidence she has provided.

As well as the listed cases there is another paper (PMID: 31271789) describing 4 unrelated cases with de novo variants in CDC42 (p.C188Y, p.R186C, p.*192C*24). The patients predominantly had systemic autoinflammatory disease and development of HLH.

Therefore there is enough evidence to rate this gene as Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.153 CDC42 Ivone Leong Gene: cdc42 has been classified as Green List (High Evidence).
Fetal anomalies v1.41 TUBA8 Rebecca Foulger Classified gene: TUBA8 as Amber List (moderate evidence)
Fetal anomalies v1.41 TUBA8 Rebecca Foulger Added comment: Comment on list classification: The reanalysis in PMID:28388629 casts doubt that TUBA8 is responsible for the morphological phenotypes initially reported in PMID:19896110. Only 2 families (of possible shared descent) were reported. Therefore insufficient evidence for Green rating. Downgraded from Green to Amber.
Fetal anomalies v1.41 TUBA8 Rebecca Foulger Gene: tuba8 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.40 TUBA8 Rebecca Foulger commented on gene: TUBA8: In 4 affected members of 2 consanguineous Pakistani families with MIM:613180, Abdollahi et al. (2009, PMID:19896110) identified a homozygous 14-bp deletion 11 bp upstream of the exon 2 splice site junction in TUBA8. The families may have common ancestory. All obligate carriers were heterozygous. The patients had neonatal hypotonia, profound mental retardation, essentially no psychomotor development, optic nerve hypoplasia, and thickened cortex with polymicrogyria and absent corpus callosum. BUT due to lack of a mouse TUBA8 phenotype, the authors in PMID:28388629 (Diggle et al 2017) reanalysed their patients from PMID:19896110 and found an additional LOF variant in SNAP29 (p.Ser163Lysfs*6). The authors suggest that SNAP29 deficiency, rather than TUBA8 deficiency, may be responsible for the patient phenotypes.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.152 CDC42 Ivone Leong Publications for gene: CDC42 were set to 31601675; 32303876; 32231661
COVID-19 research v0.189 KARS Sarah Leigh commented on gene: KARS: New gene name for KARS is KARS1
COVID-19 research v0.189 KARS Sarah Leigh Tag new-gene-name tag was added to gene: KARS.
COVID-19 research v0.189 ZFHX3 Sarah Leigh reviewed gene: ZFHX3: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 WSCD1 Sarah Leigh reviewed gene: WSCD1: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 UNC5CL Sarah Leigh reviewed gene: UNC5CL: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 TAPT1 Sarah Leigh reviewed gene: TAPT1: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 SPNS3 Sarah Leigh reviewed gene: SPNS3: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 RPAIN Sarah Leigh reviewed gene: RPAIN: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 PROM1 Sarah Leigh reviewed gene: PROM1: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 PKD1L3 Sarah Leigh reviewed gene: PKD1L3: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 NUP88 Sarah Leigh reviewed gene: NUP88: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 MLKL Sarah Leigh reviewed gene: MLKL: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 MIS12 Sarah Leigh reviewed gene: MIS12: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 LDB2 Sarah Leigh reviewed gene: LDB2: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 KARS Sarah Leigh reviewed gene: KARS: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 HYDIN Sarah Leigh reviewed gene: HYDIN: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 CC2D2A Sarah Leigh reviewed gene: CC2D2A: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
COVID-19 research v0.189 BCAR1 Sarah Leigh reviewed gene: BCAR1: Rating: RED; Mode of pathogenicity: ; Publications: 32348764; Phenotypes: Influenza A Virus-Specific Antibody Responses; Mode of inheritance:
Fetal anomalies v1.40 TUBA8 Rebecca Foulger Phenotypes for gene: TUBA8 were changed from POLYMICROGYRIA WITH OPTIC NERVE HYPOPLASIA to POLYMICROGYRIA WITH OPTIC NERVE HYPOPLASIA; Cortical dysplasia, complex, with other brain malformations 8, 613180
Fetal anomalies v1.39 TUBA8 Rebecca Foulger Publications for gene: TUBA8 were set to
Fetal anomalies v1.38 TUBA8 Rebecca Foulger Tag for-review tag was added to gene: TUBA8.
Fetal anomalies v1.38 PAICS Rebecca Foulger Classified gene: PAICS as Amber List (moderate evidence)
Fetal anomalies v1.38 PAICS Rebecca Foulger Added comment: Comment on list classification: Added to the panel and rated Red by Zornitza. Phenotype is appropriate for the panel, but insufficient cases to support causation. Therefore rated Amber, awaiting further publications/clinical evidence. Not yet associated with a disorder in Gene2Phenotype.
Fetal anomalies v1.38 PAICS Rebecca Foulger Gene: paics has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.37 PAICS Rebecca Foulger Phenotypes for gene: PAICS were changed from Polyhydramnios; multiple congenital abnormalities to Polyhydramnios; multiple congenital abnormalities; early neonatal death
Fetal anomalies v1.36 PAICS Rebecca Foulger changed review comment from: PMID:31600779. Pelet et al. report an AR inborn error of de novo purine synthesis due to homozygous missense vairant in PAICS (c.158A>G; p.Lys53Arg) in 2 siblings from the Faroe islands. Catalytic activity of the mutant protein was approx 25% of wild type levels. The siblings had multiple malformations resulting in early neonatal death.; to: PMID:31600779. Pelet et al. report an AR inborn error of de novo purine synthesis due to homozygous missense variant in PAICS (c.158A>G; p.Lys53Arg) in 2 siblings from the Faroe islands. Catalytic activity of the mutant protein was approx 25% of wild type levels. The siblings had multiple malformations resulting in early neonatal death.
Fetal anomalies v1.36 PAICS Rebecca Foulger commented on gene: PAICS
Fetal anomalies v1.36 MSL3 Rebecca Foulger Phenotypes for gene: MSL3 were changed from MSL3 syndrome to MSL3 syndrome; Basilicata-Akhtar syndrome, 301032
Fetal anomalies v1.35 CNOT3 Rebecca Foulger Phenotypes for gene: CNOT3 were changed from CNOT3 syndrome; Intellectual developmental disorder with speech delay, 618672 autism, and dysmorphic facies to CNOT3 syndrome; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, 618672
Fetal anomalies v1.34 CNOT3 Rebecca Foulger Phenotypes for gene: CNOT3 were changed from CNOT3 syndrome to CNOT3 syndrome; Intellectual developmental disorder with speech delay, 618672 autism, and dysmorphic facies
COVID-19 research v0.187 ZFHX3 Sarah Leigh gene: ZFHX3 was added
gene: ZFHX3 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: ZFHX3 was set to
COVID-19 research v0.187 WSCD1 Sarah Leigh gene: WSCD1 was added
gene: WSCD1 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: WSCD1 was set to
COVID-19 research v0.187 UNC5CL Sarah Leigh gene: UNC5CL was added
gene: UNC5CL was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: UNC5CL was set to
COVID-19 research v0.187 TAPT1 Sarah Leigh gene: TAPT1 was added
gene: TAPT1 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: TAPT1 was set to
COVID-19 research v0.187 SPNS3 Sarah Leigh gene: SPNS3 was added
gene: SPNS3 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: SPNS3 was set to
COVID-19 research v0.187 RPAIN Sarah Leigh gene: RPAIN was added
gene: RPAIN was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: RPAIN was set to
COVID-19 research v0.187 PROM1 Sarah Leigh gene: PROM1 was added
gene: PROM1 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: PROM1 was set to
COVID-19 research v0.187 PKD1L3 Sarah Leigh gene: PKD1L3 was added
gene: PKD1L3 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: PKD1L3 was set to
COVID-19 research v0.187 NUP88 Sarah Leigh gene: NUP88 was added
gene: NUP88 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: NUP88 was set to
COVID-19 research v0.187 MLKL Sarah Leigh gene: MLKL was added
gene: MLKL was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: MLKL was set to
COVID-19 research v0.187 MIS12 Sarah Leigh gene: MIS12 was added
gene: MIS12 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: MIS12 was set to
COVID-19 research v0.187 LDB2 Sarah Leigh gene: LDB2 was added
gene: LDB2 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: LDB2 was set to
COVID-19 research v0.187 KARS Sarah Leigh gene: KARS was added
gene: KARS was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: KARS was set to
COVID-19 research v0.187 HYDIN Sarah Leigh gene: HYDIN was added
gene: HYDIN was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: HYDIN was set to
COVID-19 research v0.187 CC2D2A Sarah Leigh gene: CC2D2A was added
gene: CC2D2A was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: CC2D2A was set to
COVID-19 research v0.187 BCAR1 Sarah Leigh gene: BCAR1 was added
gene: BCAR1 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: BCAR1 was set to
Cardiac arrhythmias - additional genes v1.10 TANGO2 Sarah Leigh Classified gene: TANGO2 as Green List (high evidence)
Cardiac arrhythmias - additional genes v1.10 TANGO2 Sarah Leigh Gene: tango2 has been classified as Green List (High Evidence).
Cardiac arrhythmias - additional genes v1.9 TANGO2 Sarah Leigh gene: TANGO2 was added
gene: TANGO2 was added to Cardiac arrhythmias - additional genes. Sources: Expert Review
Mode of inheritance for gene: TANGO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TANGO2 were set to 26805782; 30245509
Phenotypes for gene: TANGO2 were set to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration 616878
Review for gene: TANGO2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 10 variants reported in at least 14 unrelated cases, with arrhythmias in 8 unrelated cases.

Gene suggested by Rowenna Roberts, Clinical Scientist.
Sources: Expert Review
Likely inborn error of metabolism v2.7 TANGO2 Sarah Leigh Publications for gene: TANGO2 were set to 26805782; 26805781; 30245509
Likely inborn error of metabolism v2.6 TANGO2 Sarah Leigh Publications for gene: TANGO2 were set to 26805782; 26805781; 30245509
Likely inborn error of metabolism v2.6 TANGO2 Sarah Leigh Publications for gene: TANGO2 were set to 26805782; 26805781
Undiagnosed metabolic disorders v1.414 TANGO2 Sarah Leigh Publications for gene: TANGO2 were set to
Rhabdomyolysis and metabolic muscle disorders v1.39 TANGO2 Sarah Leigh edited their review of gene: TANGO2: Added comment: Gene suggested by Rowenna Roberts, Clinical Scientist.; Changed phenotypes: Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration 616878
Ketotic hypoglycaemia v1.4 TANGO2 Sarah Leigh Classified gene: TANGO2 as Green List (high evidence)
Ketotic hypoglycaemia v1.4 TANGO2 Sarah Leigh Gene: tango2 has been classified as Green List (High Evidence).
Ketotic hypoglycaemia v1.3 TANGO2 Sarah Leigh gene: TANGO2 was added
gene: TANGO2 was added to Ketotic hypoglycaemia. Sources: Expert Review
Mode of inheritance for gene: TANGO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TANGO2 were set to 26805782; 30245509
Phenotypes for gene: TANGO2 were set to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration 616878
Review for gene: TANGO2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 10 variants reported in at least 14 unrelated cases.
Gene suggested by Rowenna Roberts, Clinical Scientist.
Sources: Expert Review
COVID-19 research v0.186 PIK3CG Ivone Leong Classified gene: PIK3CG as Green List (high evidence)
COVID-19 research v0.186 PIK3CG Ivone Leong Gene: pik3cg has been classified as Green List (High Evidence).
Rhabdomyolysis and metabolic muscle disorders v1.39 TANGO2 Sarah Leigh Classified gene: TANGO2 as Green List (high evidence)
Rhabdomyolysis and metabolic muscle disorders v1.39 TANGO2 Sarah Leigh Gene: tango2 has been classified as Green List (High Evidence).
COVID-19 research v0.185 PIK3CG Ivone Leong gene: PIK3CG was added
gene: PIK3CG was added to Viral susceptibility. Sources: Expert list
Mode of inheritance for gene: PIK3CG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIK3CG were set to 32001535; 31554793
Phenotypes for gene: PIK3CG were set to Immune dysregulation; HLH-like; childhood-onset antibody defects; cytopenias; T lymphocytic pneumonitis and colitis
Review for gene: PIK3CG was set to GREEN
Added comment: "Two individuals with complex immunological phenotypes reported and a mouse model. Sources: Literature
Zornitza Stark (Australian Genomics), 30 Apr 2020" - review copied from Primary immunodeficiency (Version 2.151).

"Comment on list classification: Gene added by Zornitza Stark (Australian Genomics) with recommended Green status based on provided evidence. There is enough evidence for this gene to be rated Green.
Ivone Leong (Genomics England Curator), 5 May 2020" - review copied from Primary immunodeficiency (Version 2.151).
Sources: Expert list
Rhabdomyolysis and metabolic muscle disorders v1.38 TANGO2 Sarah Leigh gene: TANGO2 was added
gene: TANGO2 was added to Rhabdomyolysis and metabolic muscle disorders. Sources: Expert Review
Mode of inheritance for gene: TANGO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TANGO2 were set to 26805782; 30245509
Phenotypes for gene: TANGO2 were set to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration 616878
Review for gene: TANGO2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 10 variants reported in at least 14 unrelated cases, in which rabdomyolysis was reported in 11 unrelated cases.
Sources: Expert Review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.151 PIK3CG Ivone Leong Classified gene: PIK3CG as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.151 PIK3CG Ivone Leong Added comment: Comment on list classification: Gene added by Zornitza Stark (Australian Genomics) with recommended Green status based on provided evidence. There is enough evidence for this gene to be rated Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.151 PIK3CG Ivone Leong Gene: pik3cg has been classified as Green List (High Evidence).
COVID-19 research v0.184 RIPK1 Ivone Leong Added comment: Comment on mode of inheritance: "Please note recent report of mono-allelic variants in two families.
Zornitza Stark (Australian Genomics), 30 Apr 2020" - review copied from Primary immunodeficiency (Version 2.150).

"Comment on mode of inheritance: MOI updated from Biallelic to Both monoallelic and biallelic based on new evidence provided by Zornitza Stark (Australian Genomics). PMID: 31827280.
Ivone Leong (Genomics England Curator), 5 May 2020" - review copied from Primary immunodeficiency (Version 2.150).
COVID-19 research v0.184 RIPK1 Ivone Leong Mode of inheritance for gene: RIPK1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.150 RIPK1 Ivone Leong Publications for gene: RIPK1 were set to 30026316; 30591564; 31213653; 31827280
COVID-19 research v0.183 RIPK1 Ivone Leong Publications for gene: RIPK1 were set to 30026316
Primary immunodeficiency or monogenic inflammatory bowel disease v2.149 RIPK1 Ivone Leong Added comment: Comment on mode of inheritance: MOI updated from Biallelic to Both monoallelic and biallelic based on new evidence provided by Zornitza Stark (Australian Genomics). PMID: 31827280.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.149 RIPK1 Ivone Leong Mode of inheritance for gene: RIPK1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.148 RIPK1 Ivone Leong Publications for gene: RIPK1 were set to 30026316
COVID-19 research v0.182 ITPKB Ivone Leong Classified gene: ITPKB as Amber List (moderate evidence)
COVID-19 research v0.182 ITPKB Ivone Leong Gene: itpkb has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.181 ITPKB Ivone Leong gene: ITPKB was added
gene: ITPKB was added to Viral susceptibility. Sources: Expert list
Mode of inheritance for gene: ITPKB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITPKB were set to 31987846; 14517551
Phenotypes for gene: ITPKB were set to Severe combined immunodeficiency, absent T cells, present B cells and NK cells
Review for gene: ITPKB was set to AMBER
Added comment: "Single individual with homozygous bi-allelic LoF variant reported. Sources: Literature
Zornitza Stark (Australian Genomics), 1 May 2020" - review copied from Primary immunodeficiency panel (v2.147).

"Comment on list classification: Gene added by Zornitza Stark (Australian Genomics) with a recommended Red gene rating based on evidence provided. PMID: 31987846 describes a patient born of consanguineous Egyptian parents. The patient failed to thrive and had persistent thrush shortly after birth, recurrent pneumonias beginning at age 2 months, and Klebsiella pneumoniae skin abscesses at age 6 and 10 months. She had severe SCID.

PMID: 14517551 is a itpkb-/- mouse. Knockout of the gene caused a severe T cell deficiency. Based on these 2 pieces of information the gene has been given an Amber gene rating.
Ivone Leong (Genomics England Curator), 5 May 2020" - review copied from Primary immunodeficiency panel (v2.147).
Sources: Expert list
COVID-19 research v0.180 SMARCD2 Sophie Hambleton reviewed gene: SMARCD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28369036; Phenotypes: neutropenia, specific granule deficiency, myelodysplasia, developmental delay, dysmorphic features; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.147 ITPKB Ivone Leong Classified gene: ITPKB as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.147 ITPKB Ivone Leong Added comment: Comment on list classification: Gene added by Zornitza Stark (Australian Genomics) with a recommended Red gene rating based on evidence provided. PMID: 31987846 describes a patient born of consanguineous Egyptian parents. The patient failed to thrive and had persistent thrush shortly after birth, recurrent pneumonias beginning at age 2 months, and Klebsiella pneumoniae skin abscesses at age 6 and 10 months. She had severe SCID.

PMID: 14517551 is a itpkb-/- mouse. Knockout of the gene caused a severe T cell deficiency. Based on these 2 pieces of information the gene has been given an Amber gene rating.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.147 ITPKB Ivone Leong Gene: itpkb has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.180 SLX4 Sophie Hambleton reviewed gene: SLX4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.180 SLC7A7 Sophie Hambleton reviewed gene: SLC7A7: Rating: GREEN; Mode of pathogenicity: None; Publications: 10080182, 28057010, 21308987; Phenotypes: lysinuric protein intolerance, failure to thrive, hyperammonaemia, encephalopathy, developmental disability, nephropathy, lupus nephritis, haemophagocytic lymphophistiocytosis, pancreatitis, pulmonary alveolar proteinosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.180 SLC39A7 Sophie Hambleton reviewed gene: SLC39A7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: agammaglobulinaemia, B cell deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.180 SH3KBP1 Sophie Hambleton reviewed gene: SH3KBP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hypogammaglobulinaemia; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency or monogenic inflammatory bowel disease v2.146 ITPKB Ivone Leong Publications for gene: ITPKB were set to 31987846
COVID-19 research v0.180 SH3BP2 Sophie Hambleton reviewed gene: SH3BP2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.145 NOS2 Ivone Leong Classified gene: NOS2 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.145 NOS2 Ivone Leong Added comment: Comment on list classification: Gene was added to panel by Zornitza Stark (Australian Genomics). The gene was given the suggested Red rating based on evidence provided by expert reviewer.

PMID: 31995689 describes a 51 year old man from Iran who had an acute cytomegalovirus (CMV) infection which progressed to CMV disease and later died from it. The researchers found a homozygous variant that causes a frameshift mutation in NOS2 that caused NOS2 deficiency, which might cause the patient to be more susceptible to lethal CMV infection. The patient was otherwise healthy until the CMV infection.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.145 NOS2 Ivone Leong Gene: nos2 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.144 NOS2 Ivone Leong Publications for gene: NOS2 were set to 12433515; 31995689
Primary immunodeficiency or monogenic inflammatory bowel disease v2.143 IFNG Ivone Leong Classified gene: IFNG as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.143 IFNG Ivone Leong Added comment: Comment on list classification: This gene has been given Red status based on expert review. PMID: 32163377 does have some functional data; however, it is cellular-based work.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.143 IFNG Ivone Leong Gene: ifng has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.142 CD4 Ivone Leong Phenotypes for gene: CD4 were changed from Selective CD4 cell deficiency; OKT4 epitope deficiency, 613949 to Selective CD4 cell deficiency; OKT4 epitope deficiency, 613949; Absence of CD4+ T cells; exuberant, relapsing, treatment-refractory warts
Primary immunodeficiency or monogenic inflammatory bowel disease v2.141 CD4 Ivone Leong Publications for gene: CD4 were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.140 CD4 Ivone Leong Phenotypes for gene: CD4 were changed from Selective CD4 cell deficiency to Selective CD4 cell deficiency; OKT4 epitope deficiency, 613949
Hyperthyroidism v2.6 TTR Ivone Leong Classified gene: TTR as Green List (high evidence)
Hyperthyroidism v2.6 TTR Ivone Leong Added comment: Comment on list classification: Based on expert review by David Halsall (Cambridge University Hospitals Trust), there is enough evidence to support a gene-disease association for TTR. Therefore this gene has been given Green status.
Hyperthyroidism v2.6 TTR Ivone Leong Gene: ttr has been classified as Green List (High Evidence).
Hyperthyroidism v2.5 TTR Ivone Leong Phenotypes for gene: TTR were changed from # 145680 HYPERTHYROXINEMIA, DYSTRANSTHYRETINEMIC; DTTRH to [Dystransthyretinemic hyperthyroxinemia], 145680; DTTRH
Hyperthyroidism v2.4 TTR Ivone Leong Publications for gene: TTR were set to PMID: 31590893; 26522458
COVID-19 research v0.180 IL6 Sarah Leigh Classified gene: IL6 as Amber List (moderate evidence)
COVID-19 research v0.180 IL6 Sarah Leigh Gene: il6 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.179 IL6 Sarah Leigh changed review comment from: Strong association was observed between an IL6promoter polymorphism (G-174C) and susceptibility to KS in HIV-infected men (P?=?.0035). Homozygotes for IL6 allele G, associated with increased IL6 production, were overrepresented among patients with KS (P?=?.0046), whereas allele C homozygotes were underrepresented (P?=?.0062)(PMID 11001912).; to: Strong association was observed between an IL6 promoter polymorphism (G-174C) and susceptibility to Kaposi Sarcoma (KS) in HIV-infected men (P?=?.0035). Homozygotes for IL6 allele G, associated with increased IL6 production, were over represented among patients with KS (P?=?.0046), whereas allele C homozygotes were under represented (P?=?.0062)(PMID 11001912).
COVID-19 research v0.179 ERCC4 Catherine Snow commented on gene: ERCC4
COVID-19 research v0.179 ABO Catherine Snow Phenotypes for gene: ABO were changed from to Virus susceptibility
COVID-19 research v0.178 ABO Catherine Snow Classified gene: ABO as Amber List (moderate evidence)
COVID-19 research v0.178 ABO Catherine Snow Added comment: Comment on list classification: Identified by expert review. Two preprints and publication relating to ABO and Sars-COV. https://doi.org/10.1101/2020.04.08.20058073 authors found that COVID-19 positive vs negative test results were increased in blood groups A and decreased in blood groups O, consistent with previous results from Wuhan and Shenzhen (https://doi.org/10.1101/2020.03.11.20031096)
COVID-19 research v0.178 ABO Catherine Snow Gene: abo has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.35 ADAM22 Rebecca Foulger Classified gene: ADAM22 as Amber List (moderate evidence)
Intellectual disability v3.35 ADAM22 Rebecca Foulger Added comment: Comment on list classification: Set rating as Amber: 2 unrelated families with ID as part of the phenotype (PMID:27066583 and 30237576).
Intellectual disability v3.35 ADAM22 Rebecca Foulger Gene: adam22 has been classified as Amber List (Moderate Evidence).
Intellectual disability v3.34 ADAM22 Rebecca Foulger commented on gene: ADAM22: PMID:27066583. Muona et al., 2016 report a Finnish proband-parent-trio with intractable seizures and ID. Compound het variants c.1202G>A, p.Cys401Tyr and c.2396delG, p.Ser799IlefsTer96 were found in ADAM22. Functional assays showed that mutant proteins failed to form the LGI1-ADAM22 ligand-receptor complex. The variants are unlikely to be full LOF.
Intellectual disability v3.34 ADAM22 Rebecca Foulger commented on gene: ADAM22: PMID:30237576 (Maddirevula et al., 2019) searched their database of clinical exomes for homozygous variants and report an 18 year old male with Arg860* variant and recurrent seizures (Supplementary Table). His development was normal until 5 months when he had a slower gain of milestones. He has ID with severely delayed speech. Family history revealed ID and epilepsy in his old brother and in wider family.
Intellectual disability v3.34 ADAM22 Rebecca Foulger gene: ADAM22 was added
gene: ADAM22 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: ADAM22 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAM22 were set to 27066583; 30237576
Added comment: Added ADAM22 to ID panel based on literature curation for Epilepsy phenotype. Patients in PMID:27066583 (Finnish trio with compound het ADAM22 variants in the proband) and PMID:30237576 (18 year old male with Arg860* variant) both report ID alongside epilepsy.
Sources: Literature
Early onset or syndromic epilepsy v2.47 ADAM22 Rebecca Foulger changed review comment from: Comment on list classification: 2 Families with prominent seizure phenotype and biallelic ADAM22 variants reported (PMIDs:30237576, 27066583). Plus mouse model of seizures. Not yet associated with a disorder in Gene2Phenotype. Amber is appropriate rating awaiting further cases.; to: Comment on list classification: Added to panel and rated Amber by Zornitza Stark. 2 families with prominent seizure phenotype and biallelic ADAM22 variants reported (PMIDs:30237576, 27066583). Plus mouse model of seizures. Not yet associated with a disorder in Gene2Phenotype. Amber is appropriate rating awaiting further cases.
Early onset or syndromic epilepsy v2.47 ADAM22 Rebecca Foulger Classified gene: ADAM22 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.47 ADAM22 Rebecca Foulger Added comment: Comment on list classification: 2 Families with prominent seizure phenotype and biallelic ADAM22 variants reported (PMIDs:30237576, 27066583). Plus mouse model of seizures. Not yet associated with a disorder in Gene2Phenotype. Amber is appropriate rating awaiting further cases.
Early onset or syndromic epilepsy v2.47 ADAM22 Rebecca Foulger Gene: adam22 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.46 ADAM22 Rebecca Foulger Publications for gene: ADAM22 were set to 27066583; 30237576
Early onset or syndromic epilepsy v2.45 ADAM22 Rebecca Foulger commented on gene: ADAM22: Mouse model: Adam22-/- mice develop lethal seizures during the first postnatal weeks (e.g. PMID:15876356).
Early onset or syndromic epilepsy v2.45 ADAM22 Rebecca Foulger Phenotypes for gene: ADAM22 were changed from Epileptic encephalopathy, early infantile, 61, 617933 to ?Epileptic encephalopathy, early infantile, 61, 617933
Early onset or syndromic epilepsy v2.44 ADAM22 Rebecca Foulger commented on gene: ADAM22: PMID:30237576 (Maddirevula et al., 2019) searched their database of clinical exomes for homozygous variants and report an 18 year old male with an Arg860* variant in ADAM22. Seizures started age 5 months with a focal seizure, and continued with generalized tonic clonic seizures and status epilepticus (Supplementary Table). His development was normal until 5 months when he had a slower gain of milestones. He has ID with severely delayed speech. Family history revealed ID and epilepsy in his old brother and in wider family.
Early onset or syndromic epilepsy v2.44 ADAM22 Rebecca Foulger commented on gene: ADAM22
Early onset or syndromic epilepsy v2.44 ADAM22 Rebecca Foulger Phenotypes for gene: ADAM22 were changed from Epileptic encephalopathy, early infantile, 61, MIM# 617933 to Epileptic encephalopathy, early infantile, 61, 617933
COVID-19 research v0.177 IFNG Sarah Leigh Phenotypes for gene: IFNG were changed from to {AIDS, rapid progression to} 609423
Fetal anomalies v1.33 FGF20 Rebecca Foulger Classified gene: FGF20 as Red List (low evidence)
Fetal anomalies v1.33 FGF20 Rebecca Foulger Added comment: Comment on list classification: Not yet associated with a disorder in Gene2Phenotype. One consanguineous family plus functional studies in mice showing a role in kidney development. Therefore kept rating as Red awaiting further evidence.
Fetal anomalies v1.33 FGF20 Rebecca Foulger Gene: fgf20 has been classified as Red List (Low Evidence).
Fetal anomalies v1.32 FGF20 Rebecca Foulger gene: FGF20 was added
gene: FGF20 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FGF20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FGF20 were set to 22698282; 23112089
Phenotypes for gene: FGF20 were set to ?Renal hypodysplasia/aplasia 2, 615721
Added comment: Added to Fetal panel based on literature search. PMID:22698282. Barak et al., 2012 identify a homozygous frameshift truncating variant (c.337delG) in FGF20, which segregated with the disorder in a consanguineous familly. Pregnancies showed anhydramnios and the fetuses had bilateral renal agenesis. All pregnancies were terminated. Mouse model shows loss of Fgf20 resulted in kidney agenesis. Additional papers report functional experiments (in mice) that confirm role of FGF20 in kidney development (e.g. PMID:23112089).
Sources: Literature
CAKUT v1.83 FGF20 Rebecca Foulger Classified gene: FGF20 as Amber List (moderate evidence)
CAKUT v1.83 FGF20 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Amber by Zornitza. One consanguineous family plus functional data from mice studies. Therefore updated rating to Amber.
CAKUT v1.83 FGF20 Rebecca Foulger Gene: fgf20 has been classified as Amber List (Moderate Evidence).
CAKUT v1.82 FGF20 Rebecca Foulger Publications for gene: FGF20 were set to 22698282
CAKUT v1.81 FGF20 Rebecca Foulger commented on gene: FGF20: Functional experiments (in mice) confirm role of FGF20 in kidney development (e.g. PMID:23112089).
CAKUT v1.81 FGF20 Rebecca Foulger Phenotypes for gene: FGF20 were changed from Renal hypodysplasia/aplasia 2, MIM#615721 to ?Renal hypodysplasia/aplasia 2, 615721
CAKUT v1.80 FGF20 Rebecca Foulger changed review comment from: PMID:22698282. Barak et al., 2012 identify a homozygous frameshift truncating variant (c.337delG) in FGF20, which segregated with the disorder in a consanguineous familly. Pregnancies showed anhydramnios and the fetuses had bilateral renal agenesis. All pregnancies were terminated. Mouse model shows loss of Fgf20 resulted in kidney agenesis.; to: PMID:22698282. Barak et al., 2012 identify a consanguineous family where multiple pregnancies showed anhydramnios and the fetuses had bilateral renal agenesis. DNA analysis from the initial fetus identified homozygous variants in four genes expressed during early kidney development. One of these mutations was a single base-pair deletion in exon 2 of FGF20 which segregated with the disorder within the family. All pregnancies were terminated. A mouse model shows loss of Fgf20 resulted in kidney agenesis.
COVID-19 research v0.176 TNF Sarah Leigh reviewed gene: TNF: Rating: RED; Mode of pathogenicity: ; Publications: 12915457; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.176 TLR2 Sarah Leigh reviewed gene: TLR2: Rating: RED; Mode of pathogenicity: ; Publications: 17085599; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.176 SERPINA1 Sarah Leigh reviewed gene: SERPINA1: Rating: RED; Mode of pathogenicity: ; Publications: 11527807; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.176 SCN5A Sarah Leigh reviewed gene: SCN5A: Rating: RED; Mode of pathogenicity: ; Publications: 25368329; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.176 RB1 Sarah Leigh reviewed gene: RB1: Rating: RED; Mode of pathogenicity: ; Publications: 2968522, 18467589; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.176 PDCD1 Sarah Leigh reviewed gene: PDCD1: Rating: RED; Mode of pathogenicity: ; Publications: 16921384; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.176 NUP214 Sarah Leigh reviewed gene: NUP214: Rating: RED; Mode of pathogenicity: ; Publications: 31178128; Phenotypes: {Encephalopathy, acute, infection-induced, susceptibility to, 9} 618426; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.176 MET Sarah Leigh reviewed gene: MET: Rating: RED; Mode of pathogenicity: ; Publications: 9927037; Phenotypes: Hepatocellular carcinoma, childhood type, somatic 114550; Mode of inheritance: Unknown
COVID-19 research v0.176 LDLR Sarah Leigh reviewed gene: LDLR: Rating: GREEN; Mode of pathogenicity: ; Publications: 10535997, 32268133, 31386864, 31358055; Phenotypes: Hypercholesterolemia, familial, 1 143890, LDL cholesterol level QTL2 143890; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
COVID-19 research v0.176 KRT18 Sarah Leigh reviewed gene: KRT18: Rating: RED; Mode of pathogenicity: ; Publications: 8770877; Phenotypes: {Cirrhosis, noncryptogenic, susceptibility to} 215600, Cirrhosis, cryptogenic 215600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.176 IRGM Sarah Leigh reviewed gene: IRGM: Rating: RED; Mode of pathogenicity: ; Publications: 11457893; Phenotypes: murine cytomegalovirus infection; Mode of inheritance:
COVID-19 research v0.176 IL6 Sarah Leigh reviewed gene: IL6: Rating: GREEN; Mode of pathogenicity: ; Publications: 11001912; Phenotypes: {Kaposi sarcoma, susceptibility to} 148000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.176 IL4R Sarah Leigh reviewed gene: IL4R: Rating: RED; Mode of pathogenicity: ; Publications: 16189667; Phenotypes: {AIDS, slow progression to} 609423; Mode of inheritance:
COVID-19 research v0.176 IFNG Sarah Leigh reviewed gene: IFNG: Rating: AMBER; Mode of pathogenicity: ; Publications: 12854077; Phenotypes: AIDS, rapid progression to} 609423; Mode of inheritance: Unknown
COVID-19 research v0.176 IFITM3 Sarah Leigh reviewed gene: IFITM3: Rating: GREEN; Mode of pathogenicity: ; Publications: 22446628, 18505827, 32348495; Phenotypes: {Influenza, severe, susceptibility to} 614680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.176 ICAM1 Sarah Leigh reviewed gene: ICAM1: Rating: RED; Mode of pathogenicity: ; Publications: 2538243, 12853962; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.176 HTR2A Sarah Leigh reviewed gene: HTR2A: Rating: RED; Mode of pathogenicity: ; Publications: 15550673; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.176 HLA-DQB1 Sarah Leigh reviewed gene: HLA-DQB1: Rating: AMBER; Mode of pathogenicity: ; Publications: 23710940, 10609818, 12473762; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.176 HLA-C Sarah Leigh reviewed gene: HLA-C: Rating: RED; Mode of pathogenicity: ; Publications: 19935663, 21051598; Phenotypes: {HIV-1 viremia, susceptibility to} 609423; Mode of inheritance: Unknown
COVID-19 research v0.176 HFE Sarah Leigh reviewed gene: HFE: Rating: RED; Mode of pathogenicity: ; Publications: 16043695; Phenotypes: Hemochromatosis 235200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.176 HBB Sarah Leigh reviewed gene: HBB: Rating: RED; Mode of pathogenicity: ; Publications: 8168595, 2599880, 8602627; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v0.176 DMD Sarah Leigh reviewed gene: DMD: Rating: RED; Mode of pathogenicity: ; Publications: 10753926, 12118246; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
COVID-19 research v0.176 CYP2B6 Sarah Leigh reviewed gene: CYP2B6: Rating: RED; Mode of pathogenicity: ; Publications: 15622315, 20860463, 15194512, 23418033; Phenotypes: {Efavirenz central nervous system toxicity, susceptibility to} 614546, Efavirenz, poor metabolism of 614546; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.176 CX3CR1 Sarah Leigh reviewed gene: CX3CR1: Rating: AMBER; Mode of pathogenicity: ; Publications: 14607932, 10731151; Phenotypes: {Rapid progression to AIDS from HIV1 infection} 609423; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.176 CR1 Sarah Leigh reviewed gene: CR1: Rating: RED; Mode of pathogenicity: ; Publications: 16517720; Phenotypes: acute myocarditis and pericardial fibrosis due to coxsackievirus B3; Mode of inheritance: Unknown
COVID-19 research v0.176 CPT2 Sarah Leigh reviewed gene: CPT2: Rating: AMBER; Mode of pathogenicity: ; Publications: 15811315, 18306170, 20934285, 21697855; Phenotypes: {Encephalopathy, acute, infection-induced, 4, susceptibility to} 614212; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.176 CD209 Sarah Leigh reviewed gene: CD209: Rating: RED; Mode of pathogenicity: ; Publications: 15564514, 15838506, 16379498; Phenotypes: {Dengue fever, protection against} 614371, {HIV type 1, susceptibility to} 609423, {Mycobacterium tuberculosis, susceptibility to} 607948; Mode of inheritance: Unknown
COVID-19 research v0.176 CCR5 Sarah Leigh reviewed gene: CCR5: Rating: RED; Mode of pathogenicity: ; Publications: 16418398, 16418398, 9132277; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v0.176 CCND1 Sarah Leigh reviewed gene: CCND1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: {Colorectal cancer, susceptibility to} 114500, {von Hippel-Lindau syndrome, modifier of} 193300; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.176 CCL3L1 Sarah Leigh reviewed gene: CCL3L1: Rating: RED; Mode of pathogenicity: ; Publications: 15637236, 15637236, 19812560, 19812561, 19812562; Phenotypes: {HIV/AIDS, susceptibility to} 609423; Mode of inheritance: Unknown
CAKUT v1.80 FGF20 Rebecca Foulger commented on gene: FGF20
CAKUT v1.80 FAM58A Rebecca Foulger Classified gene: FAM58A as Green List (high evidence)
CAKUT v1.80 FAM58A Rebecca Foulger Added comment: Comment on list classification: FAM58A added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Green following literature review: sufficient cases to support gene:disease association, and renal phenotypes are common.
CAKUT v1.80 FAM58A Rebecca Foulger Gene: fam58a has been classified as Green List (High Evidence).
CAKUT v1.79 FAM58A Rebecca Foulger Phenotypes for gene: FAM58A were changed from STAR syndrome, MIM# 300707 to STAR syndrome, 300707; Syndactyly, Telecanthus, Anogenital malformations and Renal malformations
CAKUT v1.78 FAM58A Rebecca Foulger Added comment: Comment on mode of inheritance: Set MOI to XLD to match literature (PMID:28225384, PMID:18297069).
CAKUT v1.78 FAM58A Rebecca Foulger Mode of inheritance for gene: FAM58A was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
CAKUT v1.77 FAM58A Rebecca Foulger Mode of inheritance for gene: FAM58A was changed from Other to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
CAKUT v1.76 FAM58A Rebecca Foulger commented on gene: FAM58A: PMID:28225384 (Lefroy et al., 2017) report a 19 year old woman with STAR syndrome; phenotypes include a small left kidney and impaired renal function. The patient had a Xq28 deletion which included the whole FAM58A gene. The mother was mosaic for the deletion, and had a milder phenotype with normal renal ultrasound and renal function.
CAKUT v1.76 FAM58A Rebecca Foulger commented on gene: FAM58A
Respiratory ciliopathies including non-CF bronchiectasis v1.7 GAS2L2 Eleanor Williams Classified gene: GAS2L2 as Green List (high evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.7 GAS2L2 Eleanor Williams Added comment: Comment on list classification: Upgrading from amber to green, based on Expert review on the Primary ciliary disorders panel (https://panelapp.genomicsengland.co.uk/panels/178/gene/GAS2L2/). 2 cases plus animal model.
Respiratory ciliopathies including non-CF bronchiectasis v1.7 GAS2L2 Eleanor Williams Gene: gas2l2 has been classified as Green List (High Evidence).
Primary ciliary disorders v1.24 GAS2L2 Eleanor Williams Classified gene: GAS2L2 as Green List (high evidence)
Primary ciliary disorders v1.24 GAS2L2 Eleanor Williams Added comment: Comment on list classification: Promoting to Green based on expert review. Gene has been updated with Ensembl gene identifiers.
Primary ciliary disorders v1.24 GAS2L2 Eleanor Williams Gene: gas2l2 has been classified as Green List (High Evidence).
Osteogenesis imperfecta v2.3 TAPT1 Zornitza Stark reviewed gene: TAPT1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26365339; Phenotypes: Osteochondrodysplasia, complex lethal, Symoens-Barnes-Gistelinck type (MIM#616897); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.175 IFITM3 Ivone Leong Mode of inheritance for gene: IFITM3 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.175 IFITM3 Ivone Leong Mode of inheritance for gene: IFITM3 was changed from to BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.174 IFITM3 Ivone Leong Phenotypes for gene: IFITM3 were changed from to {Influenza, severe, susceptibility to}, 614680
COVID-19 research v0.173 IFITM3 Ivone Leong Classified gene: IFITM3 as Green List (high evidence)
COVID-19 research v0.173 IFITM3 Ivone Leong Added comment: Comment on list classification: PMID: 32348495 reports that individuals who are homozygous for the C allele of rs12252 SNP in IFITM3 is associated with more severe disease in older patients. This SNP is common in Asian populations (MAF reported on dbSNP for East Asians: 0.57; Europeans: 0.0546). This study was condicted in China with 80 patients who were confirmed to be positive for COVID-19.

PMID: 23361009 found that homozygous C allele of rs12252 is in 69% of Chinese patients who were infected with severe pandemic influenza A H1N1/09 virus infection compared with 25% who had mild infection. The homozygous C allele for rs12252 is associated with a 6-fold greater risk for severe infection than CT and TT genotypes.

Based on these studies there is enough evidence to promote this gene to Green status.
COVID-19 research v0.173 IFITM3 Ivone Leong Gene: ifitm3 has been classified as Green List (High Evidence).
COVID-19 research v0.172 IFITM3 Ivone Leong Publications for gene: IFITM3 were set to
Pain syndromes v1.9 FLVCR1 Tomislav Kokotovic gene: FLVCR1 was added
gene: FLVCR1 was added to Pain syndromes. Sources: Literature
Mode of inheritance for gene: FLVCR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLVCR1 were set to 27923065
Phenotypes for gene: FLVCR1 were set to insensitivity to pain; neurodevelopmental delay; joint hypermobility; scoliosis; dysautonomia
Penetrance for gene: FLVCR1 were set to unknown
Review for gene: FLVCR1 was set to AMBER
Added comment: Sources: Literature
Intellectual disability v3.33 VPS51 Zornitza Stark gene: VPS51 was added
gene: VPS51 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: VPS51 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS51 were set to 30624672; 31207318
Phenotypes for gene: VPS51 were set to Pontocerebellar hypoplasia, type 13, MIM# 618606
Review for gene: VPS51 was set to AMBER
Added comment: Two families reported with bi-allelic variants in this gene and global developmental delay, impaired intellectual development with absent speech, microcephaly, and progressive atrophy of the cerebellar vermis and brainstem. Additional features, including seizures and visual impairment, are variable.
Sources: Literature
Laterality disorders and isomerism v1.5 MNS1 Zornitza Stark gene: MNS1 was added
gene: MNS1 was added to Laterality disorders and isomerism. Sources: Literature
Mode of inheritance for gene: MNS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MNS1 were set to 31534215; 30148830
Phenotypes for gene: MNS1 were set to Heterotaxy; male infertility
Review for gene: MNS1 was set to GREEN
gene: MNS1 was marked as current diagnostic
Added comment: Eight families reported altogether. However, four are Amish and share same homozygous founder variant, and some of the other reported families are consanguineous and share another founder variant. A reported female with a third variant, also had a homozygous variant in DNAH5 with a blended phenotype postulated.
Sources: Literature
Differences in sex development v2.4 DHX37 Zornitza Stark gene: DHX37 was added
gene: DHX37 was added to Disorders of sex development. Sources: Literature
Mode of inheritance for gene: DHX37 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DHX37 were set to 31337883; 31745530
Phenotypes for gene: DHX37 were set to 46,XY gonadal dysgenesis; testicular regression syndrome (TRS)
Review for gene: DHX37 was set to GREEN
gene: DHX37 was marked as current diagnostic
Added comment: Seventeen individuals reported in two studies.
Sources: Literature
Cholestasis v1.3 GALM Zornitza Stark gene: GALM was added
gene: GALM was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: GALM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALM were set to 30451973; 30910422
Phenotypes for gene: GALM were set to type IV galactosaemia
Review for gene: GALM was set to GREEN
Added comment: Homozygous and compound heterozygous variants (missense, nonsense and frameshift) found in 8 Japanese patients from unrelated families with unexplained galactosaemia. (No variants in GALT, GALK1, and GALE). In vitro expression analysis and enzyme activity assay of the patients’ peripheral blood mononuclear cells showed total lack of or compromised expression of GALM protein. One homozygote for one of these variants p.(Gly142Arg) in gnomAD (African population). (Wada, Y. et al 2019; PMID: 30451973)

Note only two individuals were reported as having transient cholestasis.
Sources: Literature
Adult solid tumours cancer susceptibility v2.3 DGCR8 Zornitza Stark gene: DGCR8 was added
gene: DGCR8 was added to Adult solid tumours cancer susceptibility. Sources: Literature
Mode of inheritance for gene: DGCR8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DGCR8 were set to 31805011
Phenotypes for gene: DGCR8 were set to Early-onset multinodular goiter and schwannomatosis
Review for gene: DGCR8 was set to RED
Added comment: A germline missense variant segregates in one family with autosomal dominant Mendelian tumour susceptibility syndrome: familial multinodular goitre (MNG) with schwannomatosis. The missense is also a recurrent somatic missense variant in Wilms tumour.
Sources: Literature
Monogenic hearing loss v2.8 FOXF2 Zornitza Stark gene: FOXF2 was added
gene: FOXF2 was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: FOXF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOXF2 were set to 30561639; 22022403
Phenotypes for gene: FOXF2 were set to profound sensorineural hearing loss (SNHL); cochlea malformations; incomplete partition type I anomaly of the cochlea
Review for gene: FOXF2 was set to AMBER
Added comment: Single family: variant has functional data to demonstrate effect on protein, plus mouse model supports gene-disease association.
Sources: Literature
Cholestasis v1.3 WDR83OS Zornitza Stark gene: WDR83OS was added
gene: WDR83OS was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: WDR83OS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR83OS were set to 30250217
Phenotypes for gene: WDR83OS were set to Cholestasis
Review for gene: WDR83OS was set to RED
Added comment: One consanguineous family with 3 affected individuals found to carry a homozygous splice site variant in WDR83OS. The variant results in an aberrant truncated RNA transcript as demonstrated by RT-PCR.
Sources: Literature
Cholestasis v1.3 LSR Zornitza Stark gene: LSR was added
gene: LSR was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: LSR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSR were set to 32303357; 30250217
Phenotypes for gene: LSR were set to transient neonatal cholestasis; intellectual disability; short stature
Review for gene: LSR was set to AMBER
Added comment: Two families reported.
Sources: Literature
Cholestasis v1.3 USP53 Zornitza Stark reviewed gene: USP53: Rating: GREEN; Mode of pathogenicity: None; Publications: 30250217, 32124521; Phenotypes: Cholestasis, deafness; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
COVID-19 research v0.171 SEC61A1 Sophie Hambleton reviewed gene: SEC61A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28782633, 32325141; Phenotypes: Hypogammaglobulinaemia, recurrent infections, plasma cell deficiency, severe congenital neutropenia, tubulointerstitial and Glomerulocystic Kidney Disease with Anemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
COVID-19 research v0.171 RNU4ATAC Sophie Hambleton reviewed gene: RNU4ATAC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.171 RFWD3 Sophie Hambleton reviewed gene: RFWD3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.171 RELA Sophie Hambleton reviewed gene: RELA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: chronic mucocutaneous ulceration, autoimmune lymphoporliferative syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.171 REL Sophie Hambleton reviewed gene: REL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: combined immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.171 RANBP2 Sophie Hambleton reviewed gene: RANBP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: necrotizing encephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.171 PSMG2 Sophie Hambleton reviewed gene: PSMG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30664889; Phenotypes: CANDLE syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.171 RAD51C Sophie Hambleton reviewed gene: RAD51C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.171 RAD51 Sophie Hambleton reviewed gene: RAD51: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.171 POLR3F Sophie Hambleton reviewed gene: POLR3F: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.171 POLR3C Sophie Hambleton reviewed gene: POLR3C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.171 POLR3A Sophie Hambleton reviewed gene: POLR3A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.171 POLD2 Sophie Hambleton reviewed gene: POLD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: combined immunodeficiency, neurodevelopmental delay; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.171 POLD1 Sophie Hambleton changed review comment from: IUIS gene. Biallelic missense variant p.R1060C, that impairs association between POLD1 and POLD2, was associated with combined immunodeficiency in 3 affected members of one kindred. Allelic AD disorders cause alternative phenotypes; to: IUIS gene. Biallelic missense variant p.R1060C, that impairs association between POLD1 and POLD2, was associated with combined immunodeficiency in 3 affected members of one kindred. An unrelated case of combined immunodeficiency reported elsewhere (PMID 31449058) had 3 rare missense variants. Allelic AD disorders cause alternative phenotypes
COVID-19 research v0.171 POLD1 Sophie Hambleton reviewed gene: POLD1: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: combined immunodeficiency, T-cell lymphopenia, recurrent infections, hypogammaglobulinaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.171 PAX1 Sophie Hambleton reviewed gene: PAX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: severe combined immunodeficiency, thymic aplasia, otofaciocervical syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.171 PALB2 Sophie Hambleton reviewed gene: PALB2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.171 OAS1 Sophie Hambleton reviewed gene: OAS1: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Infantile-Onset Pulmonary Alveolar Proteinosis, Hypogammaglobulinemia.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.171 NOS2 Sophie Hambleton reviewed gene: NOS2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.171 NFE2L2 Sophie Hambleton reviewed gene: NFE2L2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: ; Phenotypes: growth retardation, developmental delay, leukodystrophy, recurrent infections, hypogammaglobulinaemia, hypohomocysteinaemia, increased G-6-P-dehydrogenase activity; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.171 MAD2L2 Sophie Hambleton reviewed gene: MAD2L2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.171 IRF9 Sophie Hambleton reviewed gene: IRF9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.171 IRF4 Sophie Hambleton reviewed gene: IRF4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Whipple's disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
COVID-19 research v0.171 IL6ST Sophie Hambleton reviewed gene: IL6ST: Rating: GREEN; Mode of pathogenicity: None; Publications: 31914175, 32207811; Phenotypes: recurrent infections, eczema, bronchiectasis, high IgE, eosinophilia, defective B cell memory, impaired acute-phase response, stuve-wiedemann syndrome, craniosynostosis; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
COVID-19 research v0.171 IL6R Sophie Hambleton reviewed gene: IL6R: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Impaired humoral immunity, hyper-IgE, recurrent infections, eczema; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.171 IL2RB Sophie Hambleton reviewed gene: IL2RB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: very early onset inflammatory bowel disease, CMV disease, dermatitis, immune dysregulation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.171 IL12RB2 Sophie Hambleton changed review comment from: IUIS gene; to: IUIS gene for MSMD, incomplete penetrance
see PMID 30578351
COVID-19 research v0.171 IL23R Sophie Hambleton reviewed gene: IL23R: Rating: ; Mode of pathogenicity: None; Publications: 30578351; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.171 IL18BP Sophie Hambleton reviewed gene: IL18BP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.171 IL12RB2 Sophie Hambleton reviewed gene: IL12RB2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.171 IFNAR1 Sophie Hambleton reviewed gene: IFNAR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Viral susceptibility, disseminated MMR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.171 HLA-DRB1 Sophie Hambleton reviewed gene: HLA-DRB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Other
Cholestasis v1.3 PPM1F Zornitza Stark gene: PPM1F was added
gene: PPM1F was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: PPM1F was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPM1F were set to 30250217; 30976738
Phenotypes for gene: PPM1F were set to sclerosing cholangitis; short stature; hypothyroidism; abnormal tongue pigmentation
Review for gene: PPM1F was set to RED
Added comment: One consanguineous family reported.
Sources: Literature
COVID-19 research v0.171 HLA-B Sophie Hambleton reviewed gene: HLA-B: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: None
Cholestasis v1.3 KIF12 Zornitza Stark gene: KIF12 was added
gene: KIF12 was added to Cholestasis. Sources: Literature
Mode of inheritance for gene: KIF12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF12 were set to 30250217; 30976738
Phenotypes for gene: KIF12 were set to Cholestasis; High Gamma-Glutamyltransferase (GGT)
Review for gene: KIF12 was set to GREEN
gene: KIF12 was marked as current diagnostic
Added comment: Five unrelated consanguineous families, with four different homozygous variants identified, some truncating, others missense.
Sources: Literature
COVID-19 research v0.171 HAVCR2 Sophie Hambleton reviewed gene: HAVCR2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Panniculitis, T-cell lymphoma, haemophagocytic lymphohistiocytosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v3.33 LRRC32 Zornitza Stark gene: LRRC32 was added
gene: LRRC32 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: LRRC32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRRC32 were set to 30976112
Phenotypes for gene: LRRC32 were set to Intellectual disability; cleft palate; proliferative retinopathy
Review for gene: LRRC32 was set to AMBER
Added comment: Three individuals from two consanguineous families segregated the same homozygous bi-allelic variant, c.1630C>T; p.(Arg544Ter), shared haplotype indicative of founder effect. Mouse model has cleft palate and neonatal death.
Sources: Literature
COVID-19 research v0.171 FERMT1 Sophie Hambleton reviewed gene: FERMT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Limb disorders v2.5 IQCE Zornitza Stark edited their review of gene: IQCE: Set current diagnostic: yes
Limb disorders v2.5 IQCE Zornitza Stark reviewed gene: IQCE: Rating: GREEN; Mode of pathogenicity: None; Publications: 31549751, 28488682; Phenotypes: Postaxial polydactyly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mitochondrial disorders v2.5 CRAT Zornitza Stark reviewed gene: CRAT: Rating: AMBER; Mode of pathogenicity: None; Publications: 29395073, 31448845; Phenotypes: Neurodegeneration with brain iron accumulation 8, MIM# 617917, Leigh syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia and cerebellar anomalies - childhood onset v2.6 THG1L Zornitza Stark gene: THG1L was added
gene: THG1L was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: THG1L was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THG1L were set to 27307223; 30214071; 31168944
Phenotypes for gene: THG1L were set to Cerebellar ataxia
Review for gene: THG1L was set to GREEN
Added comment: Four Ashkenazi Jewish families reported, with same homozygous variant, p.V55A in affected individuals. Another individual from different ethnicity also reported. A carrier rate of 0.8%, but no THG1L V55A homozygotes, was found in a cohort of 3,232 unrelated Ashkenazi Jewish individuals, and no homozygotes found in Exac or gnomAD.
Sources: Literature
Congenital disorders of glycosylation v2.6 GALNT2 Zornitza Stark gene: GALNT2 was added
gene: GALNT2 was added to Congenital disorders of glycosylation. Sources: Literature
Mode of inheritance for gene: GALNT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALNT2 were set to 32293671
Phenotypes for gene: GALNT2 were set to Congenital disorder of glycosylation
Review for gene: GALNT2 was set to GREEN
gene: GALNT2 was marked as current diagnostic
Added comment: Seven individuals from four families reported with bi-allelic LOF variants and global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. Suggest adding to ID and epilepsy panels.
Sources: Literature
Severe microcephaly v2.6 C7orf43 Zornitza Stark gene: C7orf43 was added
gene: C7orf43 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: C7orf43 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C7orf43 were set to 30715179
Phenotypes for gene: C7orf43 were set to Microcephaly 25, primary, autosomal recessive, MIM# 618351
Review for gene: C7orf43 was set to AMBER
Added comment: Single family reported: three affected siblings with homozygous truncating variant. Supportive zebrafish model. HGNC approved name: MAP11.
Sources: Literature
Retinal disorders v2.8 SLC6A6 Zornitza Stark gene: SLC6A6 was added
gene: SLC6A6 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: SLC6A6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC6A6 were set to 31345061; 31903486; 29886034
Phenotypes for gene: SLC6A6 were set to Early retinal degeneration; cardiomyopathy
Review for gene: SLC6A6 was set to AMBER
Added comment: Different homozygous missense variants in 2 unrelated consanguineous families with early retinal degeneration, some functional studies. Patients in one of the families also had cardiomyopathy. (PMIDs: 31345061, 31903486) One dilated cardiomyopathy patient with a homozygous deletion at a splice site (PMID: 29886034).
Sources: Literature
Familial non syndromic congenital heart disease v1.51 ADAMTS19 Zornitza Stark gene: ADAMTS19 was added
gene: ADAMTS19 was added to Familial non syndromic congenital heart disease. Sources: Literature
Mode of inheritance for gene: ADAMTS19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAMTS19 were set to 31844321
Phenotypes for gene: ADAMTS19 were set to Non-syndromic heart valve disease
Review for gene: ADAMTS19 was set to AMBER
Added comment: PMID: 31844321; Wünnemann 2020: 4 affected in 2 unrelated consanguineous families with non-syndromic heart valve disease. 1 family with an intragenic (exon 1-8) deletion and 1 nonsense variant. Carriers unaffected. Homozygous knockout mice for Adamts19 show aortic valve dysfunction, recapitulating aspects of the human phenotype
Sources: Literature
Skeletal dysplasia v2.7 POLR1B Zornitza Stark gene: POLR1B was added
gene: POLR1B was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: POLR1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR1B were set to 31649276
Phenotypes for gene: POLR1B were set to Treacher-Collins syndrome type 4
Review for gene: POLR1B was set to GREEN
gene: POLR1B was marked as current diagnostic
Added comment: Five unrelated families and a zebrafish model, variant inherited in two of the families, once from affected parent and once from mosaic parent. Note four of the families had missense variants affecting same residue, p.Arg1003
Sources: Literature
Hereditary neuropathy or pain disorder v1.4 C1orf194 Zornitza Stark gene: C1orf194 was added
gene: C1orf194 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: C1orf194 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: C1orf194 were set to 31199454
Phenotypes for gene: C1orf194 were set to Charcot-Marie-Tooth disease, intermediate or demyelinating
Review for gene: C1orf194 was set to AMBER
Added comment: Two unrelated families with missense variants, one with intermediate CMT, the other with demyelinating CMT. Different phenotypic manifestations may relate to different mechanism, but this remains to be fully elucidated. Supportive mouse model.
Sources: Literature
Skeletal dysplasia v2.7 UBA2 Zornitza Stark gene: UBA2 was added
gene: UBA2 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: UBA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: UBA2 were set to 31332306; 31587267
Phenotypes for gene: UBA2 were set to Split-Hand/Foot Malformation; Aplasia Cutis Congenita; Ectrodactyly
Review for gene: UBA2 was set to AMBER
Added comment: PMID: 31332306 - a single individual with a de novo PTC and split hand/foot malformation (SHFM). Additional two multigenic CNVs including this gene in individuals with SHFM and ectrodactyly. Authors mention an additional de novo missense but the patient didnt have SHFM, argue low penetrance PMID: 31587267 - a mother and son with aplasia cutis congenita (ACC), with a heterozygous PTC. Son also has ectrodactyly. Authors note an additional de novo missense in a patient with ACC.
Sources: Literature
Optic neuropathy v2.3 MCAT Zornitza Stark gene: MCAT was added
gene: MCAT was added to Optic neuropathy. Sources: Literature
Mode of inheritance for gene: MCAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCAT were set to 31915829
Phenotypes for gene: MCAT were set to progressive autosomal recessive optic neuropathy
Review for gene: MCAT was set to RED
Added comment: Single family reported.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.139 CD4 Zornitza Stark changed review comment from: Single individual reported, functional data, emerging gene.; to: Single individual reported, functional data, emerging gene.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.139 CD4 Zornitza Stark reviewed gene: CD4: Rating: AMBER; Mode of pathogenicity: None; Publications: 31781092; Phenotypes: Absence of CD4+ T cells, exuberant, relapsing, treatment-refractory warts; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.139 IFNG Zornitza Stark gene: IFNG was added
gene: IFNG was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IFNG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFNG were set to 32163377
Phenotypes for gene: IFNG were set to Mendelian susceptibility to mycobacterial disease
Review for gene: IFNG was set to RED
Added comment: Two cousins with MSMD and homozygous intragenic deletion, some functional data.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.139 NOS2 Zornitza Stark gene: NOS2 was added
gene: NOS2 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: NOS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NOS2 were set to 12433515; 31995689
Phenotypes for gene: NOS2 were set to {Malaria, resistance to} 611162; Disseminated CMV disease
Review for gene: NOS2 was set to RED
Added comment: Promoter polymorphisms linked to malarial resistance. Single individual reported with homozygous NOS2 LOF variant and disseminated, progressive CMV disease.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.139 ITPKB Zornitza Stark gene: ITPKB was added
gene: ITPKB was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: ITPKB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ITPKB were set to 31987846
Phenotypes for gene: ITPKB were set to Severe combined immunodeficiency, absent T cells, present B cells and NK cells
Review for gene: ITPKB was set to RED
Added comment: Single individual with homozygous bi-allelic LoF variant reported.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.139 CDC42 Zornitza Stark gene: CDC42 was added
gene: CDC42 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: CDC42 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDC42 were set to 31601675; 32303876; 32231661
Phenotypes for gene: CDC42 were set to Neonatal-onset cytopaenia with dyshaematopoiesis; autoinflammation; rash; HLH
Review for gene: CDC42 was set to GREEN
Added comment: PMID 31601675: four unrelated individuals with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. All shared the same de novo CDC42 variant (Chr1:22417990C>T, p.R186C). Another pair of sibs reported in PMID 32303876 with infantile myelofibrosis and myeloproliferation and same variant (parental mosaicism). Yet another individual in PMID 32231661 with different de novo variant, p.Cys81Tyr who in addition developed haematological malignancy and also had syndromic features, including ID. Note other missense variants in this gene cause Takenouchi-Kosaki syndrome, MIM# 616737
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.139 RIPK1 Zornitza Stark edited their review of gene: RIPK1: Added comment: Please note recent report of mono-allelic variants in two families.; Changed publications: 30026316, 30591564, 31213653, 31827280; Changed phenotypes: Severe immunodeficiency, arthritis, and intestinal inflammation, Immunodeficiency 57, MIM#618108; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.139 PIK3CG Zornitza Stark gene: PIK3CG was added
gene: PIK3CG was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: PIK3CG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIK3CG were set to 32001535; 31554793
Phenotypes for gene: PIK3CG were set to Immune dysregulation; HLH-like; childhood-onset antibody defects; cytopenias; T lymphocytic pneumonitis and colitis
Review for gene: PIK3CG was set to GREEN
Added comment: Two individuals with complex immunological phenotypes reported and a mouse model.
Sources: Literature
CAKUT v1.76 EXOC3L2 Rebecca Foulger Classified gene: EXOC3L2 as Amber List (moderate evidence)
CAKUT v1.76 EXOC3L2 Rebecca Foulger Gene: exoc3l2 has been classified as Amber List (Moderate Evidence).
CAKUT v1.75 EXOC3L2 Rebecca Foulger Classified gene: EXOC3L2 as No list
CAKUT v1.75 EXOC3L2 Rebecca Foulger Added comment: Comment on list classification: Gene was added to panel and rated Green by Chirag Patel. Updated rating from Grey to Amber. Most reported cases are from fetuses (e.g. PMID: 27894351) and therefore EXOC3L2 is more appropriate on Fetal panel.
CAKUT v1.75 EXOC3L2 Rebecca Foulger Gene: exoc3l2 has been removed from the panel.
CAKUT v1.74 EXOC3L2 Rebecca Foulger commented on gene: EXOC3L2: PMID: 27894351: Shaheen et al., 2016 examined 371 individuals from 265 families with ciliopathy phenotypes. They identified a LOF variant in EXOC3L2 and a lethal phenotype that resembles Meckel–Gruber syndrome (severe posterior fossa malformation with kidney enlargement) in one family.
CAKUT v1.74 EXOC3L2 Rebecca Foulger commented on gene: EXOC3L2: PMID: 28749478: Shamseldin et al., 2018 performed exome sequencing as part of molecular autopsy in a cohort of 44 families with at least one death or lethal fetal malformation. They report one fetus with a biallelic EXOC3L2 variant and a phenotype similar to Meckel-Gruber syndrome.
Fetal anomalies v1.31 EXOC3L2 Rebecca Foulger Classified gene: EXOC3L2 as Green List (high evidence)
Fetal anomalies v1.31 EXOC3L2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green: 3 unrelated fetal cases (PMIDs:27894351,28749478,30327448).
Fetal anomalies v1.31 EXOC3L2 Rebecca Foulger Gene: exoc3l2 has been classified as Green List (High Evidence).
Fetal anomalies v1.30 EXOC3L2 Rebecca Foulger changed review comment from: PMID: 27894351: Shaheen et al., 2016 examined 371 individuals from 265 families with ciliopathy phenotypes. They identified a LOF variant in EXOC3L2 and a lethal phenotype that resembles Meckel–Gruber syndrome (severe posterior fossa malformation with kidney enlargement) in one family.; to: PMID: 27894351: Shaheen et al., 2016 examined 371 individuals from 265 families with ciliopathy phenotypes. They identified a LOF variant in EXOC3L2 and a lethal phenotype that resembles Meckel–Gruber syndrome (severe posterior fossa malformation with kidney enlargement) in one family (reviewed briefly in PMID:28749478).
Fetal anomalies v1.30 EXOC3L2 Rebecca Foulger commented on gene: EXOC3L2: PMID: 27894351: Shaheen et al., 2016 examined 371 individuals from 265 families with ciliopathy phenotypes. They identified a LOF variant in EXOC3L2 and a lethal phenotype that resembles Meckel–Gruber syndrome (severe posterior fossa malformation with kidney enlargement) in one family.
Fetal anomalies v1.30 EXOC3L2 Rebecca Foulger Publications for gene: EXOC3L2 were set to 30327448; 28749478
Fetal anomalies v1.29 EXOC3L2 Rebecca Foulger Publications for gene: EXOC3L2 were set to 30327448
Fetal anomalies v1.28 EXOC3L2 Rebecca Foulger commented on gene: EXOC3L2: PMID: 28749478: Shamseldin et al., 2018 performed exome sequencing as part of molecular autopsy in a cohort of 44 families with at least one death or lethal fetal malformation. They report one fetus with a biallelic EXOC3L2 variant and a phenotype similar to Meckel-Gruber syndrome.
Fetal anomalies v1.28 EXOC3L2 Rebecca Foulger gene: EXOC3L2 was added
gene: EXOC3L2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: EXOC3L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC3L2 were set to 30327448
Phenotypes for gene: EXOC3L2 were set to Dandy-Walker malformation
Added comment: Added to panel based on PMID:30327448: Shalata et al., 2019 report 3 fetuses from a family with homozygous variants in EXOC3L2 (missense p.Leu41Gln) and severe forms of Dandy-Walker that were detectable by prenatal ultrasound.
Sources: Literature
CAKUT v1.74 EXOC3L2 Rebecca Foulger commented on gene: EXOC3L2
CAKUT v1.74 EXOC3L2 Rebecca Foulger Publications for gene: EXOC3L2 were set to PMID: 30327448, 28749478, 27894351
CAKUT v1.73 DHCR7 Rebecca Foulger changed review comment from: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Amber. Renal phenotypes are only seen in approximately 25% of SLOS patients, and renal anomalies are more commonly detected prenatally than postnatally (PMID:23059950) so DHCR7 is more suited to the Fetal anomalies panel.; to: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Amber. Renal phenotypes are only seen in approximately 25% of SLOS patients, and renal anomalies are more commonly detected prenatally than postnatally (PMID:23059950) so DHCR7 is more appropriate for the Fetal anomalies panel.
CAKUT v1.73 DHCR7 Rebecca Foulger changed review comment from: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Amber. Renal phenotypes are only seen in approximately 25% of SLOS patients, and renal anomalies are more commonly detected prenatally than postnatally (PMID:23059950).; to: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Amber. Renal phenotypes are only seen in approximately 25% of SLOS patients, and renal anomalies are more commonly detected prenatally than postnatally (PMID:23059950) so DHCR7 is more suited to the Fetal anomalies panel.
CAKUT v1.73 DHCR7 Rebecca Foulger Classified gene: DHCR7 as Amber List (moderate evidence)
CAKUT v1.73 DHCR7 Rebecca Foulger Gene: dhcr7 has been classified as Amber List (Moderate Evidence).
CAKUT v1.72 DHCR7 Rebecca Foulger Classified gene: DHCR7 as No list
CAKUT v1.72 DHCR7 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Amber. Renal phenotypes are only seen in approximately 25% of SLOS patients, and renal anomalies are more commonly detected prenatally than postnatally (PMID:23059950).
CAKUT v1.72 DHCR7 Rebecca Foulger Gene: dhcr7 has been removed from the panel.
CAKUT v1.71 DHCR7 Rebecca Foulger commented on gene: DHCR7: PMID:9678700. Ryan et al., 1998 reviewed all known UK cases of SLOS. Half had been terminated or died in infancy. 14 (29%) had structural renal abnormalities.
CAKUT v1.71 DHCR7 Rebecca Foulger commented on gene: DHCR7: PMID:23059950. Nowaczyk and Irons, 2012 note that approximately 25% of affected individuals have renal anomalies (most common being renal hypoplasia or agenesis, renal cortical cysts, hydronephrosis and structural anomalies of the collecting system). They also note that renal anomalies are amongst the phenotypes seen more commonly prenatally than postnatally.
CAKUT v1.71 DHCR7 Rebecca Foulger commented on gene: DHCR7: PMID:10069707. Kratz and Kelley, 1999 report on prenatal diagnosis of SLOS. Fetal phenotypes included renal agenesis, renal pyelectasis, hydronephrosis (4 patients)
Fetal anomalies v1.27 DHCR7 Rebecca Foulger commented on gene: DHCR7: PMID:31840946 (Schoner et al., 2020) performed autopsies and DHCR7 gene analyses in 8 fetuses suspected of having SLOS. 5/9 fetuses presented with classic SLOS features including 4 with atrial/atrioventricular septal defects and renal anomalies, and one with additional bilateral renal agenesis and a Dandy-Walker cyst. Two fetuses were mildly affected and two fetuses showed additional holoprosencephaly. DHCR7 variants were confirmed in cases 1-5 and 7.
CAKUT v1.71 DHCR7 Rebecca Foulger Phenotypes for gene: DHCR7 were changed from Smith-Lemli-Opitz syndrome, MIM# 270400 to Smith-Lemli-Opitz syndrome, 270400; renal agenesis
CAKUT v1.70 DHCR7 Rebecca Foulger Publications for gene: DHCR7 were set to 3812577; 10069707; 23059950; 9678700
CAKUT v1.69 DHCR7 Rebecca Foulger commented on gene: DHCR7
Fetal anomalies v1.27 DHCR7 Rebecca Foulger Publications for gene: DHCR7 were set to
Early onset or syndromic epilepsy v2.43 CTU2 Rebecca Foulger Classified gene: CTU2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v2.43 CTU2 Rebecca Foulger Added comment: Comment on list classification: Added to panel as Amber: Sufficient cases of seizures but 1 patient shows febrile seizures, and phenotype is variable. Plus just one study so far. Therefore Amber is appropriate, awaiting further evidence.
Early onset or syndromic epilepsy v2.43 CTU2 Rebecca Foulger Gene: ctu2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v2.42 CTU2 Rebecca Foulger gene: CTU2 was added
gene: CTU2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CTU2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CTU2 were set to 31301155
Phenotypes for gene: CTU2 were set to seizures; DREAM‐PL syndrome; Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, 618142
Added comment: Added to panel based on PMID:31301155 (Shaheen et al., 2019) who characterise the phenotype of 5 patients with DREAM-PL syndrome (Dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly) and summarise 4 Founder patients from previous studies (PMID:27480277, PMID:26633546). In total 6/10 patients had seizures including Generalized epilepsy, atypical absence seizures, complex febriles seizures and focal epilepsy.
Sources: Literature
Intellectual disability v3.33 CTU2 Rebecca Foulger Classified gene: CTU2 as Green List (high evidence)
Intellectual disability v3.33 CTU2 Rebecca Foulger Added comment: Comment on list classification: Gene was added to panel and rated Green by Zornitza Stark. Sufficient cases of global DD in PMID:31301155 in patients that survived infancy to support causation. Therefore updated rating from Grey to Green.
Intellectual disability v3.33 CTU2 Rebecca Foulger Gene: ctu2 has been classified as Green List (High Evidence).
Intellectual disability v3.32 CTU2 Rebecca Foulger commented on gene: CTU2
Intellectual disability v3.32 CTU2 Rebecca Foulger Phenotypes for gene: CTU2 were changed from Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, MIM#618142 to DREAM‐PL syndrome; Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, 618142
CAKUT v1.69 CTU2 Rebecca Foulger Classified gene: CTU2 as Green List (high evidence)
CAKUT v1.69 CTU2 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Zornitza Stark. The Saudi cases all share a founder variant (PMIDs:26633546, 27480277) but a more recent study by the same authors (PMID:31301155) identifies a further 4 patients with a renal phenotype as part of DREAM‐PL syndrome, and new homozygous CTU2 variants. Therefore relevant renal phenotype and sufficient unrelated cases to support association.
CAKUT v1.69 CTU2 Rebecca Foulger Gene: ctu2 has been classified as Green List (High Evidence).
CAKUT v1.68 CTU2 Rebecca Foulger Phenotypes for gene: CTU2 were changed from Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, MIM#618142 to DREAM‐PL syndrome; Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, 618142
CAKUT v1.67 CTU2 Rebecca Foulger commented on gene: CTU2: PMID:31301155 (Shaheen et al., 2019) show that biallelic CTU2 variants cause DREAM-PL syndrome (dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly) in a further 5 patients. 4/5 patients had a renal phenotype. These 5 patients had different variants to the previously described founder variant, including Ala403Cysfs*23, Leu63Pro, p.Ile505Argfs*41.
CAKUT v1.67 CTU2 Rebecca Foulger commented on gene: CTU2: PMID:27480277 (Shaheen et al., 2016) identified 2 male cousins from the United Arab Emirates with the same founder T247T variant. This founder variant has a frequency of 1/769 in Saudi Arabia.
CAKUT v1.67 CTU2 Rebecca Foulger commented on gene: CTU2
CAKUT v1.67 CHRNA3 Rebecca Foulger Classified gene: CHRNA3 as Green List (high evidence)
CAKUT v1.67 CHRNA3 Rebecca Foulger Gene: chrna3 has been classified as Green List (High Evidence).
CAKUT v1.66 CHRNA3 Rebecca Foulger Classified gene: CHRNA3 as No list
CAKUT v1.66 CHRNA3 Rebecca Foulger Added comment: Comment on list classification: Gene was added to panel and rated Green by Zornitza Stark. Sufficient cases (3 unrelated families) from one paper, plus functional studies to support causation and therefore increased rating to Green.
CAKUT v1.66 CHRNA3 Rebecca Foulger Gene: chrna3 has been removed from the panel.
CAKUT v1.65 CHRNA3 Rebecca Foulger commented on gene: CHRNA3
COVID-19 research v0.171 IRF7 Rebecca Foulger Publications for gene: IRF7 were set to 26761402; 9315633; 32086639; 25814066; 32048120; 26621750; 31154625
COVID-19 research v0.170 IRF7 Rebecca Foulger Publications for gene: IRF7 were set to 26761402; 9315633; 32086639; 25814066; 32048120; 26621750
CAKUT v1.65 CHD1L Rebecca Foulger Tag missense tag was added to gene: CHD1L.
CAKUT v1.65 CHD1L Rebecca Foulger Classified gene: CHD1L as Amber List (moderate evidence)
CAKUT v1.65 CHD1L Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber. Although there are 8 families with CAKUT and CHD1L variants, all variants are missense, and there is limited family data available for the patients in PMID:22146311. Also in PMID:22146311, only 2/3 variants were absent from controls, Patient 2 variant was inherited from an asymptomatic mother, and the variant in Patient 3 is predicted benign.
CAKUT v1.65 CHD1L Rebecca Foulger Gene: chd1l has been classified as Amber List (Moderate Evidence).
CAKUT v1.64 CHD1L Rebecca Foulger commented on gene: CHD1L: PMID:32164334 show CNVs in genes including CHD1L in 6 CAKUT patients. One patient with bilateral renal cortical cysts and renal stones (ID 41) had a duplication of 1q21.1 encompassing CHD1L.
CAKUT v1.64 CHD1L Rebecca Foulger Publications for gene: CHD1L were set to 24429398; 22146311
CAKUT v1.63 CHD1L Rebecca Foulger changed review comment from: PMID:24429398 detected heterozygous variants in CHD1L in 5 families with CAKUT (p.P333R in 1 family, p.E400G in 1 family, p.I517M in 3 Indian families).; to: PMID:24429398 (2014) detected heterozygous variants in CHD1L in 5 families with CAKUT (p.P333R in 1 family, p.E400G in 1 family, p.I517M in 3 Indian families).
CAKUT v1.63 CHD1L Rebecca Foulger commented on gene: CHD1L: PMID:24429398 detected heterozygous variants in CHD1L in 5 families with CAKUT (p.P333R in 1 family, p.E400G in 1 family, p.I517M in 3 Indian families).
CAKUT v1.63 CHD1L Rebecca Foulger commented on gene: CHD1L
Primary immunodeficiency or monogenic inflammatory bowel disease v2.139 LIG1 Rebecca Foulger Classified gene: LIG1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.139 LIG1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green. Red review pre-dates paper PMID:30395541 which provides 5 patients (3 kindreds) for evidence of association with immunodeficiency. Although severity of phenotype is variable, just sufficient cases for inclusion.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.139 LIG1 Rebecca Foulger Gene: lig1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.138 LIG1 Rebecca Foulger commented on gene: LIG1
Primary immunodeficiency or monogenic inflammatory bowel disease v2.138 NLRP1 Rebecca Foulger commented on gene: NLRP1: PMID:27662089: Zhong et al., 2016 report germline GOF variants in NLRP1 which cause two overlapping skin disorders (MSPC and FKLC), linking NLRP1 to skin inflammatory syndromes.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.138 NLRP1 Rebecca Foulger commented on gene: NLRP1
Primary immunodeficiency or monogenic inflammatory bowel disease v2.138 OAS1 Rebecca Foulger Classified gene: OAS1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.138 OAS1 Rebecca Foulger Added comment: Comment on list classification: Updated from Red to Amber, awaiting clinical review.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.138 OAS1 Rebecca Foulger Gene: oas1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.137 OAS1 Rebecca Foulger commented on gene: OAS1
COVID-19 research v0.169 PAX1 Rebecca Foulger Classified gene: PAX1 as Green List (high evidence)
COVID-19 research v0.169 PAX1 Rebecca Foulger Gene: pax1 has been classified as Green List (High Evidence).
COVID-19 research v0.168 PAX1 Rebecca Foulger gene: PAX1 was added
gene: PAX1 was added to Viral susceptibility. Sources: Other,Literature
Mode of inheritance for gene: PAX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAX1 were set to 28657137; 32111619
Phenotypes for gene: PAX1 were set to Otofaciocervical syndrome 2, 615560; Syndromic SCID
Added comment: Added PAX1 to Viral susceptibility panel as Green to match recent addition of PAX1 to Primary immunodeficiency panel (Version 2.137).
Sources: Other, Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.137 PAX1 Rebecca Foulger Classified gene: PAX1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.137 PAX1 Rebecca Foulger Added comment: Comment on list classification: Added to panel and rated Green by Zornitza Stark. Updated rating from Grey to Green based on 2 papers (PMID:28657137 and PMID:32111619): 8 individuals from 4 unrelated families with SCID.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.137 PAX1 Rebecca Foulger Gene: pax1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.136 PAX1 Rebecca Foulger Phenotypes for gene: PAX1 were changed from Syndromic SCID; dysmorphism; ear abnormalities; otofaciocervical syndrome to Otofaciocervical syndrome 2, 615560; Syndromic SCID; dysmorphism; ear abnormalities; otofaciocervical syndrome
Primary immunodeficiency or monogenic inflammatory bowel disease v2.135 PAX1 Rebecca Foulger Publications for gene: PAX1 were set to 32111619
Primary immunodeficiency or monogenic inflammatory bowel disease v2.134 PAX1 Rebecca Foulger commented on gene: PAX1: PMID:28657137. Paganini et al., 2017 report a North African family with AR Otofaciocervical syndrome (OFCS). Two of the children died from severe combined immunodeficiency (SCID) and had nonsense homozygous variants in PAX1. Functional studies were not performed.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.134 PAX1 Rebecca Foulger commented on gene: PAX1
Primary immunodeficiency or monogenic inflammatory bowel disease v2.134 POLE Rebecca Foulger changed review comment from: PMID:23230001: 1 large consanguineous family with FILS syndrome (including immunodeficiency) and homozygous single bp substitution in POLE1.; to: PMID:23230001: 1 large consanguineous family with FILS syndrome (all but 2 patients suffered from immunodeficiency) and homozygous single bp substitution in POLE1.
Fetal anomalies v1.26 POLE Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Amber to Green: Multiple cases of IUGR from 2 papers (PMID:25948378 and PMID:30503519). Phenotype relevant to panel, and sufficient evidence to support causation.; to: Comment on list classification: Originally added to panel as Amber based on PMID:30503519. Updated rating from Amber to Green with curation of additional paper PMID:25948378 who report a separate individual with IUGR. Phenotype relevant to panel, and sufficient evidence to support causation.
Fetal anomalies v1.26 POLE Rebecca Foulger Deleted their comment
Fetal anomalies v1.26 POLE Rebecca Foulger Classified gene: POLE as Green List (high evidence)
Fetal anomalies v1.26 POLE Rebecca Foulger Gene: pole has been classified as Green List (High Evidence).
Fetal anomalies v1.25 POLE Rebecca Foulger Classified gene: POLE as Green List (high evidence)
Fetal anomalies v1.25 POLE Rebecca Foulger Gene: pole has been classified as Green List (High Evidence).
Fetal anomalies v1.24 POLE Rebecca Foulger Classified gene: POLE as Amber List (moderate evidence)
Fetal anomalies v1.24 POLE Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green: Multiple cases of IUGR from 2 papers (PMID:25948378 and PMID:30503519). Phenotype relevant to panel, and sufficient evidence to support causation.
Fetal anomalies v1.24 POLE Rebecca Foulger Gene: pole has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.23 POLE Rebecca Foulger Publications for gene: POLE were set to 23230001
Fetal anomalies v1.22 POLE Rebecca Foulger commented on gene: POLE: PMID:25948378 (Thiffault et al., 2015) report a girl homozygous for a splice variant in POLE1 (c.4444 + 3A > G). Fetal anomalies on the ultrasound included intrauterine growth restriction, short long bones, suspected skull abnormalities nad oligohydamnios.
Fetal anomalies v1.22 POLE Rebecca Foulger Phenotypes for gene: POLE were changed from IUGR; severe growth failure of prenatal onset to IUGR; severe growth failure of prenatal onset; FILS syndrome, 615139; facial dysmorphism, immunodeficiency, livedo, and short stature (FILS)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.134 POLE Rebecca Foulger Classified gene: POLE as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.134 POLE Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green following review by Zornitza Stark: >3 cases from 3 separate papers of individuals with biallelic POLE variants and a phenotype that includes immunodeficiency.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.134 POLE Rebecca Foulger Gene: pole has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.133 POLE Rebecca Foulger commented on gene: POLE: PMID:23230001: 1 large consanguineous family with FILS syndrome (including immunodeficiency) and homozygous single bp substitution in POLE1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.133 POLE Rebecca Foulger commented on gene: POLE: PMID:25948378 (Thiffault et al., 2015) report a girl with immune deficiency amongst her phenotypes. She was homozygous for a splice variant in POLE1 (c.4444 + 3A > G).
Fetal anomalies v1.21 POLE Rebecca Foulger Classified gene: POLE as Amber List (moderate evidence)
Fetal anomalies v1.21 POLE Rebecca Foulger Added comment: Comment on list classification: Added as Amber awaiting Clinical Review.
Fetal anomalies v1.21 POLE Rebecca Foulger Gene: pole has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.20 POLE Rebecca Foulger gene: POLE was added
gene: POLE was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: POLE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLE were set to 23230001
Phenotypes for gene: POLE were set to IUGR; severe growth failure of prenatal onset
Added comment: Added to panel based on prenatal phenotype reported in PMID:30503519: (Logan et al., 2018) report biallelic variants in POLE in 15 indivs from 12 families (mix of countries). All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. Phenotypically, affected individuals all had IUGR and severe growth failure of prenatal onset.
Sources: Literature
COVID-19 research v0.167 TP53 Sarah Leigh reviewed gene: TP53: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.133 POLE Rebecca Foulger commented on gene: POLE
COVID-19 research v0.167 TP53 Sarah Leigh Publications for gene: TP53 were set to 32086639; 32048120
COVID-19 research v0.166 CIB1 Sarah Leigh reviewed gene: CIB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.166 CIB1 Sarah Leigh Phenotypes for gene: CIB1 were changed from Epidermodysplasia verruciformis; Defects in intrinsic and innate immunity; CIB1 deficiency to Epidermodysplasia verruciformis 3 618267; Defects in intrinsic and innate immunity; CIB1 deficiency
CAKUT v1.63 TFAP2A Catherine Snow Publications for gene: TFAP2A were set to 21204207; 31160420
CAKUT v1.62 TFAP2A Catherine Snow Publications for gene: TFAP2A were set to 21204207; 31160420
CAKUT v1.62 TFAP2A Catherine Snow Publications for gene: TFAP2A were set to
CAKUT v1.61 TFAP2A Catherine Snow Classified gene: TFAP2A as Green List (high evidence)
CAKUT v1.61 TFAP2A Catherine Snow Added comment: Comment on list classification: TFAP2A identified by expert review. Phenotype for the gene disease association is mainly branchial cleft sinus defects, ocular anomalies such as microphthalmia and lacrimal duct obstruction and a dysmorphic facial appearance including cleft or pseudocleft lip/palate. However PMID: 21204207 - Genotype-phenotype Analysis of the Branchio-Oculo-Facial Syndrome states that renal anomalies, including dysplasia, agenesis,multicystic kidneys, and vesicoureteral reflux was seen in 12/34; 35% who had variants mainly in exon 4 &5 of the TFAP2A gene. Functional evidence PMID: 31160420 demonstrates that TFAP2A is involved in kidney development
CAKUT v1.61 TFAP2A Catherine Snow Gene: tfap2a has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.41 CACNA1H Sarah Leigh Publications for gene: CACNA1H were set to 12891677; 32227660
CAKUT v1.60 ZIC3 Catherine Snow Publications for gene: ZIC3 were set to
CAKUT v1.59 ZIC3 Catherine Snow Classified gene: ZIC3 as Green List (high evidence)
CAKUT v1.59 ZIC3 Catherine Snow Added comment: Comment on list classification: ZIC3 identified by expert review for the CAKUT panel. ZIC3 is associated with VATER/VACTERL. Renal malformations is a phenotype of this disorder. Phenotypic spectrum of ZIC3 mutation carriers is quite variable, with incomplete penetrance in males however sufficient number of unrelated cases with renal malformations for this to be classed as Green.
CAKUT v1.59 ZIC3 Catherine Snow Gene: zic3 has been classified as Green List (High Evidence).
Fetal anomalies v1.19 MYL9 Rebecca Foulger Publications for gene: MYL9 were set to
Fetal anomalies v1.18 MYL9 Rebecca Foulger Classified gene: MYL9 as Red List (low evidence)
Fetal anomalies v1.18 MYL9 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Red to match review by Rhiannon Mellis (GOSH).
Fetal anomalies v1.18 MYL9 Rebecca Foulger Gene: myl9 has been classified as Red List (Low Evidence).
Fetal anomalies v1.17 LMOD1 Rebecca Foulger Classified gene: LMOD1 as Red List (low evidence)
Fetal anomalies v1.17 LMOD1 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Red to match review by Rhiannon Mellis (GOSH).
Fetal anomalies v1.17 LMOD1 Rebecca Foulger Gene: lmod1 has been classified as Red List (Low Evidence).
Fetal anomalies v1.16 MYH11 Rebecca Foulger Publications for gene: MYH11 were set to
Fetal anomalies v1.15 MYH11 Rebecca Foulger Classified gene: MYH11 as Green List (high evidence)
Fetal anomalies v1.15 MYH11 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green to match review by Rhiannon Mellis (GOSH).
Fetal anomalies v1.15 MYH11 Rebecca Foulger Gene: myh11 has been classified as Green List (High Evidence).
Fetal anomalies v1.14 MYH11 Rebecca Foulger Added comment: Comment on mode of inheritance: Set mode of inheritance to BIALLELIC to match papers: compound het and homozygous MYH11 variants associated with MMIH.
Fetal anomalies v1.14 MYH11 Rebecca Foulger Mode of inheritance for gene: MYH11 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.13 MYLK Rebecca Foulger Publications for gene: MYLK were set to
Fetal anomalies v1.12 MYLK Rebecca Foulger Phenotypes for gene: MYLK were changed from Megacystis Microcolon Intestinal Hypoperistalsis Syndrome to Megacystis Microcolon Intestinal Hypoperistalsis Syndrome; MMIH
Fetal anomalies v1.11 MYL9 Rhiannon Mellis reviewed gene: MYL9: Rating: RED; Mode of pathogenicity: ; Publications: 29453416; Phenotypes: Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIH); Mode of inheritance:
Fetal anomalies v1.11 LMOD1 Rhiannon Mellis reviewed gene: LMOD1: Rating: RED; Mode of pathogenicity: ; Publications: 28292896; Phenotypes: Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIH); Mode of inheritance:
Fetal anomalies v1.11 MYH11 Rhiannon Mellis reviewed gene: MYH11: Rating: GREEN; Mode of pathogenicity: ; Publications: 25407000, 29575632, 31427716; Phenotypes: Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIH); Mode of inheritance:
Fetal anomalies v1.11 MYLK Rhiannon Mellis reviewed gene: MYLK: Rating: AMBER; Mode of pathogenicity: ; Publications: 28602422; Phenotypes: Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIH); Mode of inheritance:
Fetal anomalies v1.10 MYL9 Rebecca Foulger gene: MYL9 was added
gene: MYL9 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: MYL9 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MYL9 were set to Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIH)
Added comment: Added to panel as suggested by Rhiannon Mellis (GOSH).
Sources: Expert list
Fetal anomalies v1.9 LMOD1 Rebecca Foulger gene: LMOD1 was added
gene: LMOD1 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: LMOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: LMOD1 were set to Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIH)
Added comment: Added to panel as suggested by Rhiannon Mellis (GOSH).
Sources: Expert list
Fetal anomalies v1.8 MYH11 Rebecca Foulger gene: MYH11 was added
gene: MYH11 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: MYH11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MYH11 were set to Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIH)
Added comment: Added to panel as suggested by Rhiannon Mellis (GOSH).
Sources: Expert list
CAKUT v1.58 GREB1L John Sayer reviewed gene: GREB1L: Rating: GREEN; Mode of pathogenicity: None; Publications: 29220675, 29100091; Phenotypes: renal agenesis, uterus agenesis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.133 DNASE1L3 Catherine Snow Classified gene: DNASE1L3 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.133 DNASE1L3 Catherine Snow Added comment: Comment on list classification: Identified by expert review as Green. PMID: 30008451 reports a SLE patient with (c.289_290delAC/p.Thr97Ilefs*2) in DNASE1L3 in 1 patient. This variant had previously been reported in PMID: 23666765 for Hypocomplementemic Urticarial Vasculitis (HUVs) - Systemic lupus erythematosus (SLE) develops in >50% of patients with HUVS
Primary immunodeficiency or monogenic inflammatory bowel disease v2.133 DNASE1L3 Catherine Snow Gene: dnase1l3 has been classified as Green List (High Evidence).
COVID-19 research v0.165 ACE2 Rebecca Foulger commented on gene: ACE2: Preprint https://www.biorxiv.org/content/10.1101/2020.04.22.056127v1 show that ACE2 levels in the respiratory tract did not increase in association with risk factors for severe COVID-19 (e.g. age and underlying chronic comorbidities).
COVID-19 research v0.165 TMPRSS2 Rebecca Foulger commented on gene: TMPRSS2: Preprint http://biorxiv.org/cgi/content/short/2020.04.23.057190 analysed coding region variants in TMPRSS2 and the eQTL variants which may affect gene experssion. They suggest that lung-specific eQTL variants may confer different susceptibility or response to SARS-CoV-2 infection from different populations. In particular, we found that the regulatory region variant rs35074065 is associated with high expression of TMPRSS2 (but lower expression of MX1).
COVID-19 research v0.165 ACE2 Rebecca Foulger commented on gene: ACE2: Preprint https://www.biorxiv.org/content/10.1101/2020.04.24.050534v1 conclude that higher expression of ACE2 facilitated by natural variations (with different frequencies in different populations) results in ACE2 homo-dimerization which is disadvantageous for TMPRSS2 mediated cleavage of ACE2. They propose that monomeric ACE2 has higher preferential binding with SARS-CoV-2 S-Protein.
COVID-19 research v0.165 STAT2 Rebecca Foulger commented on gene: STAT2
COVID-19 research v0.165 TMPRSS2 Rebecca Foulger commented on gene: TMPRSS2: Preprint https://www.biorxiv.org/content/10.1101/2020.04.24.056259v2 suggests that ACE2 and TMPRSS2 co-expression in the prostate may explain sex differences in the observed COVID-19 disaparities.
COVID-19 research v0.165 ACE2 Rebecca Foulger commented on gene: ACE2: Preprint https://www.biorxiv.org/content/10.1101/2020.04.24.056259v2 suggests that ACE2 and TMPRSS2 co-expression in the prostate may explain sex differences in the observed COVID-19 disaparities.
COVID-19 research v0.165 IL18BP Rebecca Foulger commented on gene: IL18BP
COVID-19 research v0.165 IL18BP Rebecca Foulger Publications for gene: IL18BP were set to 32086639; 32048120; PubMed: 31213488
Primary immunodeficiency or monogenic inflammatory bowel disease v2.132 DBR1 Catherine Snow Classified gene: DBR1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.132 DBR1 Catherine Snow Added comment: Comment on list classification: DBR1 identified by expert review. DBR1 variants identified in unrelated patients from different ethnicities, each had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus
Primary immunodeficiency or monogenic inflammatory bowel disease v2.132 DBR1 Catherine Snow Gene: dbr1 has been classified as Green List (High Evidence).
COVID-19 research v0.164 CCR5 Ivone Leong Phenotypes for gene: CCR5 were changed from to {West nile virus, susceptibility to}, 610379; {HIV infection, susceptibility/resistance to}
Primary immunodeficiency or monogenic inflammatory bowel disease v2.131 DEF6 Catherine Snow Classified gene: DEF6 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.131 DEF6 Catherine Snow Added comment: Comment on list classification: Comment on list classification: Promoted from Red to Amber based on expert review. Insufficient individuals for DEF6 to be rated as Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.131 DEF6 Catherine Snow Gene: def6 has been classified as Amber List (Moderate Evidence).
Cytopenia - NOT Fanconi anaemia v1.6 EFL1 Catherine Snow Publications for gene: EFL1 were set to 29970384, 28331068
Cytopenia - NOT Fanconi anaemia v1.5 EFL1 Catherine Snow Classified gene: EFL1 as Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v1.5 EFL1 Catherine Snow Added comment: Comment on list classification: Upgrading to Green based on further individuals identified in publication PMID: 31151987
Cytopenia - NOT Fanconi anaemia v1.5 EFL1 Catherine Snow Gene: efl1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.130 EFL1 Catherine Snow Classified gene: EFL1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.130 EFL1 Catherine Snow Added comment: Comment on list classification: EFL1 identified by expert review. Promoting from Grey to Green, sufficient number of unrelated individuals with Shwachman-Diamond like syndrome.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.130 EFL1 Catherine Snow Gene: efl1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.129 ERBIN Catherine Snow Classified gene: ERBIN as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.129 ERBIN Catherine Snow Added comment: Comment on list classification: Promoted from Red to Amber based on expert review. Only one family identified and functional studies so will remain Amber.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.129 ERBIN Catherine Snow Gene: erbin has been classified as Amber List (Moderate Evidence).
Malformations of cortical development v2.5 EMX2 Zornitza Stark changed review comment from: Please note publication disputing gene-disease association.; to: Please note publication disputing gene-disease association. Also note only pathogenic variants in ClinVar are from 1996, all the rest are VOUS/LB.
Malformations of cortical development v2.5 EMX2 Zornitza Stark reviewed gene: EMX2: Rating: AMBER; Mode of pathogenicity: None; Publications: 18409201; Phenotypes: Schizencephaly, 269160; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
COVID-19 research v0.163 FCHO1 Sophie Hambleton reviewed gene: FCHO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30822429, 32098969; Phenotypes: combined immunodeficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.163 FANCM Sophie Hambleton reviewed gene: FANCM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.163 FANCL Sophie Hambleton reviewed gene: FANCL: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.163 FANCI Sophie Hambleton reviewed gene: FANCI: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi anaemia, bone marrow failure; Mode of inheritance: None
COVID-19 research v0.163 FANCG Sophie Hambleton reviewed gene: FANCG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.163 FANCF Sophie Hambleton reviewed gene: FANCF: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi anaemia, bone marrow failure; Mode of inheritance: None
COVID-19 research v0.163 FANCE Sophie Hambleton reviewed gene: FANCE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.163 FANCD2 Sophie Hambleton reviewed gene: FANCD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.163 FANCC Sophie Hambleton reviewed gene: FANCC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.163 FANCB Sophie Hambleton reviewed gene: FANCB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi anaemia, bone marrow failure; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
COVID-19 research v0.163 FANCA Sophie Hambleton reviewed gene: FANCA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi anaemia, bone marrow failure; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.163 ERCC4 Sophie Hambleton reviewed gene: ERCC4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: xeroderma pigmentosum, Fanconi anaemia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.163 ERBIN Sophie Hambleton reviewed gene: ERBIN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.163 TMPRSS2 Rebecca Foulger commented on gene: TMPRSS2: Preprint https://www.medrxiv.org/content/10.1101/2020.04.22.20074963v1 Lopera et al shows a LACK of association between genetic variants at ACE2 and TMPRSS2 and human quantitative phenotypes. The authors recognise that the SARS-CoV-2 virus uses ACE2 for cell invasion, and the serine protease TMPRSS2 for S protein priming and therefore they investigated whether genetic variation in these two genes modulates an individual's genetic predisposition to infection and virus clearance. They examined 178 quantitative phenotypes in relation to 1,273 genetic variants located in or near ACE2 and TMPRSS2: none reached the threshold for significance though these variants may play a role in diseases such as hypertension and chronic inflammation that are often observed in the more severe COVID-19 cases.
COVID-19 research v0.163 ACE2 Rebecca Foulger commented on gene: ACE2: Preprint https://www.medrxiv.org/content/10.1101/2020.04.22.20074963v1 Lopera et al shows a LACK of association between genetic variants at ACE2 and TMPRSS2 and human quantitative phenotypes. The authors recognise that the SARS-CoV-2 virus uses ACE2 for cell invasion, and the serine protease TMPRSS2 for S protein priming and therefore they investigated whether genetic variation in these two genes modulates an individual's genetic predisposition to infection and virus clearance. They examined 178 quantitative phenotypes in relation to 1,273 genetic variants located in or near ACE2 and TMPRSS2: none reached the threshold for significance though these variants may play a role in diseases such as hypertension and chronic inflammation that are often observed in the more severe COVID-19 cases.
Additional findings health related - CNV analysis adults v0.14 Eleanor Williams Panel name changed from Additional findings health related adult CNVs to Additional findings health related - CNV analysis adults
Additional findings health related - adults v0.18 Eleanor Williams Panel name changed from Additional findings health related adult to Additional findings health related -  adults
Additional findings health related - CNV analysis children v0.11 Eleanor Williams Panel name changed from Additional findings health related child CNVs to Additional findings health related - CNV analysis children
Additional findings health related - CNV analysis adult specific v0.16 Eleanor Williams Panel name changed from Additional findings health related adult additional CNVs to Additional findings health related - CNV analysis adult specific
COVID-19 research v0.163 EFL1 Sophie Hambleton reviewed gene: EFL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.163 DEF6 Sophie Hambleton reviewed gene: DEF6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immune dysregulation, combined immunodeficiency, autoimmunity, autoimmune enteropathy, dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Additional findings health related - children v0.13 Eleanor Williams Panel name changed from Additional findings health related child to Additional findings health related - children
COVID-19 research v0.163 DBR1 Sophie Hambleton reviewed gene: DBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29474921; Phenotypes: Susceptibility to viral encephalitis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Additional findings health related - adult specific v0.15 Eleanor Williams Panel name changed from Additional findings health related adult additional genes to Additional findings health related - adult specific
COVID-19 research v0.163 BRIP1 Sophie Hambleton reviewed gene: BRIP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.163 CIB1 Sophie Hambleton reviewed gene: CIB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.163 C17orf62 Sophie Hambleton reviewed gene: C17orf62: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: chronic granulomatous disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.163 CCL2 Sophie Hambleton reviewed gene: CCL2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v0.163 ARHGEF1 Sophie Hambleton reviewed gene: ARHGEF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.163 ALPI Sophie Hambleton reviewed gene: ALPI: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: inflammatory bowel disease; Mode of inheritance: None
COVID-19 research v0.163 ACE2 Sophie Hambleton reviewed gene: ACE2: Rating: AMBER; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v0.163 CTSB Eleanor Williams changed review comment from: The Covid-19 cell atlas (https://www.covid19cellatlas.org/) lists this gene as a COVID-19/SARS-CoV-2 entry-associated gene.
I cannot find reference to the gene in the two publications listed though PMID: 32142651 and 32015507.
Sources: Other; to: The Covid-19 cell atlas (https://www.covid19cellatlas.org/) lists this gene as a COVID-19/SARS-CoV-2 entry-associated gene.
PMID: 32142651 - Hoffman et al 2020 - Cell journal - CatB/L involved in S protein priming.
COVID-19 research v0.163 CTSL Eleanor Williams changed review comment from: The Covid-19 cell atlas (https://www.covid19cellatlas.org/) lists this gene as a COVID-19/SARS-CoV-2 entry-associated gene.
I cannot find reference to the gene in the two publications listed though PMID: 32142651 and 32015507.
Sources: Other; to: The Covid-19 cell atlas (https://www.covid19cellatlas.org/) lists this gene as a COVID-19/SARS-CoV-2 entry-associated gene.
PMID: 32142651 - Hoffman et al 2020 - Cell journal - CatB/L involved in S protein priming.
COVID-19 research v0.163 CTSL Eleanor Williams gene: CTSL was added
gene: CTSL was added to Viral susceptibility. Sources: Other
Mode of inheritance for gene: CTSL was set to Unknown
Added comment: The Covid-19 cell atlas (https://www.covid19cellatlas.org/) lists this gene as a COVID-19/SARS-CoV-2 entry-associated gene.
I cannot find reference to the gene in the two publications listed though PMID: 32142651 and 32015507.
Sources: Other
COVID-19 research v0.162 CTSB Eleanor Williams gene: CTSB was added
gene: CTSB was added to Viral susceptibility. Sources: Other
Mode of inheritance for gene: CTSB was set to Unknown
Added comment: The Covid-19 cell atlas (https://www.covid19cellatlas.org/) lists this gene as a COVID-19/SARS-CoV-2 entry-associated gene.
I cannot find reference to the gene in the two publications listed though PMID: 32142651 and 32015507.
Sources: Other
COVID-19 research v0.161 ACE2 Eleanor Williams changed review comment from: PMID: 32015507 - Zhou et al 2020 - Nature article. Confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.; to: PMID: 32015507 - Zhou et al 2020 - Nature article. Confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.

PMID: 32142651 - Hoffman et al 2020 - demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry
COVID-19 research v0.161 ACE2 Eleanor Williams Publications for gene: ACE2 were set to 14647384; 15897467; 16007097; 32142651
COVID-19 research v0.160 ACE2 Eleanor Williams edited their review of gene: ACE2: Added comment: PMID: 32015507 - Zhou et al 2020 - Nature article. Confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.; Changed publications: 32015507
Intellectual disability v3.31 CDK19 Zornitza Stark reviewed gene: CDK19: Rating: GREEN; Mode of pathogenicity: None; Publications: 32330417; Phenotypes: Intellectual disability, epileptic encephalopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
COVID-19 research v0.160 ABO Owen Siggs gene: ABO was added
gene: ABO was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: ABO was set to Other
Publications for gene: ABO were set to 15784866
Review for gene: ABO was set to AMBER
Added comment: Preliminary suggestion from preprints (https://www.medrxiv.org/content/10.1101/2020.03.11.20031096v2 & https://www.preprints.org/manuscript/202003.0356/v1) that ABO blood group may influence susceptibility to SARS-CoV-2 infection. Other preliminary evidence that ABO blood group may also influence susceptibility to SARS-CoV infection (PMID: 15784866). Both yet to be replicated, but suggest individuals of blood group O to be at lower risk of infection.
Sources: Literature
Fetal anomalies v1.7 PAICS Zornitza Stark gene: PAICS was added
gene: PAICS was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PAICS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAICS were set to 31600779
Phenotypes for gene: PAICS were set to Polyhydramnios; multiple congenital abnormalities
Review for gene: PAICS was set to RED
Added comment: Two sibs from single family reported with homozygous missense variant. Functional data to demonstrate effect on protein function.
Sources: Literature
COVID-19 research v0.160 TLR3 Abdelazeem Elhabyan edited their review of gene: TLR3: Added comment: I forgot to add severe influenza pneumonia in the associated phenotype in the previous comment; Changed phenotypes: Herpes simplex encephalitis predisposition , severe influenza Pneumonia ,HIV resistance to infection
COVID-19 research v0.160 TLR3 Abdelazeem Elhabyan changed review comment from: These studies demonstrate the deleterious effect of some TLR3 mutations and predisposition to Herpes simplex encephalitis in 4 separate studies on unrelated patients from different countries. TLR3 mutations in 3 children were associated with severe influenza pneumonitis. Finally, 2 other studies evaluate the protective effect of a common polymorphism of TLR3 against HIV infection in repetitively exposed individuals. Accordingly, we might find protective or deleterious effects in COVID19 patients due to different mutations of TLR3.

TLR3 is a receptor for dsRNA (intermediate in the replication of many viruses including HSV) which induces IFN response to prevent the cytopathic effects of different viruses. A heterozygous dominant-negative mutation of TLR3 was discovered in 2 unrelated children with HSE. TLR3 mutant fibroblasts from the 2 patients were infected by HSV-1 and vesicular stomatitis virus(VSV).IFNB and IFNL production were impaired in those cells, viral replication was higher and cell survival was lower in the 2 patients' cells when compared with the controls. Blood leukocyte response normally with to poly (I:C) which explains why the disease is not disseminated and also explains the redundant role of TLR3 in blood cells(13).
Similar findings were reported in a polish child in 2011, however, the patient here was compound heterozygous for a missense mutation leading to autosomal recessive inheritance of TLR3 deficiency(14).
Treatment with IFN alpha and beta canceled the effect of the dominant-negative mutation increasing the causality relationship between TLR3 mutants and viral immune response(13).
Relatives of the 2 patients with the same mutation did not show decreased interferon response nor they showed HSE as a complication of HSV which means that this mutation does not have full penetrance(13).

In another study, 110 patients with HSE were sequenced (exons of TLR3) to establish a new association of TLR3 mutations and HSE. The study reported 5 novel variants other than those previously described in the literature. 2 of them were not pathogenically demonstrated by in vitro studies while 3 of them were pathogenic with similar findings to those described above. Additionally, they found 3 patients with the same mutations previously described in the literature so the total of patients with deleterious TLR3 mutations would be 6 out of 110. 4 of those 6 patients(66%) with TLR6 mutations had a relapse In contrast to 12 out of 120(total cohort) (10%)(15).

In a recent study done on 16 patients with adult-onset HSE using whole-exome sequencing(WES), 1 patient was discovered to have TLR3 deficiency, while 8 other patients had mutations in other genes in the TLR3 pathway(2 patients with a mutation in IRF3, 2 patients with mutations in STAT1, 2 patients with mutations in TRIF, 1 patient with a mutation in TYK2,1 patients with a mutation in MAVS, and finally 1 patient with a mutation in TBK1)(16)

A common polymorphism in TLR3(rs3775291) was linked to increased resistance to HIV1 infection by the genotyping study of Spanish and Italian cohorts with a P value of .023 and .029 respectively. The study compared HIV exposed seronegative cohort(IV drug abuse and sexually active ) with controls. Repetitive HIV exposure in the cohort was evidenced by HCV seropositivity. In vitro infection of PBMCs with HIV showed increased resistance in cells carrying the allele and also TLR3 stimulation by TLR3 agonists showed an increased level of expression of CD69, IL-6, and CCL3(17).

A similar study was conducted on the Caucasian population showing the protective effect of the allele against HIV infection(18).

Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients’ iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I, and/or III IFN–mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature(PMID: 31217193
)




13.Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522–1527. doi:10.1126/science.1139522

14.Guo Y, Audry M, Ciancanelli M, et al. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med. 2011;208(10):2083–2098. doi:10.1084/jem.20101568

15.Lim HK, Seppänen M, Hautala T, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology. 2014;83(21):1888–1897. doi:10.1212/WNL.0000000000000999

16.Mørk N, Kofod-Olsen E, Sørensen KB, et al. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun. 2015;16(8):552–566. doi:10.1038/gene.2015.46

17.Sironi M, Biasin M, Cagliani R, et al. A common polymorphism in TLR3 confers natural resistance to HIV-1 infection. J Immunol. 2012;188(2):818–823. doi:10.4049/jimmunol.1102179

18.Huik K, Avi R, Pauskar M, et al. Association between TLR3 rs3775291 and resistance to HIV among highly exposed Caucasian intravenous drug users. Infect Genet Evol. 2013;20:78–82. doi:10.1016/j.meegid.2013.08.008

19.Lim HK, Huang SXL, Chen J, et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med. 2019;216(9):2038–2056. doi:10.1084/jem.20181621; to: These studies demonstrate the deleterious effect of some TLR3 mutations and predisposition to Herpes simplex encephalitis in 4 separate studies on unrelated patients from different countries. TLR3 mutations in 3 children were associated with severe influenza pneumonitis. Finally, 2 other studies evaluate the protective effect of a common polymorphism of TLR3 against HIV infection in repetitively exposed individuals. Accordingly, we might find protective or deleterious effects in COVID19 patients due to different mutations of TLR3.

TLR3 is a receptor for dsRNA (intermediate in the replication of many viruses including HSV) which induces IFN response to prevent the cytopathic effects of different viruses. A heterozygous dominant-negative mutation of TLR3 was discovered in 2 unrelated children with HSE. TLR3 mutant fibroblasts from the 2 patients were infected by HSV-1 and vesicular stomatitis virus(VSV).IFNB and IFNL production were impaired in those cells, viral replication was higher and cell survival was lower in the 2 patients' cells when compared with the controls. Blood leukocyte response normally with to poly (I:C) which explains why the disease is not disseminated and also explains the redundant role of TLR3 in blood cells(13).
Similar findings were reported in a polish child in 2011, however, the patient here was compound heterozygous for a missense mutation leading to autosomal recessive inheritance of TLR3 deficiency(14).
Treatment with IFN alpha and beta canceled the effect of the dominant-negative mutation increasing the causality relationship between TLR3 mutants and viral immune response(13).
Relatives of the 2 patients with the same mutation did not show decreased interferon response nor they showed HSE as a complication of HSV which means that this mutation does not have full penetrance(13).

In another study, 110 patients with HSE were sequenced (exons of TLR3) to establish a new association of TLR3 mutations and HSE. The study reported 5 novel variants other than those previously described in the literature. 2 of them were not pathogenically demonstrated by in vitro studies while 3 of them were pathogenic with similar findings to those described above. Additionally, they found 3 patients with the same mutations previously described in the literature so the total of patients with deleterious TLR3 mutations would be 6 out of 110. 4 of those 6 patients(66%) with TLR6 mutations had a relapse In contrast to 12 out of 120(total cohort) (10%)(15).

In a recent study done on 16 patients with adult-onset HSE using whole-exome sequencing(WES), 1 patient was discovered to have TLR3 deficiency, while 8 other patients had mutations in other genes in the TLR3 pathway(2 patients with a mutation in IRF3, 2 patients with mutations in STAT1, 2 patients with mutations in TRIF, 1 patient with a mutation in TYK2,1 patients with a mutation in MAVS, and finally 1 patient with a mutation in TBK1)(16)

A common polymorphism in TLR3(rs3775291) was linked to increased resistance to HIV1 infection by the genotyping study of Spanish and Italian cohorts with a P value of .023 and .029 respectively. The study compared HIV exposed seronegative cohort(IV drug abuse and sexually active ) with controls. Repetitive HIV exposure in the cohort was evidenced by HCV seropositivity. In vitro infection of PBMCs with HIV showed increased resistance in cells carrying the allele and also TLR3 stimulation by TLR3 agonists showed an increased level of expression of CD69, IL-6, and CCL3(17).

A similar study was conducted on the Caucasian population showing the protective effect of the allele against HIV infection(18).

Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients’ iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I, and/or III IFN–mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature(PMID: 31217193
)




13.Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522–1527. doi:10.1126/science.1139522

14.Guo Y, Audry M, Ciancanelli M, et al. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med. 2011;208(10):2083–2098. doi:10.1084/jem.20101568

15.Lim HK, Seppänen M, Hautala T, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology. 2014;83(21):1888–1897. doi:10.1212/WNL.0000000000000999

16.Mørk N, Kofod-Olsen E, Sørensen KB, et al. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun. 2015;16(8):552–566. doi:10.1038/gene.2015.46

17.Sironi M, Biasin M, Cagliani R, et al. A common polymorphism in TLR3 confers natural resistance to HIV-1 infection. J Immunol. 2012;188(2):818–823. doi:10.4049/jimmunol.1102179

18.Huik K, Avi R, Pauskar M, et al. Association between TLR3 rs3775291 and resistance to HIV among highly exposed Caucasian intravenous drug users. Infect Genet Evol. 2013;20:78–82. doi:10.1016/j.meegid.2013.08.008

19.Lim HK, Huang SXL, Chen J, et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med. 2019;216(9):2038–2056. doi:10.1084/jem.20181621
COVID-19 research v0.160 TLR3 Abdelazeem Elhabyan reviewed gene: TLR3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Herpes simplex encephalitis predisposition , HIV resistance to infection; Mode of inheritance: Other
COVID-19 research v0.160 UNC93B1 Abdelazeem Elhabyan reviewed gene: UNC93B1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Other
COVID-19 research v0.160 PHB2 Rebecca Foulger gene: PHB2 was added
gene: PHB2 was added to Viral susceptibility. Sources: Other,Literature
Mode of inheritance for gene: PHB2 was set to Unknown
Added comment: Added to panel based on presence in UniProt COVID portal: https://covid-19.uniprot.org/uniprotkb/Q99623
Sources: Other, Literature
COVID-19 research v0.159 DDX1 Rebecca Foulger gene: DDX1 was added
gene: DDX1 was added to Viral susceptibility. Sources: Other,Literature
Mode of inheritance for gene: DDX1 was set to Unknown
Publications for gene: DDX1 were set to 20573827
Added comment: Added to panel based on presence in UniProt COVID portal: https://covid19.uniprot.org/uniprotkb/Q92499. The cellular RNA helicase DDX1 interacts with coronavirus nonstructural protein 14 and enhances viral replication (PMID:20573827).
Sources: Other, Literature
COVID-19 research v0.158 MPP5 Rebecca Foulger gene: MPP5 was added
gene: MPP5 was added to Viral susceptibility. Sources: Other,Literature
Mode of inheritance for gene: MPP5 was set to Unknown
Publications for gene: MPP5 were set to 20861307
Added comment: Added to panel based on presence in the UniProt COVID portal (https://covid-19.uniprot.org/uniprotkb/Q8N3R9). Acts as an interaction partner for human SARS coronavirus envelope protein E (MPP5 aka PALS1) (PMID:20861307).
Sources: Other, Literature
COVID-19 research v0.157 SMAD3 Rebecca Foulger gene: SMAD3 was added
gene: SMAD3 was added to Viral susceptibility. Sources: Other,Literature
Mode of inheritance for gene: SMAD3 was set to Unknown
Publications for gene: SMAD3 were set to 18055455
Added comment: Added to panel based on presence in the UniProt COVID portal: https://covid-19.uniprot.org/uniprotkb/P84022. SMAD3 interacts with SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein (PMID:18055455).
Sources: Other, Literature
COVID-19 research v0.156 CCL11 Sarah Leigh Publications for gene: CCL11 were set to
COVID-19 research v0.155 CCL11 Sarah Leigh Classified gene: CCL11 as Red List (low evidence)
COVID-19 research v0.155 CCL11 Sarah Leigh Added comment: Comment on list classification: A cytokine (inflammatory biomarker), that is released in response to viral infections. Increased levels of CCL11 amongst other cytokines, is associated with immunity to West Nile virus (PMID 30915442). A haplotype that included c.-1385G>A was associated with resistance to HIV-1 infection (PMID 14571188).
COVID-19 research v0.155 CCL11 Sarah Leigh Gene: ccl11 has been classified as Red List (Low Evidence).
COVID-19 research v0.154 PHB Rebecca Foulger gene: PHB was added
gene: PHB was added to Viral susceptibility. Sources: Other
Mode of inheritance for gene: PHB was set to Unknown
Added comment: Added to panel based on presence in the UniProt COVID portal: https://covid-19.uniprot.org/uniprotkb/P35232.
Sources: Other
COVID-19 research v0.153 ITGAL Rebecca Foulger gene: ITGAL was added
gene: ITGAL was added to Viral susceptibility. Sources: Literature,Other
Mode of inheritance for gene: ITGAL was set to Unknown
Publications for gene: ITGAL were set to 18020948
Added comment: Added to panel based on presence in the UniProt COVID portal:
https://covid-19.uniprot.org/uniprotkb/P20701. Data in PMID:18020948 suggests ITGAL (LFA-1) to be an attachment factor or the receptor for SARS-CoV on human leukocytes. Kept rating as Red awaiting Expert Review.
Sources: Literature, Other
COVID-19 research v0.152 SGTA Rebecca Foulger Classified gene: SGTA as Red List (low evidence)
COVID-19 research v0.152 SGTA Rebecca Foulger Added comment: Comment on list classification: Kept rating as Red awaiting expert review. Role for protein in viral infection, but no population studies/SNP analyses yet.
COVID-19 research v0.152 SGTA Rebecca Foulger Gene: sgta has been classified as Red List (Low Evidence).
COVID-19 research v0.151 SGTA Rebecca Foulger gene: SGTA was added
gene: SGTA was added to Viral susceptibility. Sources: Other
Mode of inheritance for gene: SGTA was set to Unknown
Publications for gene: SGTA were set to 28356524; 24675744
Added comment: Added to panel based on presence in the UniProt COVID portal (https://covid-19.uniprot.org/uniprotkb/O43765). In case of infection by polyomavirus, involved in the virus endoplasmic reticulum membrane penetration and infection via protein interactions.
Sources: Other
COVID-19 research v0.150 ADAM17 Rebecca Foulger Publications for gene: ADAM17 were set to 22010916; 20603312; 25058236; 32086639; 11149563; 28930861; 32048120; 25171914
COVID-19 research v0.149 ACE2 Rebecca Foulger Classified gene: ACE2 as Green List (high evidence)
COVID-19 research v0.149 ACE2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green. Multiple functional data demonstrates a role for ACE2 as a receptor for Coronaviruses. Plus a vast amount of preprint data that suggests SNPs in ACE2 should be explored for regional differences.
COVID-19 research v0.149 ACE2 Rebecca Foulger Gene: ace2 has been classified as Green List (High Evidence).
COVID-19 research v0.148 TMPRSS2 Rebecca Foulger Classified gene: TMPRSS2 as Green List (high evidence)
COVID-19 research v0.148 TMPRSS2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green on this research panel: Known mechanisms for involvement in viral infection (including proteolytic cleavage of the viral receptor, ACE2) plus variants identified in preprints as candidates for COVID-19 severity.
COVID-19 research v0.148 TMPRSS2 Rebecca Foulger Gene: tmprss2 has been classified as Green List (High Evidence).
COVID-19 research v0.147 TMPRSS2 Rebecca Foulger commented on gene: TMPRSS2
COVID-19 research v0.147 TMPRSS2 Rebecca Foulger Publications for gene: TMPRSS2 were set to 31488196; 32142651; 24227843
COVID-19 research v0.146 TMPRSS2 Rebecca Foulger Publications for gene: TMPRSS2 were set to 31488196
COVID-19 research v0.145 ACE2 Rebecca Foulger commented on gene: ACE2: ACE2 gene present in the UniProt COVID portal (https://covid-19.uniprot.org/ 6-April-2020) which provides the latest available pre-release UniProtKB data for the SARS-CoV-2 coronavirus and other entries relating to the COVID-19 outbreak.
COVID-19 research v0.145 IL23A Rebecca Foulger commented on gene: IL23A
COVID-19 research v0.145 IL23A Rebecca Foulger Publications for gene: IL23A were set to
COVID-19 research v0.144 IL22 Rebecca Foulger Classified gene: IL22 as Red List (low evidence)
COVID-19 research v0.144 IL22 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Red: mouse model in PMID:22952908 suggests IL22 deficiency promotes resistance. IL22 administration in PMID:25395539 report possible viral protection.
COVID-19 research v0.144 IL22 Rebecca Foulger Gene: il22 has been classified as Red List (Low Evidence).
COVID-19 research v0.143 IL22 Rebecca Foulger commented on gene: IL22: Mouse model in PMID:22952908: Il22(-/-) mice were more resistant to lethal West Nile virus (WNV) encephalitis.
Hereditary neuropathy or pain disorder v1.4 JAG1 Zornitza Stark gene: JAG1 was added
gene: JAG1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: JAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAG1 were set to 32065591; 25707699
Phenotypes for gene: JAG1 were set to Peripheral neuropathy
Mode of pathogenicity for gene: JAG1 was set to Other
Review for gene: JAG1 was set to GREEN
Added comment: Two unrelated families reported with CMT type 2. Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Pre-existing rat model.
Sources: Literature
COVID-19 research v0.141 FURIN Eleanor Williams gene: FURIN was added
gene: FURIN was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: FURIN was set to Unknown
Added comment: Preprint - https://doi.org/10.1101/2020.04.18.047951- Zhong et al
Found Furin is expressed in oral mucosal cells. A Furin cutting site has been identified in SARS-CoV-2 (https://doi.org/10.1101/2020.02.10.942185 - preprint)
Sources: Literature
COVID-19 research v0.140 ACE2 Eleanor Williams changed review comment from: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al
Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al
Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al
Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the
virus to infect the host cell.

Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko
Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants.

Preprint - https://www.medrxiv.org/content/10.1101/2020.04.03.20047977v1 - Renieri et al
Using the Network of Italian Genomes (NIG), they mined around 7000 exomes from 5 different Centers looking for ACE2 variants. Identified variants with a potential impact on protein stability. 3 missense changed identified that have never been reported in the Eastern Asia population, were predicted to interfere with protein cleavage and stabilization. Rare truncating variants that are likely to interfere with the internalization process and one missense variant, p.Trp69Cys, predicted to interfere with 2019-nCov spike protein binding were also observed.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.12.037580v1 - Asseleta et al
ACE2 SNP rs2285666 (also called G8790A), more common in Italians and Europeans that East Asians. This variant was extensively studied as a potential risk factor for hypertension, type 2 diabetes, and coronary artery disease hence possibly constituting a predisposing factor also for the comorbidities observed in COVID-19 patients.
; to: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al
Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al
Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al
Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the
virus to infect the host cell.

Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko
Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants.

Preprint - https://www.medrxiv.org/content/10.1101/2020.04.03.20047977v1 - Renieri et al
Using the Network of Italian Genomes (NIG), they mined around 7000 exomes from 5 different Centers looking for ACE2 variants. Identified variants with a potential impact on protein stability. 3 missense changed identified that have never been reported in the Eastern Asia population, were predicted to interfere with protein cleavage and stabilization. Rare truncating variants that are likely to interfere with the internalization process and one missense variant, p.Trp69Cys, predicted to interfere with 2019-nCov spike protein binding were also observed.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.12.037580v1 - Asselta et al
ACE2 SNP rs2285666 (also called G8790A), more common in Italians and Europeans that East Asians. This variant was extensively studied as a potential risk factor for hypertension, type 2 diabetes, and coronary artery disease hence possibly constituting a predisposing factor also for the comorbidities observed in COVID-19 patients.
COVID-19 research v0.140 ACE2 Eleanor Williams changed review comment from: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al
Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al
Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al
Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the
virus to infect the host cell.

Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko
Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants.

Preprint - https://www.medrxiv.org/content/10.1101/2020.04.03.20047977v1 - Renieri et al
Using the Network of Italian Genomes (NIG), they mined around 7000 exomes from 5 different Centers looking for ACE2 variants. Identified variants with a potential impact on protein stability. 3 missense changed identified that have never been reported in the Eastern Asia population, were predicted to interfere with protein cleavage and stabilization. Rare truncating variants that are likely to interfere with the internalization process and one missense variant, p.Trp69Cys, predicted to interfere with 2019-nCov spike protein binding were also observed.
; to: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al
Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al
Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al
Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the
virus to infect the host cell.

Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko
Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants.

Preprint - https://www.medrxiv.org/content/10.1101/2020.04.03.20047977v1 - Renieri et al
Using the Network of Italian Genomes (NIG), they mined around 7000 exomes from 5 different Centers looking for ACE2 variants. Identified variants with a potential impact on protein stability. 3 missense changed identified that have never been reported in the Eastern Asia population, were predicted to interfere with protein cleavage and stabilization. Rare truncating variants that are likely to interfere with the internalization process and one missense variant, p.Trp69Cys, predicted to interfere with 2019-nCov spike protein binding were also observed.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.12.037580v1 - Asseleta et al
ACE2 SNP rs2285666 (also called G8790A), more common in Italians and Europeans that East Asians. This variant was extensively studied as a potential risk factor for hypertension, type 2 diabetes, and coronary artery disease hence possibly constituting a predisposing factor also for the comorbidities observed in COVID-19 patients.
Monogenic hearing loss v2.8 ABCC1 Zornitza Stark gene: ABCC1 was added
gene: ABCC1 was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: ABCC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ABCC1 were set to 31273342
Phenotypes for gene: ABCC1 were set to Nonsyndromic hearing loss
Review for gene: ABCC1 was set to AMBER
Added comment: Total of 3 variants reported in 3 families with post lingual ADSNHL, including 1 which segregates in a large family (10 affected)

The variant identified in the large multiplex family is present in gnomAD (10 hets), but onset noted to be in 2nd or 3rd decade of life. Functional studies performed. Other 2 variants reported absent in gnomAD. In light of gnomad frequency of one of the variants, suggest Amber rating.
Sources: Literature
COVID-19 research v0.140 DMBT1 Eleanor Williams gene: DMBT1 was added
gene: DMBT1 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: DMBT1 was set to Unknown
Review for gene: DMBT1 was set to RED
Added comment: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.16.045617v1 - Han et al
Found using single cell transcriptomics that DMBT1 (a viral binding scavenger) was highly expressed in alveolar type II cells relative to other lung epithelial subsets and its expression positively correlated with ACE2.
Sources: Literature
Intellectual disability v3.31 GNAI2 Zornitza Stark gene: GNAI2 was added
gene: GNAI2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GNAI2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GNAI2 were set to 31036916; 27787898
Phenotypes for gene: GNAI2 were set to Syndromic intellectual disability
Review for gene: GNAI2 was set to AMBER
Added comment: Two individuals reported, some functional data.
Sources: Literature
Intellectual disability v3.31 FEM1B Zornitza Stark gene: FEM1B was added
gene: FEM1B was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FEM1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FEM1B were set to 31036916
Phenotypes for gene: FEM1B were set to Syndromic intellectual disability
Review for gene: FEM1B was set to AMBER
Added comment: PMID: 31036916 - a single individual with de novo variant reported in a neurodevelopmental disorder cohort. Authors note another de novo case with the exact same variant (p.Arg126Gln) from the DDD study, and a 3rd patient from GeneMatcher with the same de novo missense again. The variant is in a highly constrained region of the protein. Cannot be certain the DDD and GeneMatcher individuals are unrelated, therefore I have treated as two reports for now.
Sources: Literature
Intellectual disability v3.31 WIPI2 Zornitza Stark gene: WIPI2 was added
gene: WIPI2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: WIPI2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WIPI2 were set to 30968111
Phenotypes for gene: WIPI2 were set to Intellectual developmental disorder with short stature and variable skeletal anomalies 618453
Review for gene: WIPI2 was set to RED
Added comment: Four homozygous individuals from one consanguineous family with intellectual disability, short stature and variable skeletal anomalies. Functional studies in patient cells showed impaired protein function. One to watch.
Sources: Literature
Ataxia and cerebellar anomalies - childhood onset v2.6 SLC44A1 Zornitza Stark gene: SLC44A1 was added
gene: SLC44A1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature
Mode of inheritance for gene: SLC44A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC44A1 were set to 31855247
Phenotypes for gene: SLC44A1 were set to progressive ataxia; tremor; cognitive decline; dysphagia; optic atrophy; dysarthria
Review for gene: SLC44A1 was set to GREEN
Added comment: Childhood neurodegenerative condition. Four affected individuals from three families with homozygous frameshift variants reported. Functional evidence points to impaired choline transporter function yet unchanged membrane phosphatidylcholine content. Choline treatments may be beneficial. Suggest adding to optic neuropathy and possibly other panels, including severe paediatric disorders.
Sources: Literature
Intellectual disability v3.31 GSX2 Zornitza Stark gene: GSX2 was added
gene: GSX2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: GSX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GSX2 were set to 31412107
Phenotypes for gene: GSX2 were set to Diencephalic-mesencephalic junction dysplasia syndrome 2 618646; Intellectual disability; Dystonia; Spastic tetra paresis
Review for gene: GSX2 was set to AMBER
Added comment: Two unrelated families, some functional data.
Sources: Literature
COVID-19 research v0.139 LY6E Eleanor Williams gene: LY6E was added
gene: LY6E was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: LY6E was set to Unknown
Review for gene: LY6E was set to RED
Added comment: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.02.021469v1 - Zhao et al
Found that human cell line C3A was more susceptible to human coronavirus HCoV-OC43 infection than HepG2. Ectopic expression of LY6E in HEK 293 cells inhibited the entry of HCoV-OC43. Overexpression of LY6E in C3A and A549 cells efficiently inhibited the infection of HCoV-OC43 and knockdown of LY6E expression in HepG2 significantly increased its susceptibility to HCoV-OC43 infection. LY6E also restricted the entry mediated by the envelope spike proteins of other human coronaviruses, including the currently pandemic SARS-CoV-2.
Sources: Literature
COVID-19 research v0.138 ACE2 Eleanor Williams changed review comment from: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al
Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al
Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al
Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the
virus to infect the host cell.

Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko
Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants.; to: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al
Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al
Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al
Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the
virus to infect the host cell.

Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko
Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants.

Preprint - https://www.medrxiv.org/content/10.1101/2020.04.03.20047977v1 - Renieri et al
Using the Network of Italian Genomes (NIG), they mined around 7000 exomes from 5 different Centers looking for ACE2 variants. Identified variants with a potential impact on protein stability. 3 missense changed identified that have never been reported in the Eastern Asia population, were predicted to interfere with protein cleavage and stabilization. Rare truncating variants that are likely to interfere with the internalization process and one missense variant, p.Trp69Cys, predicted to interfere with 2019-nCov spike protein binding were also observed.
COVID-19 research v0.138 TRIB3 Eleanor Williams gene: TRIB3 was added
gene: TRIB3 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: TRIB3 was set to Unknown
Publications for gene: TRIB3 were set to 27252525; https://www.biorxiv.org/content/10.1101/2020.04.07.030767v1
Added comment: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.030767v1 - de Moraes et al
Analyzed Genotype-Tissue Expression (GTEx) data to test whether lung aging is associated with transcriptional changes in human protein-coding genes that potentially interact with these viruses. Identified TRIB3 expression was decreased in older males. Found TRIB3
expressed mainly in alveolar epithelial cells that express SARS-CoV-2 receptor ACE2.

PMID: 27252525 - Tran et al 2016- Silencing of TRIB3 resulted in increased RNA and protein levels of HCV, whereas overexpression of TRIB3 decreased Hepatitis C viral replication
Sources: Literature
Early onset or syndromic epilepsy v2.40 SAMD12 Zornitza Stark gene: SAMD12 was added
gene: SAMD12 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SAMD12 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: SAMD12 were set to 30194086; 29507423
Phenotypes for gene: SAMD12 were set to Epilepsy, familial adult myoclonic, 1, MIM# 601068
Mode of pathogenicity for gene: SAMD12 was set to Other
Review for gene: SAMD12 was set to GREEN
gene: SAMD12 was marked as current diagnostic
Added comment: Repeat expansions of intronic TTTCA and TTTTA motifs within SAMD12 have been identified in over 50 Japanese and Chinese families. Most families with affected individuals were heterozygous however 4 patients from 3 families had homozygous repeat expansions, which was associated with a more severe phenotype. Western blot analysis showed decreased levels of the protein in patient brains. Note these were identified on long-read sequencing and may not be detectable by all assays.
Sources: Literature
COVID-19 research v0.137 ACE2 Eleanor Williams changed review comment from: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al
Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al
Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants.; to: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al
Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al
Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al
Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the
virus to infect the host cell.

Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko
Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants.
Intellectual disability v3.31 YARS Zornitza Stark gene: YARS was added
gene: YARS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: YARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YARS were set to 30304524; 29232904; 27633801
Phenotypes for gene: YARS were set to Intellectual disability; deafness; nystagmus; liver dysfunction
Review for gene: YARS was set to GREEN
gene: YARS was marked as current diagnostic
Added comment: Mono-allelic variants are associated with CMT. However, 10 individuals from three unrelated families reported with bi-allelic variants and a severe phenotype, comprising ID, nystagmus, deafness, liver dysfunction and a range of other features.
Sources: Literature
Skeletal dysplasia v2.7 PKDCC Zornitza Stark gene: PKDCC was added
gene: PKDCC was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: PKDCC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PKDCC were set to 30478137; 19097194
Phenotypes for gene: PKDCC were set to Rhizomelia; dysmorphism
Review for gene: PKDCC was set to AMBER
Added comment: Two unrelated consanguineous families reported with different homozygous variants
Pre-existing mouse model has similar phenotype
Sources: Literature
Primary ciliary disorders v1.22 SPEF2 Zornitza Stark gene: SPEF2 was added
gene: SPEF2 was added to Primary ciliary disorders. Sources: Literature
Mode of inheritance for gene: SPEF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPEF2 were set to 31151990; 31278745; 31048344; 31942643
Phenotypes for gene: SPEF2 were set to Spermatogenic failure 43, MIM#618751; Primary ciliary dyskinesia-like phenotype
Review for gene: SPEF2 was set to AMBER
Added comment: 4 families reported with bi-allelic variants and sperm morphological abnormalities plus recurrent sinopulmonary infections and bronchiectasis, consistent with a PCD-like phenotype. Morphological abnormalities of the respiratory cilia were not observed. Mouse model recapitulated the infertility phenotype but also had hydrocephalus and sinusitis, again arguing for broader impact on ciliary function. Note other reports of individuals with bi-allelic variants and no respiratory phenotype reported. Given respiratory phenotype is milder and currently it is unclear in what proportion of individuals it is present, Amber rating suggested.
Sources: Literature
Retinal disorders v2.8 USP45 Zornitza Stark gene: USP45 was added
gene: USP45 was added to Retinal disorders. Sources: Literature
Mode of inheritance for gene: USP45 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP45 were set to 30573563
Phenotypes for gene: USP45 were set to Lebers congenital amaurosis; retinal dystrophy
Review for gene: USP45 was set to GREEN
gene: USP45 was marked as current diagnostic
Added comment: 2 unrelated Chinese families reported with rare homozygous variants (one missense, one nonsense) and Leber congenital amaurosis. Animal knockout functional studies recapitulate retinal phenotype
Sources: Literature
Gastrointestinal neuromuscular disorders v1.12 MYH11 Zornitza Stark gene: MYH11 was added
gene: MYH11 was added to Gastrointestinal neuromuscular disorders. Sources: Expert list
Mode of inheritance for gene: MYH11 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYH11 were set to 31944481; 29575632
Phenotypes for gene: MYH11 were set to Megacystis microcolon intestinal hypoperistalsis syndrome, autosomal recessive; Dominant smooth muscle dysmotility syndrome
Review for gene: MYH11 was set to GREEN
gene: MYH11 was marked as current diagnostic
Added comment: Heterozygous dominant negative MYH11 pathogenic variants have been associated with thoracic aortic aneurysm and dissection while biallelic null alleles have been associated with megacystis microcolon intestinal hypoperistalsis syndrome. Recent report of two families with heterozygous protein‐elongating MYH11 variants affecting the SM2 isoforms of MYH11 as a cause for severe gastrointestinal dysmotility. The authors hypothesise that the mechanistic pathogenesis of this disease, dominant hypercontractile loss‐of‐function, is distinct from those implicated in other diseases involving MYH11 dysfunction.
Sources: Expert list
Intellectual disability v3.31 CACNB4 Zornitza Stark reviewed gene: CACNB4: Rating: AMBER; Mode of pathogenicity: None; Publications: 32176688; Phenotypes: Intellectual disability, epilepsy, movement disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.137 ACE2 Eleanor Williams changed review comment from: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al
Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations.; to: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al
Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations.

Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al
Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants.
COVID-19 research v0.137 ACE2 Eleanor Williams commented on gene: ACE2
Primary immunodeficiency or monogenic inflammatory bowel disease v2.128 ALPI Eleanor Williams Classified gene: ALPI as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.128 ALPI Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber. 2 cases reported plus some functional data.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.128 ALPI Eleanor Williams Gene: alpi has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.137 ALPI Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 29567797 - Parlato et al 2018- report ALPI mutations in two unrelated patients with severe intestinal inflammation and autoimmunity. WES was used. Patient 1 - non‐consanguineous parents. At 2 years old was diagnosed with coeliac disease from HLA-typing. At age 3 had recurrent abdominal pain, rectal bleeding and severe diarrhoea. Patient 2 - non‐consanguineous parents of Jewish Ashkenazi origin. Age 15 he was diagnosed with ileocolonic Crohn's disease. Compound heterozygous mutations in the ALPI gene were found in both patients. Three variants result in the substitution of residues highly conserved across species (A97T, A350V and A360) and one variant (Q439X) introducing a premature stop codon. Functional studies in HEK293T cells showed that all ALPI mutations were loss of function. ALPI expression was reduced in patients’ biopsies.; to: Not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 29567797 - Parlato et al 2018- report ALPI mutations in two unrelated patients with severe intestinal inflammation and autoimmunity. WES was used. Patient 1 - non‐consanguineous parents. At 2 years old was diagnosed with coeliac disease from HLA-typing. At age 3 had recurrent abdominal pain, rectal bleeding and severe diarrhoea. Patient 2 - non‐consanguineous parents of Jewish Ashkenazi origin. Age 15 he was diagnosed with ileocolonic Crohn's disease. Compound heterozygous mutations in the ALPI gene were found in both patients. Three variants result in the substitution of residues highly conserved across species (A97T, A350V and A360) and one variant (Q439X) introducing a premature stop codon. Functional studies in HEK293T cells showed that all ALPI mutations were loss of function. ALPI expression was reduced in patients’ biopsies.

Rated Amber by Zornitza Stark on the PID panel.
COVID-19 research v0.137 ALPI Eleanor Williams commented on gene: ALPI
Primary immunodeficiency or monogenic inflammatory bowel disease v2.127 ALPI Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 29567797 - report ALPI mutations in two unrelated patients with severe intestinal inflammation and autoimmunity. WES was used. Patient 1 - non‐consanguineous parents. At 2 years old was diagnosed with coeliac disease from HLA-typing. At age 3 had recurrent abdominal pain, rectal bleeding and severe diarrhoea. Patient 2 - non‐consanguineous parents of Jewish Ashkenazi origin. Age 15 he was diagnosed with ileocolonic Crohn's disease. Compound heterozygous mutations in the ALPI gene were found in both patients. Three variants result in the substitution of residues highly conserved across species (A97T, A350V and A360) and one variant (Q439X) introducing a premature stop codon. Functional studies in HEK293T cells showed that all ALPI mutations were loss of function. ALPI expression was reduced in patients’ biopsies.; to: Not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 29567797 - Parlato et al 2018- report ALPI mutations in two unrelated patients with severe intestinal inflammation and autoimmunity. WES was used. Patient 1 - non‐consanguineous parents. At 2 years old was diagnosed with coeliac disease from HLA-typing. At age 3 had recurrent abdominal pain, rectal bleeding and severe diarrhoea. Patient 2 - non‐consanguineous parents of Jewish Ashkenazi origin. Age 15 he was diagnosed with ileocolonic Crohn's disease. Compound heterozygous mutations in the ALPI gene were found in both patients. Three variants result in the substitution of residues highly conserved across species (A97T, A350V and A360) and one variant (Q439X) introducing a premature stop codon. Functional studies in HEK293T cells showed that all ALPI mutations were loss of function. ALPI expression was reduced in patients’ biopsies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.127 ALPI Eleanor Williams commented on gene: ALPI
Primary immunodeficiency or monogenic inflammatory bowel disease v2.127 ADAM17 Eleanor Williams Classified gene: ADAM17 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.127 ADAM17 Eleanor Williams Added comment: Comment on list classification: Changing rating from amber to green. 3 cases plus mouse model.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.127 ADAM17 Eleanor Williams Gene: adam17 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.126 ADAM17 Eleanor Williams Phenotypes for gene: ADAM17 were changed from inflammatory skin; Inflammatory skin and bowel disease, neonatal, 1; Inflammatory skin and bowel disease, neonatal 1, 614328; ADAM17 deficiency; Autoinflammatory Disorders; IBD-1; Early onset diarrhea and skin lesions to inflammatory skin; Inflammatory skin and bowel disease, neonatal, 1; Inflammatory skin and bowel disease, neonatal 1, 614328; ADAM17 deficiency; Autoinflammatory Disorders; IBD-1; Early onset diarrhea and skin lesions; Recurrent infections
Primary immunodeficiency or monogenic inflammatory bowel disease v2.125 ADAM17 Eleanor Williams Publications for gene: ADAM17 were set to 22010916; 28930861; 20603312; 32048120; 25171914; 11149563; 25058236; 32086639
COVID-19 research v0.137 ADAM17 Eleanor Williams reviewed gene: ADAM17: Rating: ; Mode of pathogenicity: None; Publications: 22010916, 26683521, 25804906, 29560122; Phenotypes: ?Inflammatory skin and bowel disease, neonatal, 1 #614328; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.124 ADAM17 Eleanor Williams commented on gene: ADAM17
Primary immunodeficiency or monogenic inflammatory bowel disease v2.124 BCL11B Eleanor Williams changed review comment from: Associated with Immunodeficiency 49 #617237 (AD) in OMIM.

PMID: 29985992 - Lessel et al 2018 - identified de novo heterozygous germline mutations in BCL11B in nine unrelated patients, namely six frameshift, two nonsense and one missense mutation. A further patient inherited a heterozygous frameshift mutation, p.(Asp534Thrfs*29), transmitted from an affected mother with. All analysed individuals exhibited developmental delay and intellectual disability and a severe reduction of peripheral ILC2s and impaired T cell development, but no overt immune deficiency. Patient E:II-1 was the only patient with suspected immunodeficiency diagnosed upon newborn screening. Other de-novo variants were also detected in some patients.

PMID: 27959755 - Punwani et al 2016 - an infant with "leaky" SCID as well as craniofacial and dermal abnormalities and the absence of a corpus callosum. Exome sequencing revealed a heterozygous de novo missense mutation, p.N441K, in BCL11B. The mutant protein had dominant negative activity, which prevented the wild-type BCL11B to bind DNA, thereby arresting development of the T-cell lineage and disrupting hematopoietic stem-cell migration. bcl11ba-deficient zebrafish recapitulated the phenotype.; to: Associated with Immunodeficiency 49 #617237 (AD) in OMIM.

PMID: 29985992 - Lessel et al 2018 - identified de novo heterozygous germline mutations in BCL11B in nine unrelated patients, namely six frameshift, two nonsense and one missense mutation. A further patient inherited a heterozygous frameshift mutation, p.(Asp534Thrfs*29), transmitted from an affected mother with. All analysed individuals exhibited developmental delay and intellectual disability and a severe reduction of peripheral ILC2s and impaired T cell development, but no overt immune deficiency. Patient E:II-1, with a missense variant, was the only patient with suspected immunodeficiency diagnosed upon newborn screening. Other de-novo variants were also detected in some patients.

PMID: 27959755 - Punwani et al 2016 - an infant with "leaky" SCID as well as craniofacial and dermal abnormalities and the absence of a corpus callosum. Exome sequencing revealed a heterozygous de novo missense mutation, p.N441K, in BCL11B. The mutant protein had dominant negative activity, which prevented the wild-type BCL11B to bind DNA, thereby arresting development of the T-cell lineage and disrupting hematopoietic stem-cell migration. bcl11ba-deficient zebrafish recapitulated the phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.124 BCL11B Eleanor Williams commented on gene: BCL11B
Primary immunodeficiency or monogenic inflammatory bowel disease v2.124 BLOC1S6 Eleanor Williams changed review comment from: Provisionally associated with ?Hermansky-pudlak syndrome 9 #614171 (AR) in OMIM.
BLOC1S6 is also known as PLDN and HPS9.

PMID: 32245340 - Michaud et al 2020 - report 1 patient presenting with ocular features of albinism. Genetic analysis revealed two compound heterozygous variants in the BLOC1S6 gene. Extended hematological studies confirmed the platelet storage pool disease with absence of dense granules and abnormal platelet aggregation. (Abstract only accessed).

PMID: 22461475 - Badolato et al 2012 - report a northern Italian girl with oculocutaneous albinism, nystagmus, and normal neurologic development who presented with recurrent cutaneous infections but without hemorrhagic episodes. She had thrombocytopenia and leukopenia, with normal platelet aggregation. WES found a homozygous nonsense mutation, c.232C > T (p.Q78X) in PLDN (BLOC1S6). This variant was confirmed homozygous in the patient and heterozygous in her parents by Sanger sequencing, and was associated with absent PLDN protein expression

PMID: 26575419 - Yousaf et al 2016 - report a Pakistani family in which the proband had a nonsense mutation is the HPS9/PLDN gene (c.232C>T, p.Gln78*). The 4-year-old female patient reported here, had Oculocutaneous albinism, photophobia, nystagmus, prolonged bleeding and clotting times, which indicate platelet dysfunction.

PMID: 21665000 - Cullinane et al 2011 - RETRACTED PAPER - report 1 9-month old male patient of Indian ancestry with a homozygous c.232C>T; p.Gln78Och mutation and HPS-like phenotype. This paper has been retracted due to falsified and/or fabricated gel images which represent expression of PLDN in fibroblasts and melanocytes.

Summary: 3 reports + retracted paper. 2 out of the 3 patients had abnormal platelet aggregation.; to: Provisionally associated with ?Hermansky-pudlak syndrome 9 #614171 (AR) in OMIM.
BLOC1S6 is also known as PLDN and HPS9.

PMID: 32245340 - Michaud et al 2020 - report 1 patient presenting with ocular features of albinism. Genetic analysis revealed two compound heterozygous variants in the BLOC1S6 gene. Extended hematological studies confirmed the platelet storage pool disease with absence of dense granules and abnormal platelet aggregation. (Abstract only accessed).

PMID: 22461475 - Badolato et al 2012 - report a northern Italian girl with oculocutaneous albinism, nystagmus, and normal neurologic development who presented with recurrent cutaneous infections but without hemorrhagic episodes. She had thrombocytopenia and leukopenia, with normal platelet aggregation. WES found a homozygous nonsense mutation, c.232C > T (p.Q78X) in PLDN (BLOC1S6). This variant was confirmed homozygous in the patient and heterozygous in her parents by Sanger sequencing, and was associated with absent PLDN protein expression

PMID: 26575419 - Yousaf et al 2016 - report a Pakistani family in which the proband had a nonsense mutation is the HPS9/PLDN gene (c.232C>T, p.Gln78*). The 4-year-old female patient reported here, had Oculocutaneous albinism, photophobia, nystagmus, prolonged bleeding and clotting times, which indicate platelet dysfunction.

PMID: 21665000 - Cullinane et al 2011 - RETRACTED PAPER - report 1 9-month old male patient of Indian ancestry with a homozygous c.232C>T; p.Gln78Och mutation and HPS-like phenotype. This paper has been retracted due to falsified and/or fabricated gel images which represent expression of PLDN in fibroblasts and melanocytes.

Summary: 3 reports + retracted paper. 2 out of the 3 patients had abnormal platelet aggregation. The 3rd had thrombocytopenia and leukopenia, with normal platelet aggregation.
COVID-19 research v0.137 HLA-DRB1 Catherine Snow Classified gene: HLA-DRB1 as Green List (high evidence)
COVID-19 research v0.137 HLA-DRB1 Catherine Snow Added comment: Comment on list classification: Rating as Green due to expert review and publications associated with HLA-DRB1 and viral susceptibility
COVID-19 research v0.137 HLA-DRB1 Catherine Snow Gene: hla-drb1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.124 BLOC1S6 Eleanor Williams Publications for gene: BLOC1S6 were set to 22461475,20301464,26575419
COVID-19 research v0.136 FPR2 Catherine Snow Classified gene: FPR2 as Green List (high evidence)
COVID-19 research v0.136 FPR2 Catherine Snow Added comment: Comment on list classification: Upgrading to Green based on expert review
COVID-19 research v0.136 FPR2 Catherine Snow Gene: fpr2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.123 BLOC1S6 Eleanor Williams reviewed gene: BLOC1S6: Rating: ; Mode of pathogenicity: None; Publications: 32245340, 22461475, 26575419, 21665000; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.135 MPO Catherine Snow changed review comment from: Comment on list classification: Based on an external review detailing a number of publications where MPO is reviewed because of its association in the regulation of (neutrophil extracellular traps) NET formation upgrading from Amber to Green; to: Comment on list classification: Based on an external review detailing a number of publications where MPO is reviewed because of its association in the regulation of (neutrophil extracellular traps) NET formation upgrading from Amber to Green

Should also be noted that elevated levels of inflammatory mediators (including IL-6, IL-8, and MPO) in the airway of chronic/extended or recurrent RSV infection are associated with faster lung function decline in COPD patients. PMID: 32227102
COVID-19 research v0.135 MPO Catherine Snow Publications for gene: MPO were set to 9354683; 15108282; 9637725; 32082301; 27574522; 21703402; 29325098; 29769163; 24968347
COVID-19 research v0.134 MPO Catherine Snow Classified gene: MPO as Green List (high evidence)
COVID-19 research v0.134 MPO Catherine Snow Added comment: Comment on list classification: Based on an external review detailing a number of publications where MPO is reviewed because of its association in the regulation of (neutrophil extracellular traps) NET formation upgrading from Amber to Green
COVID-19 research v0.134 MPO Catherine Snow Gene: mpo has been classified as Green List (High Evidence).
COVID-19 research v0.133 MPO Catherine Snow Publications for gene: MPO were set to 9354683; 15108282; 9637725; 32082301; 27574522; 21703402; 29325098; 29769163; 24968347
COVID-19 research v0.132 MPO Catherine Snow Publications for gene: MPO were set to 9354683; 15108282; 9637725; 32082301
Primary immunodeficiency or monogenic inflammatory bowel disease v2.123 C17orf62 Eleanor Williams Classified gene: C17orf62 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.123 C17orf62 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. 6 Icelandic related cases with same variant, another variant identified in Saudia Arabian individual with related phenotype. Mouse model and functional studies support the role of this gene in Chronic granulomatous disease
Primary immunodeficiency or monogenic inflammatory bowel disease v2.123 C17orf62 Eleanor Williams Gene: c17orf62 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.122 C17orf62 Eleanor Williams Phenotypes for gene: C17orf62 were changed from Autosomal recessive CGD EROS; Congenital defects of phagocyte number or function to Autosomal recessive CGD EROS; Congenital defects of phagocyte number or function; Chronic granulomatous disease
Primary immunodeficiency or monogenic inflammatory bowel disease v2.121 C17orf62 Eleanor Williams Publications for gene: C17orf62 were set to 30312704; 30361506; 32086639; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.120 C17orf62 Eleanor Williams commented on gene: C17orf62
Primary immunodeficiency or monogenic inflammatory bowel disease v2.120 CIB1 Eleanor Williams Classified gene: CIB1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.120 CIB1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from Grey to Green. There are more than 3 cases with plausible disease causing variants.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.120 CIB1 Eleanor Williams Gene: cib1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.119 CIB1 Eleanor Williams reviewed gene: CIB1: Rating: ; Mode of pathogenicity: None; Publications: 30068544; Phenotypes: Epidermodysplasia verruciformis 3 #618267; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.119 IL18BP Ivone Leong Classified gene: IL18BP as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.119 IL18BP Ivone Leong Added comment: Comment on list classification: Gene given Red gene status based on expert review. This gene is also found in the IUIS 2019 paper (PMID: 31953710)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.119 IL18BP Ivone Leong Gene: il18bp has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.118 IL18BP Ivone Leong Publications for gene: IL18BP were set to 31213488
Primary immunodeficiency or monogenic inflammatory bowel disease v2.117 IL12RB2 Ivone Leong Publications for gene: IL12RB2 were set to 30578351; 31953710
Primary immunodeficiency or monogenic inflammatory bowel disease v2.117 IL12RB2 Ivone Leong Publications for gene: IL12RB2 were set to 30578351
Primary immunodeficiency or monogenic inflammatory bowel disease v2.116 IL12RB2 Ivone Leong Classified gene: IL12RB2 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.116 IL12RB2 Ivone Leong Added comment: Comment on list classification: Gene given Red gene status based on expert review. This gene is also found in the IUIS 2019 paper (PMID: 31953710)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.116 IL12RB2 Ivone Leong Gene: il12rb2 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.115 IL23R Ivone Leong Classified gene: IL23R as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.115 IL23R Ivone Leong Added comment: Comment on list classification: Gene given Red gene status based on expert review. This gene is also found in the IUIS 2019 paper (PMID: 31953710)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.115 IL23R Ivone Leong Gene: il23r has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.114 IL23R Ivone Leong Publications for gene: IL23R were set to 30578351
Primary immunodeficiency or monogenic inflammatory bowel disease v2.113 POLR3F Ivone Leong Classified gene: POLR3F as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.113 POLR3F Ivone Leong Added comment: Comment on list classification: Gene given Red gene status based on expert review. This gene is also found in the IUIS 2019 paper (PMID: 31953710)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.113 POLR3F Ivone Leong Gene: polr3f has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.112 POLR3F Ivone Leong Publications for gene: POLR3F were set to 30211253
Primary immunodeficiency or monogenic inflammatory bowel disease v2.111 IRF4 Ivone Leong Publications for gene: IRF4 were set to 29537367
Primary immunodeficiency or monogenic inflammatory bowel disease v2.110 IRF4 Ivone Leong Classified gene: IRF4 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.110 IRF4 Ivone Leong Added comment: Comment on list classification: Gene given Red gene status based on expert review. This gene is also found in the IUIS 2019 paper (PMID: 31953710)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.110 IRF4 Ivone Leong Gene: irf4 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.109 CD247 Ivone Leong Publications for gene: CD247 were set to 16672702; 26690594; 17170122; 27555457; 25688246; https://doi.org/10.14785/lpsn-2014-0012
Primary immunodeficiency or monogenic inflammatory bowel disease v2.108 SLC7A7 Ivone Leong Classified gene: SLC7A7 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.108 SLC7A7 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. SLC7A7 causes lysinuric protein intolerance (LPI) and immunodeficiency is one of the phenotypes. There are >3 unrelated cases reported on OMIM.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.108 SLC7A7 Ivone Leong Gene: slc7a7 has been classified as Green List (High Evidence).
COVID-19 research v0.131 AKT1 Sarah Leigh Added comment: Comment on phenotypes: OMIM cites a general phenotypic description for Cowden syndrome 1 (158350) includes Immunodeficiency in some patients (PMID 26246517).
COVID-19 research v0.131 AKT1 Sarah Leigh Phenotypes for gene: AKT1 were changed from to Cowden syndrome 6 615109
COVID-19 research v0.130 AKT1 Sarah Leigh Publications for gene: AKT1 were set to 17931677
COVID-19 research v0.129 AKT1 Sarah Leigh Publications for gene: AKT1 were set to
COVID-19 research v0.128 AKT1 Sarah Leigh Classified gene: AKT1 as Red List (low evidence)
COVID-19 research v0.128 AKT1 Sarah Leigh Added comment: Comment on list classification: AKT1 gene product can inhibit apoptosis through phosphorylation,
and the inhibition of pro-apoptotic mediators to contribute to the maintenance of the virus latent state and may facilitate transformation of human lymphotropic virus type 1 infected cells (PMID 17931677).
COVID-19 research v0.128 AKT1 Sarah Leigh Gene: akt1 has been classified as Red List (Low Evidence).
Nephrocalcinosis or nephrolithiasis v2.13 VPS33B Rebecca Foulger Classified gene: VPS33B as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v2.13 VPS33B Rebecca Foulger Gene: vps33b has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v2.12 VPS33B Rebecca Foulger gene: VPS33B was added
gene: VPS33B was added to Nephrocalcinosis or nephrolithiasis. Sources: Literature
Mode of inheritance for gene: VPS33B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS33B were set to 15052268; 22753090
Phenotypes for gene: VPS33B were set to Arthrogryposis, renal dysfunction, and cholestasis 1, 208085
Added comment: Added to panel as Green gene as advised by Helen Brittain, Genomics England Clinical Team. This rating should be reviewed by GLHs at the date of next GMS panel update. ARC phenotype (MIM:208085) is appropriate for the panel, and sufficient cases to support causation (see also the other ARC gene, VIPAS39).
Sources: Literature
Nephrocalcinosis or nephrolithiasis v2.11 VIPAS39 Rebecca Foulger Classified gene: VIPAS39 as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v2.11 VIPAS39 Rebecca Foulger Gene: vipas39 has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v2.10 VIPAS39 Rebecca Foulger commented on gene: VIPAS39: PMID:20190753 (Cullinane et al., 2010) identify biallelic (homozygous or compound het) variants in 7 probands from consanguineous families with ARC (MIM:613404) from various ethnic backgrounds (Turkish, Croation, Israeli Arab, Italian). Variants include Q179X, T250ArgfsX279, R220X, Q291X, M1R. The paper does not further discuss the kidney phenotype.
Nephrocalcinosis or nephrolithiasis v2.10 VIPAS39 Rebecca Foulger gene: VIPAS39 was added
gene: VIPAS39 was added to Nephrocalcinosis or nephrolithiasis. Sources: Literature
Mode of inheritance for gene: VIPAS39 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VIPAS39 were set to 20190753
Phenotypes for gene: VIPAS39 were set to Arthrogryposis, renal dysfunction, and cholestasis 2, 613404
Added comment: Added to panel as Green following advice from Helen Brittain, Genomics England Clinical Team. Nephrocalcinosis is a feature of the phenotype. Other syndromes are on this panel (Lesch-Nyhan and Lowe syndrome) as Green, and therefore rated Green to match. This rating should be reviewed by GLHs at the date of next GMS panel update.
Sources: Literature
Unexplained young onset end-stage renal disease v1.10 VIPAS39 Rebecca Foulger Phenotypes for gene: VIPAS39 were changed from Arthrogryposis, renal dysfunction, and cholestasis 2, 613404 to Arthrogryposis, renal dysfunction, and cholestasis 2, 613404
Unexplained young onset end-stage renal disease v1.9 VIPAS39 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Red to Green following advice from Helen Brittain, Genomics England Clinical Team. PMID:20190753 (Cullinane et al., 2010) identify biallelic (homozygous or compound het) variants in 7 probands from consanguineous families with ARC (MIM:613404) from various ethnic backgrounds (Turkish, Croation, Israeli Arab, Italian). Variants include Q179X, T250ArgfsX279, R220X, Q291X, M1R. The paper does not further discuss the kidney phenotype but the other ARC syndrome gene, VPS33B, is already green on this panel.; to: Comment on list classification: Updated rating from Red to Green following advice from Helen Brittain, Genomics England Clinical Team. PMID:20190753 (Cullinane et al., 2010) identify biallelic (homozygous or compound het) variants in 7 probands from consanguineous families with ARC (MIM:613404) from various ethnic backgrounds (Turkish, Croation, Israeli Arab, Italian). Variants include Q179X, T250ArgfsX279, R220X, Q291X, M1R. The paper does not further discuss the kidney phenotype but the other ARC syndrome gene, VPS33B, is already green on this panel. This rating should be reviewed by GLHs at the date of next GMS panel update.
Unexplained young onset end-stage renal disease v1.9 VIPAS39 Rebecca Foulger Classified gene: VIPAS39 as Green List (high evidence)
Unexplained young onset end-stage renal disease v1.9 VIPAS39 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green following advice from Helen Brittain, Genomics England Clinical Team. PMID:20190753 (Cullinane et al., 2010) identify biallelic (homozygous or compound het) variants in 7 probands from consanguineous families with ARC (MIM:613404) from various ethnic backgrounds (Turkish, Croation, Israeli Arab, Italian). Variants include Q179X, T250ArgfsX279, R220X, Q291X, M1R. The paper does not further discuss the kidney phenotype but the other ARC syndrome gene, VPS33B, is already green on this panel.
Unexplained young onset end-stage renal disease v1.9 VIPAS39 Rebecca Foulger Gene: vipas39 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v1.8 VIPAS39 Rebecca Foulger Publications for gene: VIPAS39 were set to
Additional findings reproductive carrier status v0.4 Eleanor Williams Panel types changed to Additional Findings
Additional findings health related v0.110 Eleanor Williams Panel types changed to Additional Findings
Additional findings health related - CNV analysis adults v0.9 Eleanor Williams Panel types changed to Super Panel; Additional Findings
Additional findings health related - adults v0.9 Eleanor Williams Panel types changed to Super Panel; Additional Findings
Additional findings health related - CNV analysis adult specific v0.15 Eleanor Williams Panel types changed to Component Of Super Panel; Additional Findings
Additional findings health related - CNV analysis children v0.10 Eleanor Williams Panel types changed to Component Of Super Panel; Additional Findings
Additional findings health related - children v0.12 Eleanor Williams Panel types changed to Component Of Super Panel; Additional Findings
Additional findings health related - adult specific v0.14 Eleanor Williams Panel types changed to Component Of Super Panel; Additional Findings
CAKUT v1.58 BMP4 Rebecca Foulger commented on gene: BMP4: Kept rating as Amber following agreement from Helen Brittain, Genomics England Clinical Team: evidence is borderline and. further cases or supportive evidence is needed to be confident of a causal link. Rated Amber but can be re-assessed by GLH groups at a future date.
CAKUT v1.58 CENPF Rebecca Foulger commented on gene: CENPF: Kept rating as Amber following agreement from Helen Brittain, Genomics England Clinical Team: the evidence for a congenital renal anomaly is borderline, and in view of two families only, Amber is appropriate until further families are identified.
Limb disorders v2.5 CEP55 Rebecca Foulger Classified gene: CEP55 as Green List (high evidence)
Limb disorders v2.5 CEP55 Rebecca Foulger Added comment: Comment on list classification: Rated as Green after agreement with Eleanor Williams- relevant phenotype for panel, and sufficient cases to support association.
Limb disorders v2.5 CEP55 Rebecca Foulger Gene: cep55 has been classified as Green List (High Evidence).
Limb disorders v2.5 CEP55 Rebecca Foulger Classified gene: CEP55 as Green List (high evidence)
Limb disorders v2.5 CEP55 Rebecca Foulger Added comment: Comment on list classification: Rated as Green after agreement with Eleanor Williams- relevant phenotype for panel, and sufficient cases to support association.
Limb disorders v2.5 CEP55 Rebecca Foulger Gene: cep55 has been classified as Green List (High Evidence).
Renal ciliopathies v1.15 CEP55 Rebecca Foulger Classified gene: CEP55 as Amber List (moderate evidence)
Renal ciliopathies v1.15 CEP55 Rebecca Foulger Added comment: Comment on list classification: Rated as Amber on advice from Helen Brittain: all of the cases are prenatal / peri-natal lethal so better suited to Fetal panel.
Renal ciliopathies v1.15 CEP55 Rebecca Foulger Gene: cep55 has been classified as Amber List (Moderate Evidence).
Renal ciliopathies v1.14 CEP55 Rebecca Foulger Publications for gene: CEP55 were set to 28295209
Renal ciliopathies v1.13 CEP55 Rebecca Foulger gene: CEP55 was added
gene: CEP55 was added to Renal ciliopathies. Sources: Literature
Mode of inheritance for gene: CEP55 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP55 were set to 28295209
Phenotypes for gene: CEP55 were set to Meckel-like syndrome; autosomal recessive lethal ciliopathy; renal dysplasia
Review for gene: CEP55 was set to AMBER
Added comment: Added CEP55 to renal ciliopathy panel as Amber after agreement from Helen Brittain, Genomics England Clinical Team. PMID:28295209 (Bondeson et al) report a Swedish couple with 2 affected male fetuses homozygous for CEP55 p.Arg86*. Although the phenotype differed between fetuses, both exhibited kidney phenotypes (including renal dysplasia). Segregation analysis supported the gene:disease association, and haplotype analysis suggested a founder effect. The authors concluded the phenotype was consistent with an AR lethal ciliopathy. The lethal phenotype is similar to that reported in individuals in PMID:30622327 (Rawlins et al., 2019) and PMID:28264986 (Frosk et al, 2017).
Sources: Literature
Limb disorders v2.4 CEP55 Rebecca Foulger commented on gene: CEP55: PMID:32100459 (Barrie et al., 2020) describe 7 living indivduals (5 families) with biallelic CEP55 variants (compound het and homozygous splice site variant). The phenotype includes microcephaly, developmental delay and syndactyly. Patients 1,2,3,4 had bilateral toe syndactyly and 5th finger clinodactyly, Patient 5 had unilateral club foot. The three siblings (patients 5,6,7) all had small hands and feet.
Limb disorders v2.4 CEP55 Rebecca Foulger gene: CEP55 was added
gene: CEP55 was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: CEP55 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP55 were set to 32100459
Phenotypes for gene: CEP55 were set to microcephaly, developmental delay and bilateral toe syndactyly
Added comment: Added to Limb disorders panel on advice from Helen Brittain, Genomics England Clinical Team. Phenotype of living individuals in PMID:32100459 (Barrie et al., 2020) includes syndactyly.
Sources: Literature
Additional findings health related - CNV analysis adult specific v0.14 Eleanor Williams Panel types changed to Component Of Super Panel
Additional findings health related - CNV analysis children v0.9 Eleanor Williams Panel types changed to Component Of Super Panel
Additional findings health related - children v0.11 Eleanor Williams Panel types changed to Component Of Super Panel
Additional findings health related - adult specific v0.12 Eleanor Williams Panel types changed to Component Of Super Panel
Intellectual disability v3.31 CEP55 Rebecca Foulger Classified gene: CEP55 as Green List (high evidence)
Intellectual disability v3.31 CEP55 Rebecca Foulger Added comment: Comment on list classification: Rated CEP55 as Green: >3 unrelated cases in PMID:32100459 with DD/ID (2 of which are severe).
Intellectual disability v3.31 CEP55 Rebecca Foulger Gene: cep55 has been classified as Green List (High Evidence).
Intellectual disability v3.30 CEP55 Rebecca Foulger changed review comment from: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD was seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor/speech development was seen in unrelated patients 3 and 4.; to: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD was seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor & speech development was seen in unrelated patients 3 and 4.
Intellectual disability v3.30 CEP55 Rebecca Foulger changed review comment from: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD wax seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor/speech development was seen in unrelated patients 3 and 4.; to: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD was seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor/speech development was seen in unrelated patients 3 and 4.
Intellectual disability v3.30 CEP55 Rebecca Foulger commented on gene: CEP55: PMID:32100459 (Barrie et al., 2020) describe 7 living individuals (5 families) with biallelic variants (compound het and homozygous splice site variant) in CEP55. Global/severe DD wax seen in patient 2, and the 3 siblings (patients 5,6,7). Mild/delayed motor/speech development was seen in unrelated patients 3 and 4.
Intellectual disability v3.30 CEP55 Rebecca Foulger gene: CEP55 was added
gene: CEP55 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CEP55 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP55 were set to 32100459
Phenotypes for gene: CEP55 were set to microcephaly, delayed development, and bilateral toe syndactyly
Added comment: Added to ID panel on advice from Helen Brittain, Genomics England Clinical Team. Phenotype of living individuals in PMID:32100459 (Barrie et al., 2020) includes developmental delay.
Sources: Literature
Severe microcephaly v2.6 CEP55 Rebecca Foulger Classified gene: CEP55 as Green List (high evidence)
Severe microcephaly v2.6 CEP55 Rebecca Foulger Gene: cep55 has been classified as Green List (High Evidence).
Severe microcephaly v2.5 CEP55 Rebecca Foulger changed review comment from: PMID:32100459 (Barrie et al., 2020) describe 7 living indivduals (5 families) with biallelic CEP55 variants. Four unrelated individuals with microcephaly, speech delays, and bilateral toe syndactyly all have a common CEP55 variant c.70G>A p.(Glu24Lys) in trans with nonsense variants. Three siblings are homozygous for a consensus splice site variant near the end of the gene. These affected girls all have severely delayed development, microcephaly, and varying degrees of lissencephaly/pachygyria. The authors suggest that individuals compound het for missense + nonsense variants in CEP55 have a viable phenotype (compared to lethal MARCH phenotype).; to: PMID:32100459 (Barrie et al., 2020) describe 7 living indivduals (5 families) with biallelic CEP55 variants (compound het, or homozygous splice site variant). Three sisters (Patients 5,6,7) have severe microcephaly (-7.1 SD, -5.5, -5.5). An additional 3 unrelated patients (Patients 1,2,3) have microcephaly scores of -2 SD, -2.7 SD, and Patient 4 has borderline microcephaly. Severe microcephaly (NHS Test Directory) is defined as having an occipitofrontal circumference (OFC) beyond 3 standard deviations below the mean for age. There are 4 unrelated cases which meet this threshold (3 sisters) or are close to this threshold (3 unrelated patients) and therefore on balance have rated as Green awaiting further GLH review.
Early onset or syndromic epilepsy v2.40 CACNA1H Sarah Leigh Phenotypes for gene: CACNA1H were changed from to Hyperaldosteronism, familial, type IV 617027; {Epilepsy, childhood absence, susceptibility to, 6} 611942; {Epilepsy, idiopathic generalized, susceptibility to, 6} 611942
Early onset or syndromic epilepsy v2.39 CACNA1H Sarah Leigh Added comment: Comment on publications: PMID 32227660 presents further evidence refuting a monogenic contribution of this gene to epilepsy.
Early onset or syndromic epilepsy v2.39 CACNA1H Sarah Leigh Publications for gene: CACNA1H were set to 12891677
Severe microcephaly v2.5 CEP55 Rebecca Foulger commented on gene: CEP55: PMID:32100459 (Barrie et al., 2020) describe 7 living indivduals (5 families) with biallelic CEP55 variants. Four unrelated individuals with microcephaly, speech delays, and bilateral toe syndactyly all have a common CEP55 variant c.70G>A p.(Glu24Lys) in trans with nonsense variants. Three siblings are homozygous for a consensus splice site variant near the end of the gene. These affected girls all have severely delayed development, microcephaly, and varying degrees of lissencephaly/pachygyria. The authors suggest that individuals compound het for missense + nonsense variants in CEP55 have a viable phenotype (compared to lethal MARCH phenotype).
Severe microcephaly v2.5 CEP55 Rebecca Foulger gene: CEP55 was added
gene: CEP55 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: CEP55 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP55 were set to 32100459
Phenotypes for gene: CEP55 were set to microcephaly, speech delays, and bilateral toe syndactyly
Review for gene: CEP55 was set to GREEN
Added comment: Added to Microcephaly panel on advice from Helen Brittain, Genomics England Clinical Team. Phenotype of living individuals described in PMID:32100459 (Barrie et al., 2020) includes microcephaly.
Sources: Literature
Fetal anomalies v1.7 CEP55 Rebecca Foulger Classified gene: CEP55 as Green List (high evidence)
Fetal anomalies v1.7 CEP55 Rebecca Foulger Gene: cep55 has been classified as Green List (High Evidence).
Fetal anomalies v1.6 CEP55 Rebecca Foulger Classified gene: CEP55 as Red List (low evidence)
Fetal anomalies v1.6 CEP55 Rebecca Foulger Added comment: Comment on list classification: Added gene to panel as Green: MARCH phenotype is appropriate for fetal panel, and 3 unrelated fetal cases reported in literature. Not yet associated with a disorder in Gene2Phenotype.
Fetal anomalies v1.6 CEP55 Rebecca Foulger Gene: cep55 has been classified as Red List (Low Evidence).
Fetal anomalies v1.5 CEP55 Rebecca Foulger Publications for gene: CEP55 were set to 28264986; 28295209
Fetal anomalies v1.4 CEP55 Rebecca Foulger changed review comment from: PMID:30622327 (Rawlins et al., 2019) report a novel homozygous founder frameshift variant(p.Ile172Asnfs*17) in CEP55 in 2 siblings presenting with a lethal fetal disorder including cystic dysplastic kidneys. The variant is present at low frequency in the Amish community.; to: PMID:30622327 (Rawlins et al., 2019) report a novel homozygous founder frameshift variant (p.Ile172Asnfs*17) in CEP55 in 2 siblings presenting with a lethal fetal disorder including cystic dysplastic kidneys. The variant is present at low frequency in the Amish community.
Fetal anomalies v1.4 CEP55 Rebecca Foulger commented on gene: CEP55: PMID:30622327 (Rawlins et al., 2019) report a novel homozygous founder frameshift variant(p.Ile172Asnfs*17) in CEP55 in 2 siblings presenting with a lethal fetal disorder including cystic dysplastic kidneys. The variant is present at low frequency in the Amish community.
Fetal anomalies v1.4 CEP55 Rebecca Foulger commented on gene: CEP55: PMID:28295209. Bondeson et al report a Swedish couple with 2 affected male fetuses homozygous for CEP55 p.Arg86*. Although the phenotype differed between fetuses, both exhibited kidney phenotypes (including renal dysplaisa). Segregation analysis supported the gene:disease association, and Haplotype analysis suggested a founder effect.
Fetal anomalies v1.4 CEP55 Rebecca Foulger commented on gene: CEP55: PMID:28264986: Frosk et al, 2017 report a Dutch-German Mennonite family with 3 affected fetuses homozygous for CEP55 nonsense variant p.Ser425* presenting with MIM:236500 including renal dysplasia.
Fetal anomalies v1.4 CEP55 Rebecca Foulger gene: CEP55 was added
gene: CEP55 was added to Fetal anomalies. Sources: Other
Mode of inheritance for gene: CEP55 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP55 were set to 28264986; 28295209
Phenotypes for gene: CEP55 were set to Multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, and hydranencephaly, 236500; lethal CEP55-related syndromes
Added comment: Added to Fetal anomalies panel on advice from Helen Brittain, Genomics England Clinical Team. MARCH phenotype is appropriate for this panel.
Sources: Other
COVID-19 research v0.127 NOS2 Ivone Leong Classified gene: NOS2 as Green List (high evidence)
COVID-19 research v0.127 NOS2 Ivone Leong Gene: nos2 has been classified as Green List (High Evidence).
COVID-19 research v0.126 NOS2 Ivone Leong gene: NOS2 was added
gene: NOS2 was added to Viral susceptibility. Sources: Expert list
Mode of inheritance for gene: NOS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NOS2 were set to 31995689; 11207313
Review for gene: NOS2 was set to GREEN
Added comment: NOS2 is part of the list of genes that confer susceptibility to viral infections on the COVID Human Genetic Effort website (https://www.covidhge.com/).

PMID: 31995689 describes a 51 year old man from Iran who had an acute cytomegalovirus (CMV) infection which progressed to CMV disease and later died from it. The researchers found a homozygous variant that causes a frameshift mutation in NOS2 that caused NOS2 deficiency, which might cause the patient to be more susceptible to lethal CMV infection. It is rare for CMV to cause fatality in healthy people; however, Nos2 knockout mice are susceptible to lethal infection with murine CMV (PMID: 11207313).

Based on the above evidence NOS2 has been given Green gene status.
Sources: Expert list
COVID-19 research v0.125 ACKR1 Sarah Leigh Classified gene: ACKR1 as Red List (low evidence)
COVID-19 research v0.125 ACKR1 Sarah Leigh Added comment: Comment on list classification: PMID 19180233 noted the clinical significance of the lower neutrophil counts in individuals homozygous for the Duffy-null variant in medical decision making, as white blood cell count is a marker of immunocompetence, infection, and inflammation, and they proposed the potential utility of rs2814778 genotyping. PMID 18621010, showed that rs2814778 -46CC was greater in HIV-positive patients, and -46CC individuals had a 50% higher risk of acquiring HIV, however, -46CC was associated with slower disease progression in terms of death or development of dementia. Survival appeared to be dependent on the level of WBC (PMID 19620399).
COVID-19 research v0.125 ACKR1 Sarah Leigh Gene: ackr1 has been classified as Red List (Low Evidence).
COVID-19 research v0.124 ACKR1 Sarah Leigh Publications for gene: ACKR1 were set to
COVID-19 research v0.123 ACKR1 Sarah Leigh Phenotypes for gene: ACKR1 were changed from to [Blood group, Duffy system] 110700
COVID-19 research v0.122 ACKR1 Sarah Leigh Mode of inheritance for gene: ACKR1 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.121 TP53 Sarah Leigh Source OMIM was added to TP53.
COVID-19 research v0.121 TNF Sarah Leigh gene: TNF was added
gene: TNF was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: TNF was set to
COVID-19 research v0.121 TLR2 Sarah Leigh gene: TLR2 was added
gene: TLR2 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: TLR2 was set to
COVID-19 research v0.121 SERPINA1 Sarah Leigh gene: SERPINA1 was added
gene: SERPINA1 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: SERPINA1 was set to
COVID-19 research v0.121 SCN5A Sarah Leigh gene: SCN5A was added
gene: SCN5A was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: SCN5A was set to
COVID-19 research v0.121 RB1 Sarah Leigh gene: RB1 was added
gene: RB1 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: RB1 was set to
COVID-19 research v0.121 PDCD1 Sarah Leigh gene: PDCD1 was added
gene: PDCD1 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: PDCD1 was set to
COVID-19 research v0.121 NUP214 Sarah Leigh gene: NUP214 was added
gene: NUP214 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: NUP214 was set to
COVID-19 research v0.121 MET Sarah Leigh gene: MET was added
gene: MET was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: MET was set to
COVID-19 research v0.121 LDLR Sarah Leigh gene: LDLR was added
gene: LDLR was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: LDLR was set to
COVID-19 research v0.121 KRT18 Sarah Leigh gene: KRT18 was added
gene: KRT18 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: KRT18 was set to
COVID-19 research v0.121 IRGM Sarah Leigh gene: IRGM was added
gene: IRGM was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: IRGM was set to
COVID-19 research v0.121 IL6 Sarah Leigh gene: IL6 was added
gene: IL6 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: IL6 was set to
COVID-19 research v0.121 IL4R Sarah Leigh gene: IL4R was added
gene: IL4R was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: IL4R was set to
COVID-19 research v0.121 IFNG Sarah Leigh gene: IFNG was added
gene: IFNG was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: IFNG was set to
COVID-19 research v0.121 IFITM3 Sarah Leigh gene: IFITM3 was added
gene: IFITM3 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: IFITM3 was set to
COVID-19 research v0.121 ICAM1 Sarah Leigh gene: ICAM1 was added
gene: ICAM1 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: ICAM1 was set to
COVID-19 research v0.121 HTR2A Sarah Leigh gene: HTR2A was added
gene: HTR2A was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: HTR2A was set to
COVID-19 research v0.121 HLA-DQB1 Sarah Leigh gene: HLA-DQB1 was added
gene: HLA-DQB1 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: HLA-DQB1 was set to
COVID-19 research v0.121 HLA-C Sarah Leigh gene: HLA-C was added
gene: HLA-C was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: HLA-C was set to
COVID-19 research v0.121 HFE Sarah Leigh gene: HFE was added
gene: HFE was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: HFE was set to
COVID-19 research v0.121 HBB Sarah Leigh gene: HBB was added
gene: HBB was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: HBB was set to
COVID-19 research v0.121 DMD Sarah Leigh gene: DMD was added
gene: DMD was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: DMD was set to
COVID-19 research v0.121 CYP2B6 Sarah Leigh gene: CYP2B6 was added
gene: CYP2B6 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: CYP2B6 was set to
COVID-19 research v0.121 CX3CR1 Sarah Leigh gene: CX3CR1 was added
gene: CX3CR1 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: CX3CR1 was set to
COVID-19 research v0.121 CR1 Sarah Leigh gene: CR1 was added
gene: CR1 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: CR1 was set to
COVID-19 research v0.121 CPT2 Sarah Leigh gene: CPT2 was added
gene: CPT2 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: CPT2 was set to
COVID-19 research v0.121 CIB1 Sarah Leigh Source OMIM was added to CIB1.
COVID-19 research v0.121 CD209 Sarah Leigh gene: CD209 was added
gene: CD209 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: CD209 was set to
COVID-19 research v0.121 CCR5 Sarah Leigh gene: CCR5 was added
gene: CCR5 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: CCR5 was set to
COVID-19 research v0.121 CCND1 Sarah Leigh gene: CCND1 was added
gene: CCND1 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: CCND1 was set to
COVID-19 research v0.121 CCL3L1 Sarah Leigh gene: CCL3L1 was added
gene: CCL3L1 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: CCL3L1 was set to
COVID-19 research v0.121 CCL11 Sarah Leigh gene: CCL11 was added
gene: CCL11 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: CCL11 was set to
COVID-19 research v0.121 AKT1 Sarah Leigh gene: AKT1 was added
gene: AKT1 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: AKT1 was set to
COVID-19 research v0.121 ACKR1 Sarah Leigh gene: ACKR1 was added
gene: ACKR1 was added to Viral susceptibility. Sources: OMIM
Mode of inheritance for gene: ACKR1 was set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.107 RELA Ivone Leong Classified gene: RELA as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.107 RELA Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on expert review. As there are only 2 cases and because the phenotype are slightly different, this gene will be rated Amber until more cases emerge.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.107 RELA Ivone Leong Gene: rela has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.106 RAC2 Ivone Leong Classified gene: RAC2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.106 RAC2 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green based on expert review (Zornitza Stark) and evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.106 RAC2 Ivone Leong Gene: rac2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.105 RAC2 Ivone Leong Publications for gene: RAC2 were set to 21167572; 30654050; 30723080; 31071452; 25512081; 10758162; 31382036; 10961859
Additional findings health related - CNV analysis adults v0.0 Eleanor Williams Added Panel Additional findings health related adult CNVs
Set child panels to: Additional findings health related adult additional CNVs; Additional findings health related child CNVs
Set panel types to: Super Panel
Additional findings health related - adults v0.0 Eleanor Williams Added Panel Additional findings health related adult
Set child panels to: Additional findings health related adult additional genes; Additional findings health related child
Set panel types to: Super Panel
Additional findings health related - CNV analysis children v0.7 Eleanor Williams Panel status changed from internal to public
Additional findings health related - children v0.9 Eleanor Williams Panel status changed from internal to public
Additional findings health related - adult specific v0.9 Eleanor Williams Panel status changed from internal to public
Additional findings health related - CNV analysis adult specific v0.10 Eleanor Williams Panel status changed from internal to public
Intellectual disability v3.29 RSRC1 Zornitza Stark edited their review of gene: RSRC1: Added comment: 17 additional individuals reported.; Changed rating: GREEN; Changed publications: 28640246, 29522154, 32227164; Changed phenotypes: Intellectual developmental disorder, autosomal recessive 70, MIM# 618402; Set current diagnostic: yes
Cerebellar hypoplasia v1.39 TSEN34 Zornitza Stark reviewed gene: TSEN34: Rating: RED; Mode of pathogenicity: None; Publications: 18711368; Phenotypes: Pontocerebellar hypoplasia type 2C 612390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.120 HLA-B Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Red to Green. Although not all studies agree on the association of specific HLA-B alleles and SARS infection (e.g. PMIDs 12969506, 15243926), these studies do both report an association. PMID:18186801 do not report an association between tested HLA-B alleles and SARS development but on balance in-silico evidence also suggests that HLA-B alleles could play a role in modifying the response to the virus. Therefore Green rating is appropriate for this research panel.; to: Comment on list classification: Updated rating from Red to Green. Although not all studies agree on the association of specific HLA-B alleles and SARS infection (e.g. PMIDs 12969506, 15243926), these studies do both report an association. PMID:18186801 do not report an association between tested HLA-B alleles and SARS development, but on balance in-silico evidence also suggests that HLA-B alleles could play a role in modifying the response to the virus. Therefore Green rating is appropriate for this research panel.
COVID-19 research v0.120 HLA-B Rebecca Foulger Classified gene: HLA-B as Green List (high evidence)
COVID-19 research v0.120 HLA-B Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green. Although not all studies agree on the association of specific HLA-B alleles and SARS infection (e.g. PMIDs 12969506, 15243926), these studies do both report an association. PMID:18186801 do not report an association between tested HLA-B alleles and SARS development but on balance in-silico evidence also suggests that HLA-B alleles could play a role in modifying the response to the virus. Therefore Green rating is appropriate for this research panel.
COVID-19 research v0.120 HLA-B Rebecca Foulger Gene: hla-b has been classified as Green List (High Evidence).
Additional findings health related - CNV analysis children v0.6 VHL Eleanor Williams Transcript for gene VHL was changed from None to ENST00000256474.2; NM_000551.3
Additional findings health related - children v0.8 VHL Eleanor Williams Transcript for gene VHL was changed from None to ENST00000256474.2; NM_000551.3
Additional findings health related - children v0.7 RET Eleanor Williams Transcript for gene RET was changed from None to ENST00000355710.8; NM_020975.4
Additional findings health related - children v0.6 PCSK9 Eleanor Williams Transcript for gene PCSK9 was changed from None to ENST00000302118.5; NM_174936.3
Additional findings health related - adult specific v0.8 MUTYH Eleanor Williams Transcript for gene MUTYH was changed from None to ENST00000450313.5; NM_001128425.1
Tag adult-onset tag was added to MUTYH.
Additional findings health related - CNV analysis adult specific v0.9 MUTYH Eleanor Williams Transcript for gene MUTYH was changed from None to ENST00000450313.5; NM_001128425.1
Tag adult-onset tag was added to MUTYH.
COVID-19 research v0.119 HLA-B Rebecca Foulger commented on gene: HLA-B: PMID:15839463 (Umapathy et al., 2004). Full text is unavailable. Title: Absence of HLA B*46 in Indian population: could it be the cause for protection from SARS epidemic?
Additional findings health related - adult specific v0.7 MSH6 Eleanor Williams Transcript for gene MSH6 was changed from None to ENST00000234420.9; NM_000179.2
Tag adult-onset tag was added to MSH6.
Additional findings health related - CNV analysis adult specific v0.8 MSH6 Eleanor Williams Transcript for gene MSH6 was changed from None to ENST00000234420.9; NM_000179.2
Tag adult-onset tag was added to MSH6.
COVID-19 research v0.119 HLA-B Rebecca Foulger commented on gene: HLA-B: PMID:18540051 (Roder et al., 2008 examine the crystal structure of HLA-B*1501 in complex with a SARS coronavirus-derived nonapeptide (VQQESSFVM) (full text unavailable at time of curation).
Additional findings health related - adult specific v0.6 MSH2 Eleanor Williams Transcript for gene MSH2 was changed from None to ENST00000233146.6; NM_000251.2
Tag adult-onset tag was added to MSH2.
Additional findings health related - CNV analysis adult specific v0.7 MSH2 Eleanor Williams Transcript for gene MSH2 was changed from None to ENST00000233146.6; NM_000251.2
Tag adult-onset tag was added to MSH2.
COVID-19 research v0.119 HLA-B Rebecca Foulger commented on gene: HLA-B: PMID:32303592 (Nguyen et al., 2020) performed in-silico analysis of viral-binding affinity across HLA genotypes for SARS-CoV-2 peptides. Based on in-silico results, they suggest that individuals with HLA-B*46:01 may be vulnerable to COVID-19. Conversely, HLA-B*15:03 may enable greater immunity.
Additional findings health related - adult specific v0.5 MLH1 Eleanor Williams Transcript for gene MLH1 was changed from None to ENST00000231790.6; NM_000249.3
Tag adult-onset tag was added to MLH1.
Additional findings health related - CNV analysis adult specific v0.6 MLH1 Eleanor Williams Transcript for gene MLH1 was changed from None to ENST00000231790.6; NM_000249.3
Tag adult-onset tag was added to MLH1.
Additional findings health related - CNV analysis children v0.5 MEN1 Eleanor Williams Transcript for gene MEN1 was changed from None to ENST00000312049.10; NM_130799.2
Additional findings health related - children v0.5 MEN1 Eleanor Williams Transcript for gene MEN1 was changed from None to ENST00000312049.10; NM_130799.2
Additional findings health related - CNV analysis children v0.4 LDLR Eleanor Williams Transcript for gene LDLR was changed from None to ENST00000558518.5; NM_000527.4
Additional findings health related - children v0.4 LDLR Eleanor Williams Transcript for gene LDLR was changed from None to ENST00000558518.5; NM_000527.4
Additional findings health related - adult specific v0.4 BRCA2 Eleanor Williams Transcript for gene BRCA2 was changed from None to ENST00000544455.5; NM_000059.3
Tag adult-onset tag was added to BRCA2.
Additional findings health related - CNV analysis adult specific v0.5 BRCA2 Eleanor Williams Transcript for gene BRCA2 was changed from None to ENST00000544455.5; NM_000059.3
Tag adult-onset tag was added to BRCA2.
COVID-19 research v0.119 HLA-B Rebecca Foulger Publications for gene: HLA-B were set to 12969506; 15243926; 18186801
COVID-19 research v0.118 HLA-B Rebecca Foulger commented on gene: HLA-B
COVID-19 research v0.118 IL18 Rebecca Foulger changed review comment from: PMID:25395539 (Zhang et al 2014) report that IL-18 and IL-22 administration to mice offered protection against a broad range of RV inoculation, and may offer broad antibiral therapeutic potential.; to: PMID:25395539 (Zhang et al 2014) report that IL-18 and IL-22 administration to mice offered protection against a broad range of RV inoculation, and may offer broad antiviral therapeutic potential.
COVID-19 research v0.118 IL22 Rebecca Foulger changed review comment from: PMID:25395539 (Zhang et al 2014) report that IL-18 and IL-22 administration to mice offered protection against a broad range of RV inoculation, and may offer broad antibiral therapeutic potential.; to: PMID:25395539 (Zhang et al 2014) report that IL-18 and IL-22 administration to mice offered protection against a broad range of RV inoculation, and may offer broad antiviral therapeutic potential.
COVID-19 research v0.118 IL22 Rebecca Foulger Publications for gene: IL22 were set to 25395539
COVID-19 research v0.117 IL22 Rebecca Foulger Publications for gene: IL22 were set to
COVID-19 research v0.116 IL22 Rebecca Foulger commented on gene: IL22
COVID-19 research v0.116 IL18 Rebecca Foulger Classified gene: IL18 as Amber List (moderate evidence)
COVID-19 research v0.116 IL18 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber, based largely on PMID:31660404 who report identification of IL-18 polymorphisms that may confer a higher incidence of CMV infection (in kidney transplant patients). Additional expression assays studies in mice support a role for IL-18 in innate immunity viral response.
COVID-19 research v0.116 IL18 Rebecca Foulger Gene: il18 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.115 IL18 Rebecca Foulger commented on gene: IL18: PMID:31660404. Perez-Flores examines two SNPs in the promoter region of IL-18 gene (-607C/A (rs1946518) and -137G/C (rs187238) in 498 adult kidney transplant recipients. Results suggest that the rs1946518/rs187238 haplotype is associated with a higher incidence of post-prophylaxis cytomegalovirus (CMV) infection. Prior identification of these SNPs could help select alternative measures to prevent delayed-onset CMV infection in these patients.
COVID-19 research v0.115 IL18 Rebecca Foulger Publications for gene: IL18 were set to 15606801; 25395539
COVID-19 research v0.114 IL18 Rebecca Foulger Publications for gene: IL18 were set to 15606801
COVID-19 research v0.113 IL18 Rebecca Foulger commented on gene: IL18: PMID:25395539 (Zhang et al 2014) report that IL-18 and IL-22 administration to mice offered protection against a broad range of RV inoculation, and may offer broad antibiral therapeutic potential.
COVID-19 research v0.113 IL18 Rebecca Foulger changed review comment from: PMID:15606801 (Van Der Sluijs et al., 2005): IL18 is upregulated in after Influenza infection, and IL18 deficiency is associated with accelerated viral clearance.; to: PMID:15606801 (Van Der Sluijs et al., 2005): IL18 is upregulated in after Influenza infection, and IL18 deficiency is associated with accelerated viral clearance (mouse study).
COVID-19 research v0.113 IL18 Rebecca Foulger Publications for gene: IL18 were set to 15606801
COVID-19 research v0.112 IL18 Rebecca Foulger Publications for gene: IL18 were set to
COVID-19 research v0.111 IL18 Rebecca Foulger commented on gene: IL18
Additional findings health related - adult specific v0.3 BRCA1 Eleanor Williams Phenotypes for gene: BRCA1 were changed from Adult only; Breast and ovarian cancer predisposition; ENST00000357654.8 to Adult only; Breast and ovarian cancer predisposition
Transcript for gene BRCA1 was changed from None to ENST00000357654.8; NM_007294.3
Tag adult-onset tag was added to BRCA1.
Additional findings health related - CNV analysis adult specific v0.4 BRCA1 Eleanor Williams Phenotypes for gene: BRCA1 were changed from Adult only; ENST00000357654.8; Breast and ovarian cancer predisposition to Adult only; Breast and ovarian cancer predisposition
Transcript for gene BRCA1 was changed from None to ENST00000357654.8; NM_007294.3
Tag adult-onset tag was added to BRCA1.
Additional findings health related v0.109 BRCA1 Eleanor Williams Phenotypes for gene: BRCA1 were changed from ENST00000357654.8; Breast and ovarian cancer predisposition; Adult only to Breast and ovarian cancer predisposition; Adult only
Additional findings health related - children v0.3 APOB Eleanor Williams Transcript for gene APOB was changed from None to ENST00000233242.5; NM_000384.2
Additional findings health related - CNV analysis children v0.3 APC Eleanor Williams Transcript for gene APC was changed from None to ENST00000257430.9; NM_000038.5
Additional findings health related - children v0.2 APC Eleanor Williams Transcript for gene APC was changed from None to ENST00000257430.9; NM_000038.5
Additional findings health related - CNV analysis children v0.1 VHL Eleanor Williams gene: VHL was added
gene: VHL was added to Additional findings health related child CNVs. Sources: Expert Review Green,Other
Mode of inheritance for gene: VHL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: VHL were set to Von Hippel Lindau Syndrome; Other cancer predisposition; Adult and child
Additional findings health related - CNV analysis children v0.1 MEN1 Eleanor Williams gene: MEN1 was added
gene: MEN1 was added to Additional findings health related child CNVs. Sources: Expert Review Green,Expert list
Mode of inheritance for gene: MEN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MEN1 were set to Myltiple endocrine Neoplasia Type 1; Other cancer predisposition; Adult and child
Additional findings health related - CNV analysis children v0.1 LDLR Eleanor Williams gene: LDLR was added
gene: LDLR was added to Additional findings health related child CNVs. Sources: Expert Review Green,Expert list
Mode of inheritance for gene: LDLR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: LDLR were set to Familial hypercholesterolaemia; Adult and child
Additional findings health related - CNV analysis children v0.1 APC Eleanor Williams gene: APC was added
gene: APC was added to Additional findings health related child CNVs. Sources: Expert Review Green,Expert list
Mode of inheritance for gene: APC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: APC were set to Familial Adenomatous Polyposis; Adult and child; Bowel cancer predisposition
Additional findings health related - CNV analysis children v0.0 Eleanor Williams Added Panel Additional findings health related child CNVs
Additional findings health related - CNV analysis adult specific v0.2 MUTYH Eleanor Williams gene: MUTYH was added
gene: MUTYH was added to Additional findings health related adult additional CNVs. Sources: Expert Review Green,Other
Mode of inheritance for gene: MUTYH was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MUTYH were set to Adult only; Bowel cancer predisposition; MYH-associated polyposis
Additional findings health related - CNV analysis adult specific v0.2 MSH6 Eleanor Williams gene: MSH6 was added
gene: MSH6 was added to Additional findings health related adult additional CNVs. Sources: Expert Review Green,Other
Mode of inheritance for gene: MSH6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MSH6 were set to Bowel cancer predisposition; Adult only; Hereditary non-polyposis colorectal cancer
Additional findings health related - CNV analysis adult specific v0.2 MSH2 Eleanor Williams gene: MSH2 was added
gene: MSH2 was added to Additional findings health related adult additional CNVs. Sources: Expert Review Green,Expert list
Mode of inheritance for gene: MSH2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MSH2 were set to Bowel cancer predisposition; Adult only; Hereditary non-polyposis colorectal cancer
Additional findings health related - CNV analysis adult specific v0.2 MLH1 Eleanor Williams gene: MLH1 was added
gene: MLH1 was added to Additional findings health related adult additional CNVs. Sources: Expert Review Green,Expert list
Mode of inheritance for gene: MLH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MLH1 were set to Bowel cancer predisposition; Adult only; Hereditary non-polyposis colorectal cancer
Additional findings health related - CNV analysis adult specific v0.2 BRCA2 Eleanor Williams gene: BRCA2 was added
gene: BRCA2 was added to Additional findings health related adult additional CNVs. Sources: Expert Review Green,Expert list
Mode of inheritance for gene: BRCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: BRCA2 were set to Adult only; Breast and ovarian cancer predisposition
Additional findings health related - CNV analysis adult specific v0.2 BRCA1 Eleanor Williams gene: BRCA1 was added
gene: BRCA1 was added to Additional findings health related adult additional CNVs. Sources: Expert Review Green,Expert list
Mode of inheritance for gene: BRCA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: BRCA1 were set to Adult only; ENST00000357654.8; Breast and ovarian cancer predisposition
Additional findings health related - CNV analysis adult specific v0.0 Eleanor Williams Added Panel Additional findings health related adult additional CNVs
COVID-19 research v0.111 TMPRSS2 Catherine Snow changed review comment from: PMID: 31488196 - Host susceptibility to severe influenza A virus infection, this paper reviews genes involved and identified TMPRSS2.

This gene has also been identified in this preprint - ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy https://doi.org/10.1101/2020.03.30.20047878
Sources: Literature; to: PMID: 31488196 - Host susceptibility to severe influenza A virus infection, this paper reviews genes involved and identified TMPRSS2. Papers identified include:
PMID: 25904605 which reported that higher TMPRSS2 expression variant, rs2070788 GG genotype, was associated with higher susceptibility to severe illness in patients with A(H1N1)pdm09 influenza.
PMID: 24600012 showed that TMPRSS2 is the key host protease that activates IAVs in vivo through proteolytic cleavage of their HA proteins
PMID: 24522916 looked at knockout mice that do not express TMPRSS2 that are resistant to pulmonary disease with lethal outcome when infected with influenza A viruses of subtypes H7N9 and H1N1, whereas they are not protected from lethal H3N2 virus infection

This gene has also been identified in this preprint - ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy https://doi.org/10.1101/2020.03.30.20047878
Sources: Literature
COVID-19 research v0.111 TMPRSS2 Catherine Snow Classified gene: TMPRSS2 as Amber List (moderate evidence)
COVID-19 research v0.111 TMPRSS2 Catherine Snow Gene: tmprss2 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.110 TMPRSS2 Catherine Snow gene: TMPRSS2 was added
gene: TMPRSS2 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: TMPRSS2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TMPRSS2 were set to 31488196
Review for gene: TMPRSS2 was set to AMBER
Added comment: PMID: 31488196 - Host susceptibility to severe influenza A virus infection, this paper reviews genes involved and identified TMPRSS2.

This gene has also been identified in this preprint - ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy https://doi.org/10.1101/2020.03.30.20047878
Sources: Literature
Additional findings health related - children v0.1 VHL Eleanor Williams gene: VHL was added
gene: VHL was added to Additional findings health related child. Sources: Expert Review Green,Other
Mode of inheritance for gene: VHL was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: VHL were set to Other cancer predisposition; Von Hippel Lindau Syndrome; Adult and child
Additional findings health related - children v0.1 RET Eleanor Williams gene: RET was added
gene: RET was added to Additional findings health related child. Sources: Expert Review Green,Other
Mode of inheritance for gene: RET was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: RET were set to Other cancer predisposition; Myltiple endocrine Neoplasia Type 2; Adult and child
Mode of pathogenicity for gene: RET was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Additional findings health related - children v0.1 PCSK9 Eleanor Williams gene: PCSK9 was added
gene: PCSK9 was added to Additional findings health related child. Sources: Expert Review Green,Other
Mode of inheritance for gene: PCSK9 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PCSK9 were set to Adult and child; Familial hypercholesterolaemia
Mode of pathogenicity for gene: PCSK9 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Additional findings health related - children v0.1 MEN1 Eleanor Williams gene: MEN1 was added
gene: MEN1 was added to Additional findings health related child. Sources: Expert list,Expert Review Green
Mode of inheritance for gene: MEN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MEN1 were set to Other cancer predisposition; Adult and child; Myltiple endocrine Neoplasia Type 1
Additional findings health related - children v0.1 LDLR Eleanor Williams gene: LDLR was added
gene: LDLR was added to Additional findings health related child. Sources: Expert list,Expert Review Green
Mode of inheritance for gene: LDLR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: LDLR were set to Adult and child; Familial hypercholesterolaemia
Additional findings health related - children v0.1 APOB Eleanor Williams gene: APOB was added
gene: APOB was added to Additional findings health related child. Sources: Expert Review Green,Other
Mode of inheritance for gene: APOB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: APOB were set to Adult and child; Familial hypercholesterolaemia
Mode of pathogenicity for gene: APOB was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Additional findings health related - children v0.1 APC Eleanor Williams gene: APC was added
gene: APC was added to Additional findings health related child. Sources: Expert list,Expert Review Green
Mode of inheritance for gene: APC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: APC were set to Familial Adenomatous Polyposis; Adult and child; Bowel cancer predisposition
Additional findings health related - children v0.0 Eleanor Williams Added Panel Additional findings health related child
Additional findings health related - adult specific v0.1 MUTYH Eleanor Williams gene: MUTYH was added
gene: MUTYH was added to Additional findings health related adult additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: MUTYH was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MUTYH were set to Bowel cancer predisposition; MYH-associated polyposis; Adult only
Additional findings health related - adult specific v0.1 MSH6 Eleanor Williams gene: MSH6 was added
gene: MSH6 was added to Additional findings health related adult additional genes. Sources: Other,Expert Review Green
Mode of inheritance for gene: MSH6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MSH6 were set to Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only
Additional findings health related - adult specific v0.1 MSH2 Eleanor Williams gene: MSH2 was added
gene: MSH2 was added to Additional findings health related adult additional genes. Sources: Expert list,Expert Review Green
Mode of inheritance for gene: MSH2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MSH2 were set to Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only
Additional findings health related - adult specific v0.1 MLH1 Eleanor Williams gene: MLH1 was added
gene: MLH1 was added to Additional findings health related adult additional genes. Sources: Expert list,Expert Review Green
Mode of inheritance for gene: MLH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: MLH1 were set to Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only
Additional findings health related - adult specific v0.1 BRCA2 Eleanor Williams gene: BRCA2 was added
gene: BRCA2 was added to Additional findings health related adult additional genes. Sources: Expert list,Expert Review Green
Mode of inheritance for gene: BRCA2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: BRCA2 were set to Adult only; Breast and ovarian cancer predisposition
Additional findings health related - adult specific v0.1 BRCA1 Eleanor Williams gene: BRCA1 was added
gene: BRCA1 was added to Additional findings health related adult additional genes. Sources: Expert list,Expert Review Green
Mode of inheritance for gene: BRCA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: BRCA1 were set to Adult only; Breast and ovarian cancer predisposition; ENST00000357654.8
Additional findings health related - adult specific v0.0 Eleanor Williams Added Panel Additional findings health related adult additional genes
Primary ciliary disorders v1.22 TTC12 Zornitza Stark gene: TTC12 was added
gene: TTC12 was added to Primary ciliary disorders. Sources: Literature
Mode of inheritance for gene: TTC12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC12 were set to 31978331
Phenotypes for gene: TTC12 were set to Ciliary dyskinesia
Review for gene: TTC12 was set to GREEN
gene: TTC12 was marked as current diagnostic
Added comment: Four unrelated families with LoF variants reported with a respiratory phenotype.
Sources: Literature
Intracerebral calcification disorders v1.18 JAM2 Zornitza Stark edited their review of gene: JAM2: Set current diagnostic: yes
Intracerebral calcification disorders v1.18 JAM2 Zornitza Stark gene: JAM2 was added
gene: JAM2 was added to Intracerebral calcification disorders. Sources: Literature
Mode of inheritance for gene: JAM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JAM2 were set to 31851307
Phenotypes for gene: JAM2 were set to Primary brain calcification
Review for gene: JAM2 was set to GREEN
Added comment: Three unrelated families with bi-allelic variants reported. The clinical phenotypes of the four patients included parkinsonism (3/4), dysarthria (3/4), seizures (1/4), and probable asymptomatic (1/4), with diverse onset ages.
Sources: Literature
Intellectual disability v3.29 EIF2AK2 Zornitza Stark gene: EIF2AK2 was added
gene: EIF2AK2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIF2AK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK2 were set to 32197074
Phenotypes for gene: EIF2AK2 were set to Intellectual disability; white matter abnormalities; ataxia; regression with febrile illness
Review for gene: EIF2AK2 was set to GREEN
gene: EIF2AK2 was marked as current diagnostic
Added comment: Eight individuals with de novo variants and complex neurodevelopmental phenotype.
Sources: Literature
Intellectual disability v3.29 EIF2AK1 Zornitza Stark gene: EIF2AK1 was added
gene: EIF2AK1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: EIF2AK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EIF2AK1 were set to 32197074
Phenotypes for gene: EIF2AK1 were set to Intellectual disability; white matter abnormalities
Review for gene: EIF2AK1 was set to RED
Added comment: Single individual reported with de novo variant in this gene, one to watch.
Sources: Literature
Intellectual disability v3.29 NRROS Zornitza Stark gene: NRROS was added
gene: NRROS was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NRROS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRROS were set to 32100099; 32197075
Phenotypes for gene: NRROS were set to neurodegeneration; intracranial calcification; epilepsy
Review for gene: NRROS was set to GREEN
Added comment: Normal development or mild developmental delay until onset of regression around age of 1 concurrent with epilepsy
Biallelic LOF mutations with functional evidence of pathogenicity reported in 6 unrelated families. Suggest also add to Epilepsy panel, possibly others.
Sources: Literature
Early onset or syndromic epilepsy v2.38 SEMA6B Zornitza Stark gene: SEMA6B was added
gene: SEMA6B was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SEMA6B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEMA6B were set to 32169168
Phenotypes for gene: SEMA6B were set to Progressive myoclonic epilepsy
Review for gene: SEMA6B was set to GREEN
Added comment: Five individuals from unrelated families reported with de novo variants in the last exon, escaping NMD.
Sources: Literature
Intellectual disability v3.29 NOVA2 Zornitza Stark gene: NOVA2 was added
gene: NOVA2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NOVA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOVA2 were set to 32197073
Phenotypes for gene: NOVA2 were set to Intellectual disability; autism; hypotonia; spasticity; ataxia
Review for gene: NOVA2 was set to GREEN
gene: NOVA2 was marked as current diagnostic
Added comment: Six individuals with de novo frameshift variants resulting in C-terminal extension suggesting partial LoF as mechanism.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.104 POLD1 Ivone Leong Classified gene: POLD1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.104 POLD1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on expert review and evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.104 POLD1 Ivone Leong Gene: pold1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.103 HYOU1 Ivone Leong Phenotypes for gene: HYOU1 were changed from Hypoglycemia, inflammatory complications; Congenital defects of phagocyte number or function to Hypoglycemia, inflammatory complications; Congenital defects of phagocyte number or function; Immunodeficiency 59 and hypoglycemia, 233600
Primary immunodeficiency or monogenic inflammatory bowel disease v2.102 HYOU1 Ivone Leong Publications for gene: HYOU1 were set to 32048120; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.101 MKL1 Ivone Leong Classified gene: MKL1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.101 MKL1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on expert review and additional of second case.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.101 MKL1 Ivone Leong Gene: mkl1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.100 MKL1 Ivone Leong Publications for gene: MKL1 were set to 32048120; 26224645; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.99 POLD2 Ivone Leong Phenotypes for gene: POLD2 were changed from Polymerase d 2 deficiency; Recurrent respiratory tract infections, skin infections, warts and molluscum, short stature, intellectual disability; Immunodeficiencies affecting cellular and humoral immunity to Polymerase d 2 deficiency; Recurrent respiratory tract infections, skin infections, warts and molluscum, short stature, intellectual disability; Immunodeficiencies affecting cellular and humoral immunity; Low CD4 T cells; Low B cells, normal maturation
Primary immunodeficiency or monogenic inflammatory bowel disease v2.98 POLR3A Ivone Leong Classified gene: POLR3A as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.98 POLR3A Ivone Leong Added comment: Comment on list classification: Amber rating given based on expert review.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.98 POLR3A Ivone Leong Gene: polr3a has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.97 POLR3C Ivone Leong Classified gene: POLR3C as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.97 POLR3C Ivone Leong Added comment: Comment on list classification: Rating given based on expert review.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.97 POLR3C Ivone Leong Gene: polr3c has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.96 RNF31 Ivone Leong Classified gene: RNF31 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.96 RNF31 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on expert review and evidence of a second case.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.96 RNF31 Ivone Leong Gene: rnf31 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.95 RNF31 Ivone Leong Publications for gene: RNF31 were set to 32048120; 26008899; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.94 SEC61A1 Ivone Leong Publications for gene: SEC61A1 were set to 28782633; 32086639; 32048120
Primary immunodeficiency or monogenic inflammatory bowel disease v2.93 SH3BP2 Ivone Leong Publications for gene: SH3BP2 were set to 29669173; 22640988; 32048120; 28914985; 11381256; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.92 SH3KBP1 Ivone Leong Publications for gene: SH3KBP1 were set to 32086639; 32048120; 29636373
Primary immunodeficiency or monogenic inflammatory bowel disease v2.91 SLC39A7 Ivone Leong Classified gene: SLC39A7 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.91 SLC39A7 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on expert reviews and evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.91 SLC39A7 Ivone Leong Gene: slc39a7 has been classified as Green List (High Evidence).
COVID-19 research v0.109 PARP1 Sarah Leigh changed review comment from: PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor. Therefore, activiation of PARP1 could promote Influenza infection.
Sources: Literature; to: PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor. Therefore, activiation of PARP1 could promote Influenza infection, by interfering with the IFNAR1.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.90 PARP1 Sarah Leigh gene: PARP1 was added
gene: PARP1 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: PARP1 was set to Unknown
Publications for gene: PARP1 were set to 31915279
Review for gene: PARP1 was set to RED
Added comment: PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor. Therefore, activiation of PARP1 could promote Influenza infection, by interfering with the IFNAR1.
Sources: Literature
COVID-19 research v0.109 PARP1 Sarah Leigh gene: PARP1 was added
gene: PARP1 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: PARP1 was set to Unknown
Publications for gene: PARP1 were set to 31915279
Added comment: PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor. Therefore, activiation of PARP1 could promote Influenza infection.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.89 RECQL4 Sarah Leigh Classified gene: RECQL4 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.89 RECQL4 Sarah Leigh Gene: recql4 has been classified as Green List (High Evidence).
COVID-19 research v0.108 RECQL4 Sarah Leigh Classified gene: RECQL4 as Green List (high evidence)
COVID-19 research v0.108 RECQL4 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in 3 unrelated cases in which immunodeficiecy was a feature (PMID 16630167; 21143835; 26064716). In addition RECQL4 variants have been implicated in Acrodermatitis Enteropathica caused by SLC39A4 (p.Gly512Trp)(PMID 30174688)
COVID-19 research v0.108 RECQL4 Sarah Leigh Gene: recql4 has been classified as Green List (High Evidence).
COVID-19 research v0.107 RECQL4 Sarah Leigh Publications for gene: RECQL4 were set to 16630167
Primary immunodeficiency or monogenic inflammatory bowel disease v2.88 RECQL4 Sarah Leigh Publications for gene: RECQL4 were set to 16630167
Primary immunodeficiency or monogenic inflammatory bowel disease v2.87 RECQL4 Sarah Leigh Classified gene: RECQL4 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.87 RECQL4 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in 3 unrelated cases in which immunodeficiecy was a feature (PMID 16630167; 21143835; 26064716). In addition RECQL4 variants have been implicated in Acrodermatitis Enteropathica caused by SLC39A4 (p.Gly512Trp)(PMID 30174688)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.87 RECQL4 Sarah Leigh Gene: recql4 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.106 ELF4 Rebecca Foulger commented on gene: ELF4: Some evidence that ELF4 is involved in the anti-viral innate immune response, but no genetic data. Therefore keeping rating as Red.
COVID-19 research v0.106 ELF4 Rebecca Foulger changed review comment from: PMID:30089112 (Du et al., 2018) show that during the antiviral response, miR-221 was induced through ELF4 binding to its promoter.; to: PMID:30089112 (Du et al., 2018) show that during the antiviral response, miR-221 was induced through ELF4 binding to its promoter (mice cells, recombinant human ELF4).
COVID-19 research v0.106 ELF4 Rebecca Foulger commented on gene: ELF4: PMID:30089112 (Du et al., 2018) show that during the antiviral response, miR-221 was induced through ELF4 binding to its promoter.
COVID-19 research v0.106 ELF4 Rebecca Foulger commented on gene: ELF4
COVID-19 research v0.106 COLEC11 Rebecca Foulger commented on gene: COLEC11
COVID-19 research v0.106 CNBP Rebecca Foulger commented on gene: CNBP
Primary immunodeficiency or monogenic inflammatory bowel disease v2.86 IL18BP Zornitza Stark gene: IL18BP was added
gene: IL18BP was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: IL18BP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL18BP were set to 31213488
Phenotypes for gene: IL18BP were set to {?Hepatitis, fulminant viral, susceptibility to} 618549
Review for gene: IL18BP was set to RED
Added comment: Single individual reported with homozygous 40bp deletion in this gene and fulminant Hep A hepatitis.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.86 IRF4 Zornitza Stark gene: IRF4 was added
gene: IRF4 was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: IRF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IRF4 were set to 29537367
Phenotypes for gene: IRF4 were set to Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724
Review for gene: IRF4 was set to RED
Added comment: Single family reported with Whipple's disease and a rare missense in IRF4. Younger healthy carrier members of the family had the same variant as older affected individuals, leading the authors to speculate about age-dependent penetrance. GWAS indicates separate link with skin/hair/eye pigmentation.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.86 POLR3F Zornitza Stark gene: POLR3F was added
gene: POLR3F was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: POLR3F was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR3F were set to 30211253
Phenotypes for gene: POLR3F were set to Severe VZV infection
Review for gene: POLR3F was set to RED
Added comment: Missense variant identified in a pair of monozygotic twins. Variant was paternally inherited.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.86 IL23R Zornitza Stark gene: IL23R was added
gene: IL23R was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: IL23R was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL23R were set to 30578351
Phenotypes for gene: IL23R were set to Susceptibility to mycobacteria and Salmonella
Review for gene: IL23R was set to RED
Added comment: Single family reported.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.86 IL12RB2 Zornitza Stark gene: IL12RB2 was added
gene: IL12RB2 was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: IL12RB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL12RB2 were set to 30578351
Phenotypes for gene: IL12RB2 were set to Susceptibility to mycobacteria and Salmonella
Review for gene: IL12RB2 was set to RED
Added comment: Single individual reported, some functional data.
Sources: Expert list
Arthrogryposis v3.9 LMX1B Rebecca Foulger Publications for gene: LMX1B were set to 8403448; 19194568; 31369690; ISBN:9780199557509
Arthrogryposis v3.8 LMX1B Rebecca Foulger Publications for gene: LMX1B were set to 8403448
Arthrogryposis v3.7 LMX1B Rebecca Foulger Phenotypes for gene: LMX1B were changed from Nail-patella syndrome, 161200 to Nail-patella syndrome, 161200; Nail Patella syndrome; NPS
Arthrogryposis v3.6 LMX1B Rebecca Foulger Classified gene: LMX1B as Green List (high evidence)
Arthrogryposis v3.6 LMX1B Rebecca Foulger Added comment: Comment on list classification: Changed rating to Green with agreement from Zerin Hyder: overlap with Arthrogryposis phenotype and Nail patella syndrome.
Arthrogryposis v3.6 LMX1B Rebecca Foulger Gene: lmx1b has been classified as Green List (High Evidence).
Arthrogryposis v3.5 LMX1B Rebecca Foulger commented on gene: LMX1B: Dr Ataf Sabir notes (email, April 16 2020) that they had a 100K patient who presented with what looked like arthrogryposis, who had the Arthrogryposis panel with nil result, and on further investigation the patient had Nail Patella syndrome.
Arthrogryposis v3.5 LMX1B Ataf Sabir reviewed gene: LMX1B: Rating: ; Mode of pathogenicity: ; Publications: 19194568, 31369690, ISBN:9780199557509; Phenotypes: Nail Patella syndrome, NPS; Mode of inheritance:
Arthrogryposis v3.4 LMX1B Rebecca Foulger gene: LMX1B was added
gene: LMX1B was added to Arthrogryposis. Sources: Expert Review,Other
Mode of inheritance for gene: LMX1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LMX1B were set to 8403448
Phenotypes for gene: LMX1B were set to Nail-patella syndrome, 161200
Added comment: Added LMX1B to the Arthrogryposis panel as requested by Dr Ataf Sabir.
Sources: Expert Review, Other
Optic neuropathy v2.3 UCHL1 Zornitza Stark gene: UCHL1 was added
gene: UCHL1 was added to Optic neuropathy. Sources: Expert list
Mode of inheritance for gene: UCHL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UCHL1 were set to 29735986; 23359680; 28007905
Phenotypes for gene: UCHL1 were set to Spastic paraplegia 79, autosomal recessive (MIM#615491)
Review for gene: UCHL1 was set to GREEN
Added comment: Three families reported, optic atrophy is a consistent feature and onset of OA preceded onset of other neurological features in at least some of the reported individuals.
Sources: Expert list
Optic neuropathy v2.3 NBAS Zornitza Stark gene: NBAS was added
gene: NBAS was added to Optic neuropathy. Sources: Expert list
Mode of inheritance for gene: NBAS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NBAS were set to 20577004; 26286438
Phenotypes for gene: NBAS were set to Short stature, optic nerve atrophy, and Pelger-Huet anomaly
Review for gene: NBAS was set to GREEN
Added comment: This gene causes two recessive phenotypes: OA is not a feature of the infantile liver failure syndrome. It is however a consistent feature of the second condition: Short stature, optic nerve atrophy, and Pelger-Huet anomaly, MIM# 614800, which has predominantly been described in the Yakult.

PMID: 20577004 - Study of 30 Yakut families found ALL had OA, 33/34 patients had the same homozygous missense, founder very likely

PMID: 26286438 - 1 patient chet for a PTC and missense and had OA. Second patient (also chet PTC/missense) had NO OA.

Remains to be seen whether OA is an association with specific variants in this gene, and what the underlying mechanism for this is.
Sources: Expert list
Optic neuropathy v2.3 MECR Zornitza Stark gene: MECR was added
gene: MECR was added to Optic neuropathy. Sources: Expert list
Mode of inheritance for gene: MECR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MECR were set to 27817865; 31137067
Phenotypes for gene: MECR were set to Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities
Review for gene: MECR was set to GREEN
gene: MECR was marked as current diagnostic
Added comment: At least 6 families reported, optic atrophy is a consistent feature.
Sources: Expert list
Optic neuropathy v2.3 FDXR Zornitza Stark gene: FDXR was added
gene: FDXR was added to Optic neuropathy. Sources: Expert list
Mode of inheritance for gene: FDXR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDXR were set to 30250212; 28965846
Phenotypes for gene: FDXR were set to Auditory neuropathy and optic atrophy, MIM#617717
Review for gene: FDXR was set to GREEN
Added comment: Six unrelated families reported with bi-allelic variants in this gene, optic atrophy is a consistent feature.
Sources: Expert list
Optic neuropathy v2.3 ATAD3A Zornitza Stark reviewed gene: ATAD3A: Rating: GREEN; Mode of pathogenicity: None; Publications: 27640307, 28652416; Phenotypes: Harel-Yoon syndrome, MIM#617183; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Optic neuropathy v2.3 AP3B2 Zornitza Stark gene: AP3B2 was added
gene: AP3B2 was added to Optic neuropathy. Sources: Expert list
Mode of inheritance for gene: AP3B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP3B2 were set to 27889060
Phenotypes for gene: AP3B2 were set to Early-onset epileptic encephalopathy with optic atrophy, MIM#617276
Review for gene: AP3B2 was set to GREEN
Added comment: Optic atrophy is a feature of this neurological disorder.
Sources: Expert list
Optic neuropathy v2.3 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29181157, 26539208, 30252181, 30389403; Phenotypes: Spastic ataxia 5, autosomal recessive (MIM#614487), Spinocerebellar ataxia 28 (MIM#610246); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.86 SMARCD2 Ivone Leong Phenotypes for gene: SMARCD2 were changed from Neutropenia, developmental aberrations, skeletal abnormalities, hematopoietic stem cells, myelodysplasia; Congenital defects of phagocyte number or function to Neutropenia, developmental aberrations, skeletal abnormalities, hematopoietic stem cells, myelodysplasia; Congenital defects of phagocyte number or function; Specific granule deficiency 2, 617475
Primary immunodeficiency or monogenic inflammatory bowel disease v2.85 SMARCD2 Ivone Leong Classified gene: SMARCD2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.85 SMARCD2 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on expert review.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.85 SMARCD2 Ivone Leong Gene: smarcd2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.84 SMARCD2 Ivone Leong Publications for gene: SMARCD2 were set to 32048120; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.83 SRP54 Ivone Leong Classified gene: SRP54 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.83 SRP54 Ivone Leong Added comment: Comment on list classification: Promoted Red to Green based on expert review and evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.83 SRP54 Ivone Leong Gene: srp54 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.82 SRP54 Ivone Leong Phenotypes for gene: SRP54 were changed from Congenital defects of phagocyte number or function; Schwachman Diamond features to Congenital defects of phagocyte number or function; Schwachman Diamond features; Neutropenia, severe congenital, 8, autosomal dominant, 618752
Primary immunodeficiency or monogenic inflammatory bowel disease v2.81 TFRC Ivone Leong Classified gene: TFRC as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.81 TFRC Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on expert review and evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.81 TFRC Ivone Leong Gene: tfrc has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.80 TFRC Ivone Leong Phenotypes for gene: TFRC were changed from Recurrent infections, neutropenia, thrombocytopenia; Recurrent infections, thrombocytopenia; Immunodeficiencies affecting cellular and humoral immunity to Recurrent infections, neutropenia, thrombocytopenia; Recurrent infections, thrombocytopenia; Immunodeficiencies affecting cellular and humoral immunity; Immunodeficiency 46, 616740; T cells: normal number, poor proliferation; B cells: normal number, low memory B cells; recurrent infections, neutorpaenia; thrombocytopaenia
Primary immunodeficiency or monogenic inflammatory bowel disease v2.79 TFRC Ivone Leong Publications for gene: TFRC were set to 32048120; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.78 TGFB1 Ivone Leong Classified gene: TGFB1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.78 TGFB1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on expert review and evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.78 TGFB1 Ivone Leong Gene: tgfb1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.77 NFE2L2 Ivone Leong Classified gene: NFE2L2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.77 NFE2L2 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on exper review.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.77 NFE2L2 Ivone Leong Gene: nfe2l2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.76 NFE2L2 Ivone Leong Phenotypes for gene: NFE2L2 were changed from white matter cerebral lesions, increased level of homocysteine; Recurrent respiratory and skin infections, growth retardation, , developmental delay; Immunodeficiency, developmental delay, and hypohomocysteinemia, 617744; NFE2L2 GOF; increased expression of stress response genes; Combined immunodeficiencies with associated or syndromic features to white matter cerebral lesions, increased level of homocysteine; Recurrent respiratory and skin infections, growth retardation, , developmental delay; Immunodeficiency, developmental delay, and hypohomocysteinemia, 617744; NFE2L2 GOF; increased expression of stress response genes; Combined immunodeficiencies with associated or syndromic features; mmunodeficiency, developmental delay, and hypohomocysteinemia, 617744; Recurrent respiratory and skin infection; Growth retardation; Developmental delay, borderline ID; White matter cerebral lesions
Primary immunodeficiency or monogenic inflammatory bowel disease v2.75 TNFRSF9 Ivone Leong Classified gene: TNFRSF9 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.75 TNFRSF9 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on expert review and evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.75 TNFRSF9 Ivone Leong Gene: tnfrsf9 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.74 TOP2B Ivone Leong Classified gene: TOP2B as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.74 TOP2B Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on expert review and evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.74 TOP2B Ivone Leong Gene: top2b has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.73 TRAF3IP2 Ivone Leong Classified gene: TRAF3IP2 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.73 TRAF3IP2 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on expert review and evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.73 TRAF3IP2 Ivone Leong Gene: traf3ip2 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.72 TRIM22 Ivone Leong Classified gene: TRIM22 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.72 TRIM22 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on expert review and evidence.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.72 TRIM22 Ivone Leong Gene: trim22 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.71 TRIM22 Ivone Leong Phenotypes for gene: TRIM22 were changed from Autoinflammatory Disorders; Granulomatous colitis; Diseases of Immune Dysregulation; TRIM22 to Autoinflammatory Disorders; Granulomatous colitis; Diseases of Immune Dysregulation; TRIM22; Inflammatory bowel disease
Primary immunodeficiency or monogenic inflammatory bowel disease v2.70 USP18 Ivone Leong Classified gene: USP18 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.70 USP18 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green based on expert reviews.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.70 USP18 Ivone Leong Gene: usp18 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.69 TRAF3IP2 Ivone Leong Publications for gene: TRAF3IP2 were set to 32048120; 24120361; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.68 USP18 Ivone Leong Publications for gene: USP18 were set to 32048120; 27325888; 31272490; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.67 WDR1 Ivone Leong Classified gene: WDR1 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.67 WDR1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green based on expert review.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.67 WDR1 Ivone Leong Gene: wdr1 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.66 WDR1 Ivone Leong Publications for gene: WDR1 were set to 32048120; 27557945; 32086639
Primary immunodeficiency or monogenic inflammatory bowel disease v2.65 ZNF341 Ivone Leong Classified gene: ZNF341 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.65 ZNF341 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on expert reviews.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.65 ZNF341 Ivone Leong Gene: znf341 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.64 PIK3CD Ivone Leong Added comment: Comment on mode of inheritance: Updated MOI from Monoallelic to Both Monoallelic and biallelic based on expert review and evidence provided by Zornitza Stark (Australian Genomics).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.64 PIK3CD Ivone Leong Mode of inheritance for gene: PIK3CD was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.63 PIK3CD Ivone Leong Publications for gene: PIK3CD were set to 24165795; 24136356; 29226301
Primary immunodeficiency or monogenic inflammatory bowel disease v2.62 TCF3 Ivone Leong Added comment: Comment on mode of inheritance: Updated MOI from Monoallelic to Both Monoallelic and biallelic based on expert review and evidence provided by Zornitza Stark (Australian Genomics).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.62 TCF3 Ivone Leong Mode of inheritance for gene: TCF3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.61 STAT5B Ivone Leong Publications for gene: STAT5B were set to 13679528; 16920911; 15827093; 16787985; 17030597; 17389811; 20538865; 26703237
Primary immunodeficiency or monogenic inflammatory bowel disease v2.60 STAT5B Ivone Leong Added comment: Comment on mode of inheritance: Changed MOI from Biallelic to Both Monoallelic and biallelic based on expert review and evidence provided by Zornitza Stark (Australian Genomics). It should be noted that the AD has a dominant-negative effect.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.60 STAT5B Ivone Leong Mode of inheritance for gene: STAT5B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.59 TCF3 Ivone Leong Publications for gene: TCF3 were set to 24216514; 28532655; 29114388
Primary immunodeficiency or monogenic inflammatory bowel disease v2.58 BCL10 Ivone Leong Classified gene: BCL10 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.58 BCL10 Ivone Leong Added comment: Comment on list classification: Based on recent expert reviews and evidence, it has been decided that there is now enough evidence to support a gene-disease association. Therefore, this gene has been promoted from Amber to Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.58 BCL10 Ivone Leong Gene: bcl10 has been classified as Green List (High Evidence).
COVID-19 research v0.106 POLR3F Ivone Leong Publications for gene: POLR3F were set to 30211253
COVID-19 research v0.105 POLR3C Ivone Leong Publications for gene: POLR3C were set to 28783042
COVID-19 research v0.104 POLR3A Ivone Leong Publications for gene: POLR3A were set to 29728610; 28783042
COVID-19 research v0.103 OAS1 Ivone Leong reviewed gene: OAS1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.103 IKZF1 Ivone Leong reviewed gene: IKZF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
COVID-19 research v0.103 TMEM173 Ivone Leong reviewed gene: TMEM173: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 TCF3 Ivone Leong reviewed gene: TCF3: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 STXBP2 Ivone Leong reviewed gene: STXBP2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 STAT5B Ivone Leong reviewed gene: STAT5B: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 RANBP2 Ivone Leong reviewed gene: RANBP2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 PSMB8 Ivone Leong reviewed gene: PSMB8: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 PIK3CD Ivone Leong reviewed gene: PIK3CD: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 JAK1 Ivone Leong reviewed gene: JAK1: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 FOXN1 Ivone Leong reviewed gene: FOXN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 C3 Ivone Leong reviewed gene: C3: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 C1S Ivone Leong reviewed gene: C1S: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 C1R Ivone Leong reviewed gene: C1R: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 AICDA Ivone Leong reviewed gene: AICDA: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.103 TP53 Ivone Leong reviewed gene: TP53: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Bone marrow failure syndrome 5, 618165; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.103 SRP72 Ivone Leong reviewed gene: SRP72: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Bone marrow failure syndrome 1, 614675; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.103 RFWD3 Ivone Leong reviewed gene: RFWD3: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ?Fanconi anemia, complementation group W, 617784; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 MAD2L2 Ivone Leong reviewed gene: MAD2L2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ?Fanconi anemia, complementation group V, 617243 ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 XRCC2 Ivone Leong reviewed gene: XRCC2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ?Fanconi anemia, complementation group U, 617247; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 UBE2T Ivone Leong reviewed gene: UBE2T: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group T, 616435; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 RAD51 Ivone Leong reviewed gene: RAD51: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: ?Fanconi anemia, complementation group R, 617244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 SLX4 Ivone Leong reviewed gene: SLX4: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group P, 613951; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 RAD51C Ivone Leong reviewed gene: RAD51C: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group O, 613390; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 PALB2 Ivone Leong reviewed gene: PALB2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group N, 610832; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 FANCL Ivone Leong reviewed gene: FANCL: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group L, 614083; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 BRIP1 Ivone Leong reviewed gene: BRIP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group J, 609054; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 FANCG Ivone Leong reviewed gene: FANCG: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group G, 614082; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 FANCE Ivone Leong reviewed gene: FANCE: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group E, 600901; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 FANCD2 Ivone Leong reviewed gene: FANCD2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group D2, 227646; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 FANCC Ivone Leong reviewed gene: FANCC: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group C, 227645; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 FANCB Ivone Leong reviewed gene: FANCB: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group B, 300514; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
COVID-19 research v0.103 FANCA Ivone Leong reviewed gene: FANCA: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group A, 227650 ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 IL18BP Ivone Leong reviewed gene: IL18BP: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Defects in intrinsic and innate immunity, inborn errors of immunity related to leukocytes, IL-18BP deficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.103 IRF4 Ivone Leong reviewed gene: IRF4: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Defects in intrinsic and innate immunity, inborn errors of immunity related to leukocytes, IRF4 haploinsufficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.103 POLR3F Ivone Leong reviewed gene: POLR3F: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Defects in intrinsic and innate immunity, Predisposition to severe viral infection, RNA polymerase III deficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.103 POLR3C Ivone Leong reviewed gene: POLR3C: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Defects in intrinsic and innate immunity, Predisposition to severe viral infection, RNA polymerase III deficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.103 POLR3A Ivone Leong reviewed gene: POLR3A: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Defects in intrinsic and innate immunity, Predisposition to severe viral infection, RNA polymerase III deficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.103 CIB1 Ivone Leong reviewed gene: CIB1: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Defects in intrinsic and innate immunity, Epidermodysplasia verruciformis, CIB1 deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 IL23R Ivone Leong reviewed gene: IL23R: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Defects in intrinsic and innate immunity, Mendelian susceptibility to mycobacterial disease, IL-23R deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 IL12RB2 Ivone Leong reviewed gene: IL12RB2: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Defects in intrinsic and innate immunity, Mendelian susceptibility to mycobacterial disease, IL-12Rb2 deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.103 EFL1 Ivone Leong reviewed gene: EFL1: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Congenital defects of phagocyte number or function, Congenital neutropenias, Shwachman-Diamond Syndrome, 617941; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.102 TMEM173 Ivone Leong Source IUIS Classification December 2032 was added to TMEM173.
Mode of inheritance for gene TMEM173 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 TCF3 Ivone Leong Source IUIS Classification December 2031 was added to TCF3.
Mode of inheritance for gene TCF3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 STXBP2 Ivone Leong Source IUIS Classification December 2030 was added to STXBP2.
Mode of inheritance for gene STXBP2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 STAT5B Ivone Leong Source IUIS Classification December 2029 was added to STAT5B.
Mode of inheritance for gene STAT5B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 RANBP2 Ivone Leong Source IUIS Classification December 2028 was added to RANBP2.
Mode of inheritance for gene RANBP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 PSMB8 Ivone Leong Source IUIS Classification December 2027 was added to PSMB8.
Mode of inheritance for gene PSMB8 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 PIK3CD Ivone Leong Source IUIS Classification December 2026 was added to PIK3CD.
Mode of inheritance for gene PIK3CD was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 JAK1 Ivone Leong Source IUIS Classification December 2025 was added to JAK1.
Mode of inheritance for gene JAK1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 FOXN1 Ivone Leong Source IUIS Classification December 2024 was added to FOXN1.
Mode of inheritance for gene FOXN1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 C3 Ivone Leong Source IUIS Classification December 2022 was added to C3.
Mode of inheritance for gene C3 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 C1S Ivone Leong Source IUIS Classification December 2021 was added to C1S.
Mode of inheritance for gene C1S was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 C1R Ivone Leong Source IUIS Classification December 2020 was added to C1R.
Mode of inheritance for gene C1R was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 AICDA Ivone Leong Source IUIS Classification December 2019 was added to AICDA.
Mode of inheritance for gene AICDA was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.102 TP53 Ivone Leong gene: TP53 was added
gene: TP53 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TP53 were set to 32086639; 32048120
Phenotypes for gene: TP53 were set to Bone marrow failure syndrome 5, 618165
COVID-19 research v0.102 SRP72 Ivone Leong gene: SRP72 was added
gene: SRP72 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: SRP72 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SRP72 were set to 32086639; 32048120
Phenotypes for gene: SRP72 were set to Bone marrow failure syndrome 1, 614675
COVID-19 research v0.102 RFWD3 Ivone Leong gene: RFWD3 was added
gene: RFWD3 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: RFWD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RFWD3 were set to 32086639; 32048120
Phenotypes for gene: RFWD3 were set to ?Fanconi anemia, complementation group W, 617784
COVID-19 research v0.102 MAD2L2 Ivone Leong gene: MAD2L2 was added
gene: MAD2L2 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: MAD2L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAD2L2 were set to 32086639; 32048120
Phenotypes for gene: MAD2L2 were set to ?Fanconi anemia, complementation group V, 617243
COVID-19 research v0.102 XRCC2 Ivone Leong gene: XRCC2 was added
gene: XRCC2 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: XRCC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XRCC2 were set to 32086639; 32048120
Phenotypes for gene: XRCC2 were set to ?Fanconi anemia, complementation group U, 617247
COVID-19 research v0.102 UBE2T Ivone Leong gene: UBE2T was added
gene: UBE2T was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: UBE2T was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBE2T were set to 32086639; 32048120
Phenotypes for gene: UBE2T were set to Fanconi anemia, complementation group T, 616435
COVID-19 research v0.102 RAD51 Ivone Leong gene: RAD51 was added
gene: RAD51 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: RAD51 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAD51 were set to 32086639; 32048120
Phenotypes for gene: RAD51 were set to ?Fanconi anemia, complementation group R, 617244
COVID-19 research v0.102 SLX4 Ivone Leong gene: SLX4 was added
gene: SLX4 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: SLX4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLX4 were set to 32086639; 32048120
Phenotypes for gene: SLX4 were set to Fanconi anemia, complementation group P, 613951
COVID-19 research v0.102 RAD51C Ivone Leong gene: RAD51C was added
gene: RAD51C was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: RAD51C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RAD51C were set to 32086639; 32048120
Phenotypes for gene: RAD51C were set to Fanconi anemia, complementation group O, 613390
COVID-19 research v0.102 PALB2 Ivone Leong gene: PALB2 was added
gene: PALB2 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: PALB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PALB2 were set to 32086639; 32048120
Phenotypes for gene: PALB2 were set to Fanconi anemia, complementation group N, 610832
COVID-19 research v0.102 FANCL Ivone Leong gene: FANCL was added
gene: FANCL was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: FANCL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FANCL were set to 32086639; 32048120
Phenotypes for gene: FANCL were set to Fanconi anemia, complementation group L, 614083
COVID-19 research v0.102 BRIP1 Ivone Leong gene: BRIP1 was added
gene: BRIP1 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: BRIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRIP1 were set to 32086639; 32048120
Phenotypes for gene: BRIP1 were set to Fanconi anemia, complementation group J, 609054
COVID-19 research v0.102 FANCG Ivone Leong gene: FANCG was added
gene: FANCG was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: FANCG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FANCG were set to 32086639; 32048120
Phenotypes for gene: FANCG were set to Fanconi anemia, complementation group G, 614082
COVID-19 research v0.102 FANCE Ivone Leong gene: FANCE was added
gene: FANCE was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: FANCE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FANCE were set to 32086639; 32048120
Phenotypes for gene: FANCE were set to Fanconi anemia, complementation group E, 600901
COVID-19 research v0.102 FANCD2 Ivone Leong gene: FANCD2 was added
gene: FANCD2 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: FANCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FANCD2 were set to 32086639; 32048120
Phenotypes for gene: FANCD2 were set to Fanconi anemia, complementation group D2, 227646
COVID-19 research v0.102 FANCC Ivone Leong gene: FANCC was added
gene: FANCC was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: FANCC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FANCC were set to 32086639; 32048120
Phenotypes for gene: FANCC were set to Fanconi anemia, complementation group C, 227645
COVID-19 research v0.102 FANCB Ivone Leong gene: FANCB was added
gene: FANCB was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: FANCB was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: FANCB were set to 32086639; 32048120
Phenotypes for gene: FANCB were set to Fanconi anemia, complementation group B, 300514
COVID-19 research v0.102 FANCA Ivone Leong gene: FANCA was added
gene: FANCA was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: FANCA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FANCA were set to 32086639; 32048120
Phenotypes for gene: FANCA were set to Fanconi anemia, complementation group A, 227650
COVID-19 research v0.102 IL18BP Ivone Leong Source Expert Review Green was added to IL18BP.
Source IUIS Classification December 2019 was added to IL18BP.
Mode of inheritance for gene IL18BP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Defects in intrinsic and innate immunity; IL-18BP deficiency; inborn errors of immunity related to leukocytes for gene: IL18BP
Publications for gene IL18BP were updated from PubMed: 31213488 to 32086639; 32048120; PubMed: 31213488
Rating Changed from No List (delete) to Green List (high evidence)
COVID-19 research v0.102 IRF4 Ivone Leong gene: IRF4 was added
gene: IRF4 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: IRF4 was set to
Phenotypes for gene: IRF4 were set to Defects in intrinsic and innate immunity; IRF4 haploinsufficiency; inborn errors of immunity related to leukocytes
COVID-19 research v0.102 POLR3F Ivone Leong Source Expert Review Green was added to POLR3F.
Source IUIS Classification December 2019 was added to POLR3F.
Added phenotypes RNA polymerase III deficiency; Defects in intrinsic and innate immunity; Predisposition to severe viral infection for gene: POLR3F
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.102 POLR3C Ivone Leong Source Expert Review Green was added to POLR3C.
Source IUIS Classification December 2019 was added to POLR3C.
Added phenotypes RNA polymerase III deficiency; Defects in intrinsic and innate immunity; Predisposition to severe viral infection for gene: POLR3C
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.102 POLR3A Ivone Leong Source Expert Review Green was added to POLR3A.
Source IUIS Classification December 2019 was added to POLR3A.
Added phenotypes RNA polymerase III deficiency; Defects in intrinsic and innate immunity; Predisposition to severe viral infection for gene: POLR3A
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.102 CIB1 Ivone Leong gene: CIB1 was added
gene: CIB1 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: CIB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CIB1 were set to 32086639; 32048120
Phenotypes for gene: CIB1 were set to Epidermodysplasia verruciformis; Defects in intrinsic and innate immunity; CIB1 deficiency
COVID-19 research v0.102 IL23R Ivone Leong gene: IL23R was added
gene: IL23R was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: IL23R was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL23R were set to 32086639; 32048120
Phenotypes for gene: IL23R were set to Defects in intrinsic and innate immunity; Mendelian susceptibility to mycobacterial disease; IL-23R deficiency
COVID-19 research v0.102 IL12RB2 Ivone Leong gene: IL12RB2 was added
gene: IL12RB2 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: IL12RB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL12RB2 were set to 32086639; 32048120
Phenotypes for gene: IL12RB2 were set to Defects in intrinsic and innate immunity; Mendelian susceptibility to mycobacterial disease; IL-12Rb2 deficiency
COVID-19 research v0.102 EFL1 Ivone Leong gene: EFL1 was added
gene: EFL1 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019
Mode of inheritance for gene: EFL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFL1 were set to 32086639; 32048120
Phenotypes for gene: EFL1 were set to Congenital neutropenias; Congenital defects of phagocyte number or function; Shwachman-Diamond Syndrome, 617941
COVID-19 research v0.101 ACE2 Rebecca Foulger commented on gene: ACE2: Added ACE2 to the panel as an Amber gene: many papers demonstrate that ACE2 acts as a cell receptor for Coronaviruses (e.g. PMIDs 32142651, 15897467, 14647384).
COVID-19 research v0.101 ACE2 Rebecca Foulger Classified gene: ACE2 as Amber List (moderate evidence)
COVID-19 research v0.101 ACE2 Rebecca Foulger Gene: ace2 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.100 ACE2 Rebecca Foulger gene: ACE2 was added
gene: ACE2 was added to Viral susceptibility. Sources: Other
Mode of inheritance for gene: ACE2 was set to Unknown
Publications for gene: ACE2 were set to 14647384; 15897467; 16007097; 32142651
Review for gene: ACE2 was set to AMBER
Added comment: Sources: Other
COVID-19 research v0.99 CD4 Rebecca Foulger Publications for gene: CD4 were set to
COVID-19 research v0.98 CD4 Rebecca Foulger commented on gene: CD4
COVID-19 research v0.98 CD14 Rebecca Foulger Classified gene: CD14 as Amber List (moderate evidence)
COVID-19 research v0.98 CD14 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber: at least 2 publications supporting a link between CD14 polymorphism and viral infection (SARs and RSV).
COVID-19 research v0.98 CD14 Rebecca Foulger Gene: cd14 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.97 CD14 Rebecca Foulger Publications for gene: CD14 were set to 17913858
COVID-19 research v0.96 CD14 Rebecca Foulger commented on gene: CD14
COVID-19 research v0.96 ITGAM Catherine Snow Publications for gene: ITGAM were set to
COVID-19 research v0.95 ITGAM Catherine Snow Mode of inheritance for gene: ITGAM was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.94 ITGAM Catherine Snow Classified gene: ITGAM as Amber List (moderate evidence)
COVID-19 research v0.94 ITGAM Catherine Snow Gene: itgam has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.93 ITGAM Catherine Snow reviewed gene: ITGAM: Rating: AMBER; Mode of pathogenicity: None; Publications: 29712964, 32257537; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.93 RC3H1 Sarah Leigh Classified gene: RC3H1 as Amber List (moderate evidence)
COVID-19 research v0.93 RC3H1 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (lasted edited 01/27/2017) or in Gen2Phen. PMID 31636267 reports a biallelic nonsense variant (p.R688*), in a case with immune dysregulation syndrome
characterized by severe hyperinflammation in a consanguineous family. The association of this variant with the phenotype is supported by functional studies and mouse model (PMID 15917799).
COVID-19 research v0.93 RC3H1 Sarah Leigh Gene: rc3h1 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.57 RC3H1 Sarah Leigh Classified gene: RC3H1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.57 RC3H1 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (lasted edited 01/27/2017) or in Gen2Phen. PMID 31636267 reports a biallelic nonsense variant (p.R688*), in a case with immune dysregulation syndrome
characterized by severe hyperinflammation in a consanguineous family. The association of this variant with the phenotype is supported by functional studies and mouse model (PMID 15917799).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.57 RC3H1 Sarah Leigh Gene: rc3h1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.92 RC3H1 Sarah Leigh Publications for gene: RC3H1 were set to PMID: 31636267
Primary immunodeficiency or monogenic inflammatory bowel disease v2.56 RC3H1 Sarah Leigh Publications for gene: RC3H1 were set to PMID: 31636267
COVID-19 research v0.91 CCL5 Rebecca Foulger Classified gene: CCL5 as Amber List (moderate evidence)
COVID-19 research v0.91 CCL5 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber: Some evidence that CCL5 (aka RANTES) polymorphisms may be associated with viral infections, including SARS.
COVID-19 research v0.91 CCL5 Rebecca Foulger Gene: ccl5 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.90 CCL5 Rebecca Foulger Publications for gene: CCL5 were set to 17540042; 22576913
COVID-19 research v0.89 CCL5 Rebecca Foulger commented on gene: CCL5: PMID:30175654 (El-Bendary et al., 2019) report rs3817655 polymorphism in CCL5 may be associated with spontaneous clearance of Hepatitis C virus (HCV).
COVID-19 research v0.89 CCL5 Rebecca Foulger commented on gene: CCL5: PMID:31874580 (Sheng et al. 2019) study suggests that the CCL5 rs2107538 polymorphism was correlated with TB (infectious disease caused by Mycobacterium tuberculosis) susceptibility in Caucasians. The rs2107538 polymorphism is suggested to affect CCL5 expression.
COVID-19 research v0.89 CCL5 Rebecca Foulger Publications for gene: CCL5 were set to 17540042
COVID-19 research v0.88 CCL5 Rebecca Foulger commented on gene: CCL5
COVID-19 research v0.88 CCL2 Rebecca Foulger Classified gene: CCL2 as Green List (high evidence)
COVID-19 research v0.88 CCL2 Rebecca Foulger Added comment: Comment on list classification: Updated rating of CCL2 from Red to Green. 3 publications supporting an association between CCL2 SNP(s) and viral infections including HIV, Japanese encephalitis and SARs. Additional evidence that CCL2 levels are raised after viral infection.
COVID-19 research v0.88 CCL2 Rebecca Foulger Gene: ccl2 has been classified as Green List (High Evidence).
COVID-19 research v0.87 CCL2 Rebecca Foulger Phenotypes for gene: CCL2 were changed from {HIV-1, resistance to}, 609423; Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection; Susceptibility to SARS-CoV to {HIV-1, resistance to}, 609423; Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection; Susceptibility to SARS-CoV; Susceptibility to viral Japanese encephalitis
COVID-19 research v0.86 CCL2 Rebecca Foulger Publications for gene: CCL2 were set to 25818534; 26687605; 16916890; 24788844; 27260136
COVID-19 research v0.85 CCL2 Rebecca Foulger commented on gene: CCL2: PMID:29057937 (Chowdhury and Khan, 2017) report that SNPs of CCL2 (rs1024611G) and its receptor CCR2 (rs1799864A) significantly associated with Japanese encephalitis (JE) which may serve as possible genetic predisposing factor. JE is one of the major viral encephalitis in Asia and parts of Western Pacific.
COVID-19 research v0.85 PSMB10 Sarah Leigh Classified gene: PSMB10 as Amber List (moderate evidence)
COVID-19 research v0.85 PSMB10 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (last edited on 06/25/2007) or in Gen2Phen. PMID 31783057 reports a case of Proteasome-associated autoinflammatory syndrome in an infant with a biallelic variant (c.41T>C, p.Phe14Ser), together with supporting functional studies.
COVID-19 research v0.85 PSMB10 Sarah Leigh Gene: psmb10 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.55 PSMB10 Sarah Leigh Classified gene: PSMB10 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.55 PSMB10 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (last edited on 06/25/2007) or in Gen2Phen. PMID 31783057 reports a case of Proteasome-associated autoinflammatory syndrome in an infant with a biallelic variant (c.41T>C, p.Phe14Ser), together with supporting functional studies.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.55 PSMB10 Sarah Leigh Gene: psmb10 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.84 PSMB10 Sarah Leigh Phenotypes for gene: PSMB10 were changed from Proteasome-associated autoinflammatory syndrome to Proteasome-associated autoinflammatory syndrome (PRAAS)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.54 PSMB10 Sarah Leigh Phenotypes for gene: PSMB10 were changed from Proteasome-associated autoinflammatory syndrome to Proteasome-associated autoinflammatory syndrome (PRAAS)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.53 NFKBID Sarah Leigh Classified gene: NFKBID as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.53 NFKBID Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. The only variants are structural rearrangements that include NFKBID amongst other genes. PMID 26973645 reports "heterozygous mutation in the nfkbid gene encoding the atypical IκB protein IκBNS led to reduced steady state IgM and IgG3 antibody levels and impaired response to vaccination with TI-2 antigens in mice". Thus, variants in human NFKBID may also result in reduced levels of IgM and IgG3 and compromized vaccination responses.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.53 NFKBID Sarah Leigh Gene: nfkbid has been classified as Red List (Low Evidence).
COVID-19 research v0.83 NFKBID Sarah Leigh Classified gene: NFKBID as Red List (low evidence)
COVID-19 research v0.83 NFKBID Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. The only variants are structural rearrangements that include NFKBID amongst other genes. PMID 26973645 reports "heterozygous mutation in the nfkbid gene encoding the atypical IκB protein IκBNS led to reduced steady state IgM and IgG3 antibody levels and impaired response to vaccination with TI-2 antigens in mice". Thus, variants in human NFKBID may also result in reduced levels of IgM and IgG3 and compromized vaccination responses.
COVID-19 research v0.83 NFKBID Sarah Leigh Gene: nfkbid has been classified as Red List (Low Evidence).
COVID-19 research v0.82 NFKBID Sarah Leigh Publications for gene: NFKBID were set to
Primary immunodeficiency or monogenic inflammatory bowel disease v2.52 NFKBID Sarah Leigh Publications for gene: NFKBID were set to
Intellectual disability v3.29 GAD1 Sarah Leigh Phenotypes for gene: GAD1 were changed from ?Cerebral palsy, spastic quadriplegic, 1; Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele to ?Cerebral palsy, spastic quadriplegic, 1 603513; Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele
Early onset or syndromic epilepsy v2.38 GAD1 Sarah Leigh Phenotypes for gene: GAD1 were changed from Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele to ?Cerebral palsy, spastic quadriplegic, 1 603513; Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele
Early onset or syndromic epilepsy v2.37 GAD1 Sarah Leigh Publications for gene: GAD1 were set to https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Early onset or syndromic epilepsy v2.36 GAD1 Sarah Leigh Classified gene: GAD1 as Green List (high evidence)
Early onset or syndromic epilepsy v2.36 GAD1 Sarah Leigh Gene: gad1 has been classified as Green List (High Evidence).
COVID-19 research v0.81 SART3 Catherine Snow reviewed gene: SART3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Intellectual disability v3.28 GAD1 Sarah Leigh Publications for gene: GAD1 were set to 26503795; 24896178; 26350204; https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Intellectual disability v3.27 GAD1 Sarah Leigh Added comment: Comment on publications: https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085 new publication, without a PMID
Intellectual disability v3.27 GAD1 Sarah Leigh Publications for gene: GAD1 were set to 26503795; 24896178; 26350204; https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Intellectual disability v3.27 GAD1 Sarah Leigh Added comment: Comment on publications: https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085 new publication, without a PMID
Intellectual disability v3.27 GAD1 Sarah Leigh Publications for gene: GAD1 were set to
Intellectual disability v3.26 GAD1 Sarah Leigh Phenotypes for gene: GAD1 were changed from ?Cerebral palsy, spastic quadriplegic, 1 to ?Cerebral palsy, spastic quadriplegic, 1; Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele
Intellectual disability v3.25 GAD1 Sarah Leigh Classified gene: GAD1 as Green List (high evidence)
Intellectual disability v3.25 GAD1 Sarah Leigh Added comment: Comment on list classification: Five biallelic loss of function variants reported in 11 cases in 6 unrelated families. All cases had epilepsy syndrome, 10 profound intellectual disabilty (1 case died at day 9 of life) and other nuerological and developement features. Supportive functional studies were also presented
Intellectual disability v3.25 GAD1 Sarah Leigh Gene: gad1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v2.35 GAD1 Sarah Leigh gene: GAD1 was added
gene: GAD1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: GAD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GAD1 were set to https://doi-org.ezproxy.library.qmul.ac.uk/10.1093/brain/awaa085
Phenotypes for gene: GAD1 were set to Developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele
Review for gene: GAD1 was set to GREEN
Added comment: Five biallelic loss of function variants reported in 11 cases in 6 unrelated families. All cases had epilepsy syndrome, 10 profound intellectual disabilty (1 case died at day 9 of life) and other nuerological and developement features. Supportive functional studies were also presented.
Sources: Literature
Mitochondrial disorders v2.5 UQCRB Zornitza Stark reviewed gene: UQCRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 23281071, 28275242; Phenotypes: Mitochondrial complex III deficiency, nuclear type 3, 615158; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorders v2.5 SDHB Zornitza Stark reviewed gene: SDHB: Rating: GREEN; Mode of pathogenicity: None; Publications: 22972948, 26925370, 27604842; Phenotypes: Complex II deficiency, mitochondrial leucoencephalopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability v3.24 NUP188 Zornitza Stark reviewed gene: NUP188: Rating: GREEN; Mode of pathogenicity: None; Publications: 32021605, 28726809, 32275884; Phenotypes: microcephaly, ID, cataract, structural brain abnormalities, hypoventilation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mitochondrial disorders v2.5 MRPS23 Zornitza Stark reviewed gene: MRPS23: Rating: GREEN; Mode of pathogenicity: None; Publications: 26741492, 17873122, 25663021, 28752220; Phenotypes: Hepatic disease, Combined respiratory chain complex deficiencies, Cardiomyopathy, Tubulopathy, Lactic acidosis, Structural brain abnormalities; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 STAT5B Zornitza Stark reviewed gene: STAT5B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29844444; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 TCF3 Zornitza Stark reviewed gene: TCF3: Rating: GREEN; Mode of pathogenicity: None; Publications: 30063982; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 PIK3CD Zornitza Stark reviewed gene: PIK3CD: Rating: GREEN; Mode of pathogenicity: None; Publications: 31073077; Phenotypes: Severe bacterial infections, autoimmunity; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 REL Zornitza Stark reviewed gene: REL: Rating: RED; Mode of pathogenicity: None; Publications: 31103457; Phenotypes: Combined immunodeficiency, T cells: normal, decreased memory CD4, poor proliferation, B cells: low, mostly naive, few switched memory B cells, impaired proliferation, Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic organisms, Defective innate immunity; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 ZNF341 Zornitza Stark reviewed gene: ZNF341: Rating: GREEN; Mode of pathogenicity: None; Publications: 29907691, 29907690; Phenotypes: Hyper-IgE recurrent infection syndrome 3, autosomal recessive, MIM# 618282, Mild facial dysmorphism, Early onset eczema, Recurrent bacterial skin infections, abscesses, Recurrent respiratory infections, lung abscesses and pneumothoraces, Hyperextensible joints, bone fractures, retention of primary teeth; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 WDR1 Zornitza Stark edited their review of gene: WDR1: Changed phenotypes: Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia, Neutropaenia, Poor wound healing, Severe stomatitis, Neutrophil nuclei herniate
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 WDR1 Zornitza Stark reviewed gene: WDR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27994071, 27557945, 29751004; Phenotypes: Autoinflammatory periodic fever, neutrophil dysfunction, immunodeficiency, and thrombocytopenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 USP18 Zornitza Stark reviewed gene: USP18: Rating: GREEN; Mode of pathogenicity: None; Publications: 31940699, 27325888; Phenotypes: Pseudo-TORCH syndrome 2, MIM# 617397; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 TRIM22 Zornitza Stark reviewed gene: TRIM22: Rating: GREEN; Mode of pathogenicity: None; Publications: 26836588; Phenotypes: Inflammatory bowel disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 TRAF3IP2 Zornitza Stark reviewed gene: TRAF3IP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 24120361, 31292894, 20660351; Phenotypes: Candidiasis, familial, 8, MIM# 615527; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 TOP2B Zornitza Stark reviewed gene: TOP2B: Rating: GREEN; Mode of pathogenicity: None; Publications: 31409799; Phenotypes: Antibody deficiency, Recurrent infections, Facial dysmorphism, Limb anomalies; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 TNFRSF9 Zornitza Stark reviewed gene: TNFRSF9: Rating: GREEN; Mode of pathogenicity: None; Publications: 30872117, 31501153; Phenotypes: EBV lymphoproliferation, B-cell lymphoma, Chronic active EBV infection; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 TNFRSF13B Zornitza Stark changed review comment from: Agree this gene is difficult to categorise. We have decided to include the gene in our panels, but report only the specific variants for which there is published evidence, and to report them as contributory rather than solely causative.; to: 2018: Agree this gene is difficult to categorise. We have decided to include the gene in our panels, but report only the specific variants for which there is published evidence, and to report them as contributory rather than solely causative.

2020: Variants in this gene do not readily fit the monogenic rare disease paradigm, but nevertheless there is evidence they make a contribution to CVID pathogenesis. We have 'whitelisted' specific variants and are reporting them separately as susceptibility alleles. It is unlikely that further evidence will alter this interpretation, this is more of a question about reporting policy.
COVID-19 research v0.81 IL18BP Abdelazeem Elhabyan gene: IL18BP was added
gene: IL18BP was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: IL18BP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IL18BP were set to PubMed: 31213488
Mode of pathogenicity for gene: IL18BP was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added comment: Inherited IL-18BP deficiency in human fulminant viral hepatitis

Fulminant viral hepatitis (FVH) is a devastating and unexplained condition that strikes otherwise healthy individuals during primary infection with common liver-tropic viruses. We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in the uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepatitis by unleashing IL-18. These findings provide proof-of-principle that FVH can be caused by single-gene inborn errors that selectively disrupt liver-specific immunity. They also show that human IL-18 is toxic to the liver and that IL-18BP is its antidote.
Sources: Literature
COVID-19 research v0.81 HLA-DRB1 Abdelazeem Elhabyan gene: HLA-DRB1 was added
gene: HLA-DRB1 was added to Viral susceptibility. Sources: Literature
Mode of inheritance for gene: HLA-DRB1 was set to Unknown
Publications for gene: HLA-DRB1 were set to PMID: 19445991,26456283,19597844,10823757,
Penetrance for gene: HLA-DRB1 were set to unknown
Mode of pathogenicity for gene: HLA-DRB1 was set to Other
Review for gene: HLA-DRB1 was set to GREEN
Added comment: Association of human leukocyte antigen class II alleles with severe acute respiratory syndrome in the Vietnamese population PMID: 19445991,

HLA-DRB1*12 was more frequently shown in SARS patients than in controls (corrected p = 0.042). HLA-DRB1*1202, the predominant allele in the Vietnamese population showed the strongest association with SARS in a dominant model (corrected p = 0.0065 and 0.0052, depending on the controls to be compared). Our results and accumulated data on HLA in the Asian populations would help in the understanding of associations with emerging infectious diseases.

Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses PMID: 26456283
The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation

Clear and Independent Associations of Several HLA-DRB1 Alleles With Differential Antibody Responses to Hepatitis B Vaccination in Youth
PMID: 19597844
To confirm and refine associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination, we have analyzed 255 HIV-1 seropositive (HIV(+)) youth and 80 HIV-1 seronegatives (HIV(-)) enrolled into prospective studies. In univariate analyses that focused on HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes, the DRB1*03 allele group and DRB1*0701 were negatively associated with the responder phenotype (serum Ab concentration > or = 10 mIU/mL) (P = 0.026 and 0.043, respectively). Collectively, DRB1*03 and DRB1*0701 were found in 42 (53.8%) out of 78 non-responders (serum Ab <10 mIU/mL), 65 (40.6%) out of 160 medium responders (serum Ab 10-1,000 mIU/mL), and 27 (27.8%) out of 97 high responders (serum Ab >1,000 mIU/mL) (P < 0.001 for trend). Meanwhile, DRB1*08 was positively associated with the responder phenotype (P = 0.010), mostly due to DRB1*0804 (P = 0.008).

Influence of HLA Supertypes on Susceptibility and Resistance to Human Immunodeficiency Virus Type 1 Infection
PMID: 10823757
To determine whether HLA polymorphism influences HIV-1 susceptibility, a longitudinal cohort of highly HIV-1-exposed female sex workers based in Nairobi, Kenya, was prospectively analyzed. Decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related HLA alleles (A2/6802 supertype; incidence rate ratio [IRR], 0.45; 95% confidence interval [CI], 0.27-0.72; P=.0003). The alleles in this supertype are known in some cases to present the same peptide epitopes for T cell recognition. In addition, resistance to HIV-1 infection was independently associated with HLA DRB1*01 (IRR, 0.22; 95% CI, 0.06-0.60; P=.0003), which suggests that anti-HIV-1 class II restricted CD4 effector mechanisms may play an important role in protecting against viral challenge
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 NFE2L2 Zornitza Stark reviewed gene: NFE2L2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29018201; Phenotypes: Immunodeficiency, developmental delay, and hypohomocysteinemia, MIM# 617744, Recurrent respiratory and skin infection, Growth retardation, Developmental delay, borderline ID, White matter cerebral lesions; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 TGFB1 Zornitza Stark reviewed gene: TGFB1: Rating: AMBER; Mode of pathogenicity: None; Publications: 29483653; Phenotypes: Inflammatory bowel disease, immunodeficiency, and encephalopathy MIM# 618213; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 TFRC Zornitza Stark reviewed gene: TFRC: Rating: AMBER; Mode of pathogenicity: None; Publications: 26642240; Phenotypes: Immunodeficiency 46, MIM# 616740, T cells: normal number, poor proliferation, B cells: normal number, low memory B cells, recurrent infections, neutorpaenia, thrombocytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 SRP54 Zornitza Stark reviewed gene: SRP54: Rating: GREEN; Mode of pathogenicity: None; Publications: 29914977, 28972538; Phenotypes: Neutropenia, severe congenital, 8, autosomal dominant, MIM# 618752; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 SPPL2A Zornitza Stark reviewed gene: SPPL2A: Rating: AMBER; Mode of pathogenicity: None; Publications: 30127434; Phenotypes: Susceptibility to mycobacteria and Salmonella; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 SMARCD2 Zornitza Stark reviewed gene: SMARCD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28369036, 28369034; Phenotypes: Specific granule deficiency 2, MIM# 617475, Neutropaenia, Neurodevelopmental abnormalities in some, Myelodysplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 SLC7A7 Zornitza Stark reviewed gene: SLC7A7: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lysinuric protein intolerance, MIM# 222700, Hyper-inflammatory response of macrophages, Normal NK cell function, Lysinuric protein intolerance, Bleeding tendency, Alverolar proteinosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 SLC39A7 Zornitza Stark reviewed gene: SLC39A7: Rating: GREEN; Mode of pathogenicity: None; Publications: 30718914; Phenotypes: Antibody deficiency, early onset infections, blistering dermatosis, failure to thrive, thrombocytopaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 SH3KBP1 Zornitza Stark reviewed gene: SH3KBP1: Rating: RED; Mode of pathogenicity: None; Publications: 29636373, 21708930; Phenotypes: Immunodeficiency 61, MIM# 300310; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 SH3BP2 Zornitza Stark reviewed gene: SH3BP2: Rating: RED; Mode of pathogenicity: None; Publications: 26152156, 25705883, 25470448, 25220465; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 SEC61A1 Zornitza Stark reviewed gene: SEC61A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27392076, 28782633; Phenotypes: Hyperuricemic nephropathy, familial juvenile, 4, MIM# 617056, Hypogammaglobulinaemia, Severe recurrent respiratory tract infections; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 RNF31 Zornitza Stark reviewed gene: RNF31: Rating: AMBER; Mode of pathogenicity: None; Publications: 26008899, 30936877; Phenotypes: Immune deficiency, Autoinflammation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 RELA Zornitza Stark reviewed gene: RELA: Rating: AMBER; Mode of pathogenicity: None; Publications: 28600438, 29305315; Phenotypes: Mucocutaneous ulceration, chronic, MIM# 618287, Impaired NFkB activation, reduced production of inflammatory cytokines, autoimmune cytopaenias; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 RAC2 Zornitza Stark edited their review of gene: RAC2: Changed phenotypes: SCID, recurrent bacterial and viral infections, lymphoproliferation, neutropaenia, reticular dysgenesis, deafness, selective IgA deficiency, Reduced Ab responses following vaccination, Neutrophil immunodeficiency syndrome, MIM# 608203, Common variable immunodeficiency
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 RAC2 Zornitza Stark reviewed gene: RAC2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32198141, 31919089, 31382036, 31071452, 30723080, 30654050, 25512081; Phenotypes: SCID, recurrent bacterial and viral infections, lymphoproliferation, neutropaenia, reticular dysgenesis, deafness, selective IgA deficiency, Reduced Ab responses following vaccination; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 PTEN Zornitza Stark changed review comment from: GI polyps and diverticula are a feature of Cowden syndrome. The link between variants in PTEN and monogenic IBD appears based largely on experimental/mouse model evidence. There is a series of 34 individuals with PTEN variants and a range of autoimmune phenotypes reported in 22266152, including colitis. Considering PTEN-related conditions are relatively common as are auto-immune disorders, I am not convinced this is enough for causality.; to: GI polyps and diverticula are a feature of Cowden syndrome. The link between variants in PTEN and monogenic IBD appears based largely on experimental/mouse model evidence. There is a series of 34 individuals with PTEN variants and a range of autoimmune phenotypes reported in 22266152, including colitis. Considering PTEN-related conditions are relatively common as are auto-immune disorders, I am not convinced this is enough for causality. I also note this gene is Amber on the PID panel.
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 PTEN Zornitza Stark reviewed gene: PTEN: Rating: AMBER; Mode of pathogenicity: None; Publications: 23962154, 24882466, 25352295, 22266152; Phenotypes: Colitis; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 PSMG2 Zornitza Stark reviewed gene: PSMG2: Rating: RED; Mode of pathogenicity: None; Publications: 30664889; Phenotypes: CANDLE syndrome, Chronic atypical neutrophilic dermatitis with lipodystrophy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 POLR3C Zornitza Stark gene: POLR3C was added
gene: POLR3C was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: POLR3C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR3C were set to 28783042
Phenotypes for gene: POLR3C were set to Severe VZV infection
Review for gene: POLR3C was set to AMBER
Added comment: One individual with POLR3C variant and another individual with both POL3RA and POL3RC variants.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 POLR3A Zornitza Stark gene: POLR3A was added
gene: POLR3A was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: POLR3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR3A were set to 28783042; 29728610
Phenotypes for gene: POLR3A were set to Severe VZV infection
Review for gene: POLR3A was set to AMBER
Added comment: Two individuals with mono allelic POLR3A variants and another individual with both POLR3A and a POLR3C variants reported.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 POLE Zornitza Stark reviewed gene: POLE: Rating: GREEN; Mode of pathogenicity: None; Publications: 30503519, 23230001, 25948378; Phenotypes: FILS syndrome, MIM# 615139, IMAGE-I syndrome, MIM# 618336; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 POLD2 Zornitza Stark reviewed gene: POLD2: Rating: RED; Mode of pathogenicity: None; Publications: 31449058; Phenotypes: Low CD4 T cells, Low B cells, normal maturation, recurrent respiratory tract infections, skin infections, warts and molluscum, short stature, intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 POLD1 Zornitza Stark reviewed gene: POLD1: Rating: AMBER; Mode of pathogenicity: None; Publications: 31629014, 31449058; Phenotypes: Low CD4 T cells, Low B cells, normal maturation, recurrent respiratory tract infections, skin infections, warts and molluscum, short stature, intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 PAX1 Zornitza Stark gene: PAX1 was added
gene: PAX1 was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: PAX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAX1 were set to 32111619
Phenotypes for gene: PAX1 were set to Syndromic SCID; dysmorphism; ear abnormalities; otofaciocervical syndrome
Review for gene: PAX1 was set to GREEN
gene: PAX1 was marked as current diagnostic
Added comment: 6 individuals from three unrelated families.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 OAS1 Zornitza Stark reviewed gene: OAS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29455859; Phenotypes: infantile-onset pulmonary alveolar proteinosis, hypogammaglobulinemia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 NOP10 Zornitza Stark reviewed gene: NOP10: Rating: RED; Mode of pathogenicity: None; Publications: 17507419; Phenotypes: Dyskeratosis congenita, autosomal recessive 1, MIM#224230; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 NLRP1 Zornitza Stark reviewed gene: NLRP1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 27965258, 31484767, 27662089; Phenotypes: Autoinflammation with arthritis and dyskeratosis, MIM# 617388, Palmoplantar carcinoma, multiple self-healing 615225, Recurrent respiratory papillomatosis; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 MYO5B Zornitza Stark reviewed gene: MYO5B: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Microvillus inclusion disease, MIM# 251850; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 MKL1 Zornitza Stark reviewed gene: MKL1: Rating: AMBER; Mode of pathogenicity: None; Publications: 32128589, 26224645; Phenotypes: Neutropaenia with combined immune deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 LIG1 Zornitza Stark reviewed gene: LIG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30395541; Phenotypes: Combined immunodeficiency, Lymphopaenia, Hypogammaglobulinaemia, Recurrent bacterial and viral infections, Growth retardation, Sun sensitivity, radiation sensitivity, Macrocytosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 PSMA3 Abdelazeem Elhabyan reviewed gene: PSMA3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 PSMA3 Abdelazeem Elhabyan Deleted their review
COVID-19 research v0.81 PSMB4 Abdelazeem Elhabyan reviewed gene: PSMB4: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 26829627,; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 PSMA3 Abdelazeem Elhabyan reviewed gene: PSMA3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.81 POLR3C Abdelazeem Elhabyan reviewed gene: POLR3C: Rating: RED; Mode of pathogenicity: None; Publications: 28783042; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.81 POLR3A Abdelazeem Elhabyan changed review comment from: This gene is responsible for A subunit of Polymerase which sense DNA in viral infection eg Varicella Zoster. SARS-CoV-2 is an RNA virus.

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections(PMID: 28783042)

We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity
Different classes of PRRs are involved in recognition of virus infections, including membrane-associated TLRs; cytosolic retinoic acid–inducible gene 1–like (RIG-I–like) receptors, which sense RNA; and DNA sensors (24). Each of these classes of PRRs stimulates production of IFNs, which exhibit antiviral activity through their ability to induce IFN-stimulated genes (ISGs). With respect to DNA sensors, TLR9 detects unmethylated DNA, RNA polymerase III (POL III) recognizes AT-rich DNA, while gamma-interferon-inducible protein 16 (IFI16) and cyclic GMP-AMP synthase (cGAS) sense double-stranded DNA in a sequence-independent manner (25–29).




Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection
PMID: 29728610

Recently, deficiency in the cytosolic DNA sensor RNA Polymerase III was described in children with severe primary varicella-zoster virus (VZV) infection in the CNS and lungs. In the present study we examined adult patients with VZV CNS infection caused by viral reactivation. By whole exome sequencing we identified mutations in POL III genes in two of eight patients. These mutations were located in the coding regions of the subunits POLR3A and POLR3E. In functional assays, we found impaired expression of antiviral and inflammatory cytokines in response to the POL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls. Altogether, this study provides significant extension on the current knowledge on susceptibility to VZV infection by demonstrating mutations in POL III genes associated with impaired immunological sensing of AT-rich DNA in adult patients with VZV CNS infection.; to: This gene is responsible for A subunit of Polymerase which senses DNA viruses especially AT-rich regions eg Varicella Zoster. SARS-CoV-2 is an RNA virus.

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections(PMID: 28783042)

We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity
Different classes of PRRs are involved in recognition of virus infections, including membrane-associated TLRs; cytosolic retinoic acid–inducible gene 1–like (RIG-I–like) receptors, which sense RNA; and DNA sensors (24). Each of these classes of PRRs stimulates production of IFNs, which exhibit antiviral activity through their ability to induce IFN-stimulated genes (ISGs). With respect to DNA sensors, TLR9 detects unmethylated DNA, RNA polymerase III (POL III) recognizes AT-rich DNA, while gamma-interferon-inducible protein 16 (IFI16) and cyclic GMP-AMP synthase (cGAS) sense double-stranded DNA in a sequence-independent manner (25–29).




Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection
PMID: 29728610

Recently, deficiency in the cytosolic DNA sensor RNA Polymerase III was described in children with severe primary varicella-zoster virus (VZV) infection in the CNS and lungs. In the present study we examined adult patients with VZV CNS infection caused by viral reactivation. By whole exome sequencing we identified mutations in POL III genes in two of eight patients. These mutations were located in the coding regions of the subunits POLR3A and POLR3E. In functional assays, we found impaired expression of antiviral and inflammatory cytokines in response to the POL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls. Altogether, this study provides significant extension on the current knowledge on susceptibility to VZV infection by demonstrating mutations in POL III genes associated with impaired immunological sensing of AT-rich DNA in adult patients with VZV CNS infection.
COVID-19 research v0.81 POLR3A Abdelazeem Elhabyan reviewed gene: POLR3A: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 28783042,29728610; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.81 ACE Abdelazeem Elhabyan reviewed gene: ACE: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.81 NRAS Abdelazeem Elhabyan reviewed gene: NRAS: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 21595878,12670913,; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 IRF9 Zornitza Stark reviewed gene: IRF9: Rating: AMBER; Mode of pathogenicity: None; Publications: 30826365, 30143481; Phenotypes: Immunodeficiency 65, susceptibility to viral infections 618648; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.81 MRE11 Abdelazeem Elhabyan reviewed gene: MRE11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.81 MPO Abdelazeem Elhabyan reviewed gene: MPO: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27574522,21703402,29325098,29769163,24968347; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 IL6ST Zornitza Stark reviewed gene: IL6ST: Rating: GREEN; Mode of pathogenicity: None; Publications: 32207811, 28747427, 30309848, 12370259, 16041381, 31914175; Phenotypes: Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523, Stuve-Wiedemann-like syndrome: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response., Hyper-IgE syndrome, autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 IL6R Zornitza Stark reviewed gene: IL6R: Rating: AMBER; Mode of pathogenicity: None; Publications: 31235509; Phenotypes: Recurrent pyogenic infections, cold abscesses, High circulating IL-6 levels, High IgE; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 IL2RB Zornitza Stark reviewed gene: IL2RB: Rating: GREEN; Mode of pathogenicity: None; Publications: 31040184, 31040185; Phenotypes: Immunodeficiency 63 with lymphoproliferation and autoimmunity, MIM# 618495, Lymphoproliferation, lymphadenopathy, hepatosplenomegaly, autoimmune haemolytic anaemia, dermatitis, enteropathy, hypergammaglobulinaemia, recurrent viral (EBV, CMV) infections; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 IL17F Zornitza Stark reviewed gene: IL17F: Rating: RED; Mode of pathogenicity: None; Publications: 21350122; Phenotypes: Candidiasis, familial, 6, autosomal dominant, MIM# 613956; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 ICOSLG Zornitza Stark reviewed gene: ICOSLG: Rating: AMBER; Mode of pathogenicity: None; Publications: 31532372, 30498080; Phenotypes: Combined immunodeficiency, recurrent bacterial and viral infections, neutropaenia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 HYOU1 Zornitza Stark reviewed gene: HYOU1: Rating: RED; Mode of pathogenicity: None; Publications: 27913302; Phenotypes: Immunodeficiency 59 and hypoglycemia, MIM# 233600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 HAVCR2 Zornitza Stark reviewed gene: HAVCR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30374066, 30792187; Phenotypes: T-cell lymphoma, subcutaneous panniculitis-like, MIM# 618398; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.81 KRAS Abdelazeem Elhabyan reviewed gene: KRAS: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.81 GUCY2C Abdelazeem Elhabyan reviewed gene: GUCY2C: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 FCHO1 Zornitza Stark reviewed gene: FCHO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32098969, 30822429; Phenotypes: Combined immunodeficiency, T cells: low, poor proliferation, B cells: normal number, Recurrent infections (viral, mycobacteria, bacterial, fungal), lymphoproliferation, Failure to thrive, Increased activation-induced T-cell death, Defective clathrin-mediated endocytosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.81 FPR2 Abdelazeem Elhabyan reviewed gene: FPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 28928730, 27034344,29738458,31398292,29127186; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 ERBIN Zornitza Stark reviewed gene: ERBIN: Rating: AMBER; Mode of pathogenicity: None; Publications: 28126831; Phenotypes: Recurrent respiratory infections, Susceptibility to S.aureus, Eczema, Hyperextensible joints, Scoliosis, Arterial dilatation in some; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 EFL1 Zornitza Stark gene: EFL1 was added
gene: EFL1 was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: EFL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFL1 were set to 28331068; 31151987
Phenotypes for gene: EFL1 were set to Shwachman-Diamond syndrome 2, MIM# 617941
Review for gene: EFL1 was set to GREEN
gene: EFL1 was marked as current diagnostic
Added comment: Six unrelated families reported, two had the same homozygous variant, one family single variant plus 'expression defect' identified. Neutropaenia is part of the phenotype, and other SDS genes are part of the PID panel.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 DNASE1L3 Zornitza Stark reviewed gene: DNASE1L3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22019780, 30008451; Phenotypes: Systemic lupus erythematosus 16, MIM# 614420; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 DEF6 Zornitza Stark reviewed gene: DEF6: Rating: AMBER; Mode of pathogenicity: None; Publications: 31308374; Phenotypes: Systemic autoimmunity; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 DBR1 Zornitza Stark reviewed gene: DBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29474921; Phenotypes: Viral infections of the brainstem; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 CSF2RB Zornitza Stark reviewed gene: CSF2RB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.81 FPR2 Abdelazeem Elhabyan Deleted their review
COVID-19 research v0.81 FPR2 Abdelazeem Elhabyan commented on gene: FPR2
Infantile enterocolitis & monogenic inflammatory bowel disease v1.16 COL7A1 Zornitza Stark reviewed gene: COL7A1: Rating: RED; Mode of pathogenicity: None; Publications: 27537055, 25058236; Phenotypes: Epidermolysis bullosa dystrophica, AR, MIM# 226600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 CIB1 Zornitza Stark gene: CIB1 was added
gene: CIB1 was added to Primary immunodeficiency. Sources: Expert list
Mode of inheritance for gene: CIB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CIB1 were set to 30068544
Phenotypes for gene: CIB1 were set to Epidermodysplasia verruciformis 3 618267; HPV infections and cancer of the skin
Review for gene: CIB1 was set to GREEN
Added comment: Underlying defect of innate immunity, though phenotype is dermatological. 24 individuals from 6 families reported. Part of IUIS classification 2019.
Sources: Expert list
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 C17orf62 Zornitza Stark reviewed gene: C17orf62: Rating: GREEN; Mode of pathogenicity: None; Publications: 30361506, 30312704, 28351984; Phenotypes: Chronic granulomatous disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 BLOC1S6 Zornitza Stark edited their review of gene: BLOC1S6: Changed rating: AMBER
COVID-19 research v0.81 MRE11 Sarah Leigh Classified gene: MRE11 as Amber List (moderate evidence)
COVID-19 research v0.81 MRE11 Sarah Leigh Added comment: Comment on list classification: Immunodeficiency does not appear to be a feature of Ataxia-telangiectasia-like disorder 1 604391. However, as part of the MRE11-RAD50-NBS1 Complex it is part of the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection (pmid 29709199). Hence, variants in MRE11, could reduce the response to viral DNA integration in host cells,allowing infections to be propogated.
COVID-19 research v0.81 MRE11 Sarah Leigh Gene: mre11 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.80 MRE11 Sarah Leigh Publications for gene: MRE11 were set to 8445618; 10612394; 15574463; 32212377
Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 MRE11 Sarah Leigh Publications for gene: MRE11 were set to 8445618; 10612394; 15574463; 32212377
Primary immunodeficiency or monogenic inflammatory bowel disease v2.50 MRE11 Sarah Leigh changed review comment from: Comment on list classification: Immunodeficiency does not appear to be a feature of Ataxia-telangiectasia-like disorder 1 604391. However, as part of the MRE11-RAD50-NBS1 Complex it is part of the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection. Hence, variants in MRE11, could reduce the response to viral DNA integration in host cells,allowing infections to be propogated. ; to: Comment on list classification: Immunodeficiency does not appear to be a feature of Ataxia-telangiectasia-like disorder 1 604391. However, as part of the MRE11-RAD50-NBS1 Complex it is part of the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection (pmid 29709199). Hence, variants in MRE11, could reduce the response to viral DNA integration in host cells,allowing infections to be propogated.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.50 MRE11 Sarah Leigh changed review comment from: Comment on list classification: Immunodeficiency does not appear to be a feature of Ataxia-telangiectasia-like disorder 1 604391; to: Comment on list classification: Immunodeficiency does not appear to be a feature of Ataxia-telangiectasia-like disorder 1 604391. However, as part of the MRE11-RAD50-NBS1 Complex it is part of the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection. Hence, variants in MRE11, could reduce the response to viral DNA integration in host cells,allowing infections to be propogated.
COVID-19 research v0.79 MRE11 Sarah Leigh Classified gene: MRE11 as Red List (low evidence)
COVID-19 research v0.79 MRE11 Sarah Leigh Added comment: Comment on list classification: Immunodeficiency does not appear to be a feature of Ataxia-telangiectasia-like disorder 1 604391
COVID-19 research v0.79 MRE11 Sarah Leigh Gene: mre11 has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.50 MRE11 Sarah Leigh Classified gene: MRE11 as Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.50 MRE11 Sarah Leigh Added comment: Comment on list classification: Immunodeficiency does not appear to be a feature of Ataxia-telangiectasia-like disorder 1 604391
Primary immunodeficiency or monogenic inflammatory bowel disease v2.50 MRE11 Sarah Leigh Gene: mre11 has been classified as Red List (Low Evidence).
COVID-19 research v0.78 MRE11 Sarah Leigh Publications for gene: MRE11 were set to 10612394; 8445618; 15574463
Primary immunodeficiency or monogenic inflammatory bowel disease v2.49 MRE11 Sarah Leigh Publications for gene: MRE11 were set to 8445618; 10612394; 15574463
Primary immunodeficiency or monogenic inflammatory bowel disease v2.48 MRE11 Sarah Leigh Publications for gene: MRE11 were set to 8445618; 10612394; 15574463
COVID-19 research v0.77 SNORA31 Catherine Snow Classified gene: SNORA31 as Green List (high evidence)
COVID-19 research v0.77 SNORA31 Catherine Snow Added comment: Comment on list classification: Rating Green following external review
COVID-19 research v0.77 SNORA31 Catherine Snow Gene: snora31 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.47 SNORA31 Catherine Snow Classified gene: SNORA31 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.47 SNORA31 Catherine Snow Added comment: Comment on list classification: Rating as Green following external review
Primary immunodeficiency or monogenic inflammatory bowel disease v2.47 SNORA31 Catherine Snow Gene: snora31 has been classified as Green List (High Evidence).
COVID-19 research v0.76 POLR3A Rebecca Foulger changed review comment from: Added POLR3A to panel based on presence on VCGS 'Susceptibility to Viral Infections' panel: https://panelapp.agha.umccr.org/panels/237/; to: Added POLR3A to panel based on presence on VCGS 'Susceptibility to Viral Infections' panel V0.22: https://panelapp.agha.umccr.org/panels/237/
COVID-19 research v0.76 POLR3C Rebecca Foulger changed review comment from: Added POLR3C to panel based on presence on VCGS 'Susceptibility to Viral Infections' panel: https://panelapp.agha.umccr.org/panels/237/; to: Added POLR3C to panel based on presence on VCGS 'Susceptibility to Viral Infections' panel V0.22: https://panelapp.agha.umccr.org/panels/237/
COVID-19 research v0.76 POLR3F Rebecca Foulger changed review comment from: Added POLR3F to panel based on presence on VCGS 'Susceptibility to Viral Infections' panel: https://panelapp.agha.umccr.org/panels/237/; to: Added POLR3F to panel based on presence on VCGS 'Susceptibility to Viral Infections' panel V0.22: https://panelapp.agha.umccr.org/panels/237/
COVID-19 research v0.76 POLR3F Rebecca Foulger commented on gene: POLR3F
COVID-19 research v0.76 POLR3C Rebecca Foulger commented on gene: POLR3C
COVID-19 research v0.76 POLR3A Rebecca Foulger commented on gene: POLR3A
COVID-19 research v0.76 POLR3F Rebecca Foulger gene: POLR3F was added
gene: POLR3F was added to Viral susceptibility. Sources: Expert Review Red,Victorian Clinical Genetics Services,Expert list
Mode of inheritance for gene: POLR3F was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR3F were set to 30211253
Phenotypes for gene: POLR3F were set to Severe VZV infection
COVID-19 research v0.76 POLR3C Rebecca Foulger gene: POLR3C was added
gene: POLR3C was added to Viral susceptibility. Sources: Victorian Clinical Genetics Services,Expert list,Expert Review Amber
Mode of inheritance for gene: POLR3C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR3C were set to 28783042
Phenotypes for gene: POLR3C were set to Severe VZV infection
COVID-19 research v0.76 POLR3A Rebecca Foulger gene: POLR3A was added
gene: POLR3A was added to Viral susceptibility. Sources: Victorian Clinical Genetics Services,Expert list,Expert Review Amber
Mode of inheritance for gene: POLR3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR3A were set to 29728610; 28783042
Phenotypes for gene: POLR3A were set to Severe VZV infection
COVID-19 research v0.75 DBR1 Abdelazeem Elhabyan changed review comment from: I found that it has been promoted from the Australling susceptibility to viral infections on this link
https://panelapp.agha.umccr.org/panels/237/gene/DBR1/
This is based on this notion :
Seven individuals from three unrelated families with viral brainstem encephalitis and bi-allelic hypomorphic variants.

When I reviewed the paper, I found a notion of influenza viral encephalitis among other viruses(eg HSV-1) and a suggestion that this predisposition to the disease is due to involvement of DBR1 in intrinsic resistance of brainstem cells to those viruses via the enzyme encoded by DBR1.; to: I found that it has been promoted from the Australling susceptibility to viral infections on this link
https://panelapp.agha.umccr.org/panels/237/gene/DBR1/

This is based on this notion in this paper :
https://pubmed.ncbi.nlm.nih.gov/29474921/
Seven individuals from three unrelated families with viral brainstem encephalitis and bi-allelic hypomorphic variants.

When I reviewed the paper, I found a notion of influenza viral encephalitis among other viruses(eg HSV-1) and a suggestion that this predisposition to the disease is due to the involvement of DBR1 in intrinsic resistance of brainstem cells to those viruses via the enzyme encoded by DBR1.
COVID-19 research v0.75 DBR1 Abdelazeem Elhabyan commented on gene: DBR1: I found that it has been promoted from the Australling susceptibility to viral infections on this link
https://panelapp.agha.umccr.org/panels/237/gene/DBR1/
This is based on this notion :
Seven individuals from three unrelated families with viral brainstem encephalitis and bi-allelic hypomorphic variants.

When I reviewed the paper, I found a notion of influenza viral encephalitis among other viruses(eg HSV-1) and a suggestion that this predisposition to the disease is due to involvement of DBR1 in intrinsic resistance of brainstem cells to those viruses via the enzyme encoded by DBR1.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.46 BLOC1S6 Zornitza Stark reviewed gene: BLOC1S6: Rating: RED; Mode of pathogenicity: None; Publications: 32245340; Phenotypes: Hermansky-Pudlak syndrome 9, MIM# 614171; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.46 BCL11B Zornitza Stark reviewed gene: BCL11B: Rating: GREEN; Mode of pathogenicity: None; Publications: 29985992, 27959755; Phenotypes: Immunodeficiency 49, MIM# 617237, Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities, MIM# 618092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v2.46 BCL10 Zornitza Stark reviewed gene: BCL10: Rating: GREEN; Mode of pathogenicity: None; Publications: 25365219, 32008135, 11163238, 12910267; Phenotypes: Immunodeficiency 37, MIM# 616098; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.46 ARHGEF1 Zornitza Stark reviewed gene: ARHGEF1: Rating: RED; Mode of pathogenicity: None; Publications: 30521495; Phenotypes: Immunodeficiency 62, MIM#618459; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.46 ALPI Zornitza Stark reviewed gene: ALPI: Rating: AMBER; Mode of pathogenicity: None; Publications: 29567797; Phenotypes: Inflammatory bowel disease; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.46 ADAM17 Zornitza Stark reviewed gene: ADAM17: Rating: GREEN; Mode of pathogenicity: None; Publications: 22010916, 29560122, 26683521, 25804906; Phenotypes: Inflammatory skin and bowel disease, neonatal, 1, MIM# 614328, Recurrent infections; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.75 MRE11 Sarah Leigh Publications for gene: MRE11 were set to 10612394; 8445618
Primary immunodeficiency or monogenic inflammatory bowel disease v2.46 MRE11 Sarah Leigh Publications for gene: MRE11 were set to 8445618; 10612394
COVID-19 research v0.74 FPR3 Catherine Snow changed review comment from: Formyl peptide receptors (FPRs) are classical chemoattractant receptors and although recently identified as being expressed in a sepsis patient derived neutrophils (PMID: 31982133) there is not enough evidence to upgrade to Amber.; to: Formyl peptide receptors (FPRs) are classical chemoattractant receptors and although FPR3 was recently identified as being expressed in a sepsis patient derived neutrophils (PMID: 31982133) there is not enough evidence to upgrade to Amber.
COVID-19 research v0.74 FPR3 Catherine Snow reviewed gene: FPR3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.74 FPR2 Catherine Snow changed review comment from: FPR2 is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses

Mouse model PMID: 31908042 Fpr2/3 knockout (KO) mice and wild‐type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals

PMID: 28928730 The review gives an overview on the pathogenesis of influenza with a focus on the role of FPR2 and discusses the advantages of using FPR2 antagonists to treat the flu. Preclinical studies have proven that FPR2 antagonists efficiently protect mice against IAV infections, by inhibiting viral replication and deleterious inflammation of the lungs; to: FPR2 is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses

Mouse model PMID: 31908042 Fpr2/3 knockout (KO) mice and wild‐type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals

PMID: 28928730 The review gives an overview on the pathogenesis of influenza with a focus on the role of FPR2 and discusses the advantages of using FPR2 antagonists to treat the flu. Preclinical studies have proven that FPR2 antagonists efficiently protect mice against IAV infections, by inhibiting viral replication and deleterious inflammation of the lungs
COVID-19 research v0.74 FPR2 Catherine Snow changed review comment from: FPR2 is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses

Mouse model PMID: 31908042 Fpr2/3 knockout (KO) mice and wild‐type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals

PMID: 28928730 The review gives an overview on the pathogenesis of influenza with a focus on the role of FPR2 and discusses the advantages of using FPR2 antagonists to treat the flu. Preclinical studies have proven that FPR2 antagonists efficiently protect mice against IAV infections, by inhibiting viral replication and deleterious inflammation of the lungs; to: FPR2 is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses

Mouse model PMID: 31908042 Fpr2/3 knockout (KO) mice and wild‐type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals

PMID: 28928730 The review gives an overview on the pathogenesis of influenza with a focus on the role of FPR2 and discusses the advantages of using FPR2 antagonists to treat the flu. Preclinical studies have proven that FPR2 antagonists efficiently protect mice against IAV infections, by inhibiting viral replication and deleterious inflammation of the lungs
COVID-19 research v0.74 FPR2 Catherine Snow Classified gene: FPR2 as Amber List (moderate evidence)
COVID-19 research v0.74 FPR2 Catherine Snow Gene: fpr2 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.73 FPR2 Catherine Snow reviewed gene: FPR2: Rating: AMBER; Mode of pathogenicity: None; Publications: 31908042, 28928730; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Primary immunodeficiency or monogenic inflammatory bowel disease v2.45 CD247 Sophie Hambleton edited their review of gene: CD247: Added comment: There are at least 2 separate published reports of SCID caused by biallelic mutations in this gene, in keeping with understanding of its role in T cell biology.; Changed rating: GREEN; Changed publications: 16672702, 17170122; Changed phenotypes: T-B+ SCID
Primary immunodeficiency or monogenic inflammatory bowel disease v2.45 BCL10 Sophie Hambleton edited their review of gene: BCL10: Added comment: Additional case report describes recurrent infections with same cellular and immunological phenotypes in a child with homozygous null mutation, hence upgrade from amber to green gene status; Changed rating: GREEN; Changed publications: 25365219, 32008135
COVID-19 research v0.73 FCGRT Catherine Snow Classified gene: FCGRT as Red List (low evidence)
COVID-19 research v0.73 FCGRT Catherine Snow Added comment: Comment on list classification: No association found.
COVID-19 research v0.73 FCGRT Catherine Snow Gene: fcgrt has been classified as Red List (Low Evidence).
COVID-19 research v0.72 FCGR3B Catherine Snow Classified gene: FCGR3B as Red List (low evidence)
COVID-19 research v0.72 FCGR3B Catherine Snow Added comment: Comment on list classification: Comment on list classification: No link to viral susceptibility some evidence of FCGR3B that variants give rise to susceptibility to develop auto-immune diseases including SLE (PMID: 26683154).
COVID-19 research v0.72 FCGR3B Catherine Snow Gene: fcgr3b has been classified as Red List (Low Evidence).
COVID-19 research v0.71 FCGR2B Catherine Snow changed review comment from: Comment on list classification: No link to viral susceptibility some evidence of FCGR2B some evidence that variants give rise to susceptibility to develop auto-immune diseases (PMID: 26683154); to: Comment on list classification: No link to viral susceptibility some evidence of FCGR2B that variants give rise to susceptibility to develop auto-immune diseases (PMID: 26683154)
COVID-19 research v0.71 FCGR2B Catherine Snow changed review comment from: Comment on list classification: No link to viral susceptibility some evidence of FCGR2B some evidence that variants give rise to susceptibility to develop auto-immune diseases; to: Comment on list classification: No link to viral susceptibility some evidence of FCGR2B some evidence that variants give rise to susceptibility to develop auto-immune diseases (PMID: 26683154)
COVID-19 research v0.71 FCGR2B Catherine Snow Classified gene: FCGR2B as Red List (low evidence)
COVID-19 research v0.71 FCGR2B Catherine Snow Added comment: Comment on list classification: No link to viral susceptibility some evidence of FCGR2B some evidence that variants give rise to susceptibility to develop auto-immune diseases
COVID-19 research v0.71 FCGR2B Catherine Snow Gene: fcgr2b has been classified as Red List (Low Evidence).
COVID-19 research v0.70 FCGR2A Catherine Snow Publications for gene: FCGR2A were set to 16185324
COVID-19 research v0.69 FCGR2A Catherine Snow Mode of inheritance for gene: FCGR2A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
COVID-19 research v0.68 FCGR2A Catherine Snow Classified gene: FCGR2A as Green List (high evidence)
COVID-19 research v0.68 FCGR2A Catherine Snow Gene: fcgr2a has been classified as Green List (High Evidence).
COVID-19 research v0.67 FCGR2A Catherine Snow Tag watchlist tag was added to gene: FCGR2A.
Tag polygenic tag was added to gene: FCGR2A.
COVID-19 research v0.67 FCGR2A Catherine Snow reviewed gene: FCGR2A: Rating: GREEN; Mode of pathogenicity: None; Publications: 19494086, 12752683, 16185324; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.67 NRAS Ellen McDonagh Mode of inheritance for gene: NRAS was changed from Unknown to Other
Primary immunodeficiency or monogenic inflammatory bowel disease v2.45 IL6 Ellen McDonagh gene: IL6 was added
gene: IL6 was added to Primary immunodeficiency. Sources: Literature
Mode of inheritance for gene: IL6 was set to Unknown
Publications for gene: IL6 were set to medRxiv 2020.04.01.20047381; doi: https://doi.org/10.1101/2020.04.01.20047381
Phenotypes for gene: IL6 were set to Potential marker for respiratory failure when infected with COVID-19
Review for gene: IL6 was set to RED
Added comment: Not yet peer-reviewed study available in medRxiv: https://www.medrxiv.org/content/10.1101/2020.04.01.20047381v1
reports an association between elevated interleukin-6 (IL-6) in COVID-19 infected patients with the need for mechanical ventilation (p=1.2.10-5). The maximal IL-6 level (cutoff 80 pg/ml) for each patient during disease predicted respiratory failure with high accuracy (p=1.7.10-8, AUC=0.98). The risk of respiratory failure for patients with IL-6 levels of ≥ 80 pg/ml was 22 times higher compared to patients with lower IL-6 levels.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.44 IL6R Ellen McDonagh reviewed gene: IL6R: Rating: ; Mode of pathogenicity: None; Publications: medRxiv 2020.04.01.20047381, doi: https://doi.org/10.1101/2020.04.01.20047381; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.66 IL17A Ivone Leong Classified gene: IL17A as Green List (high evidence)
COVID-19 research v0.66 IL17A Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green as there is enough evidence in the literature to support this.
COVID-19 research v0.66 IL17A Ivone Leong Gene: il17a has been classified as Green List (High Evidence).
COVID-19 research v0.65 IRF2BP2 Eleanor Williams Phenotypes for gene: IRF2BP2 were changed from Recurrent infections, possible autoimmunity and inflammatory disease; Predominantly Antibody Deficiencies; CVID to Recurrent infections, possible autoimmunity and inflammatory disease; Predominantly Antibody Deficiencies; CVID; Immunodeficiency, common variable, 14, MIM# 617765
COVID-19 research v0.64 IRF2BP2 Eleanor Williams Publications for gene: IRF2BP2 were set to 27016798; 32086639; 32048120
COVID-19 research v0.62 IRF2BP2 Eleanor Williams commented on gene: IRF2BP2
COVID-19 research v0.62 DBR1 Louise Daugherty Deleted their review
COVID-19 research v0.62 DBR1 Louise Daugherty Deleted their comment
COVID-19 research v0.62 FCGR1A Catherine Snow Classified gene: FCGR1A as Red List (low evidence)
COVID-19 research v0.62 FCGR1A Catherine Snow Added comment: Comment on list classification: FCGR1 is on the Immunoplex Panel offered by the University of Washington Department of Laboratory Medicine however there is currently no link to alleles and disease (PMID: 31057544)
COVID-19 research v0.62 FCGR1A Catherine Snow Gene: fcgr1a has been classified as Red List (Low Evidence).
COVID-19 research v0.61 ADAM17 Abdelazeem Elhabyan reviewed gene: ADAM17: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.61 ADAM17 Abdelazeem Elhabyan Deleted their review
COVID-19 research v0.61 ADAM17 Abdelazeem Elhabyan reviewed gene: ADAM17: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.61 ACTB Abdelazeem Elhabyan reviewed gene: ACTB: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v2.44 MPO Sarah Leigh Classified gene: MPO as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.44 MPO Sarah Leigh Added comment: Comment on list classification: Comment on list classification: PMID 3208230 outlines the role of neutrophil extracellular traps (NETs) in the control of some pathogens including viruses, by virus capture and neutralization. In vivo treatment of the mice with DNase resulted in the enhanced susceptibility of IFNAR-/- mice to the CHIKV virus. Furthermore, the levels of MPO-DNA complex in acutely CHIKV-infected patients, were correlated with the levels of NETs and the viral load in the blood, suggesting that NETs are also released in natural human infection cases. Therefore, variants that result in myeloperoxidase deficiency, may well contribute to an increased susceptiblity to viral infection. At least 9 variants have been reported in Myeloperoxidase deficiency 254600 and these could well be contributing to increased viral susceptibily.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.44 MPO Sarah Leigh Gene: mpo has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.7 NXN Ellen McDonagh Classified gene: NXN as Green List (high evidence)
Skeletal dysplasia v2.7 NXN Ellen McDonagh Added comment: Comment on list classification: Promoted to Green after expert review from Sian Ellard (by email).
Skeletal dysplasia v2.7 NXN Ellen McDonagh Gene: nxn has been classified as Green List (High Evidence).
COVID-19 research v0.60 DBR1 Louise Daugherty changed review comment from: PanelApp curators : you might need to re-review all the Green genes on this panel that were previously rated as Red on the PID panel, there may have been an error with the automatic upload changing Red Genes to Expert Review Green (https://panelapp.genomicsengland.co.uk/panels/398/gene/DBR1/), other examples are POLE2, BRCA1, BRCA2, ERCC4 etc unless there is evidence missed from the upload?; to: PanelApp curators : you might need to re-review all the Green genes on this panel that were previously rated as Red on the PID panel, there may have been an error with the automatic upload changing Red Genes to Expert Review Green (https://panelapp.genomicsengland.co.uk/panels/398/gene/DBR1/), other examples are IFNAR2, POLE2, BRCA1, BRCA2, ERCC4 etc unless there is evidence missed from the upload?
COVID-19 research v0.60 DBR1 Louise Daugherty changed review comment from: PanelApp curators : you might need to all the Green genes on this panel that were previously rated as Red on the PID panel, there may have been an error with the automatic upload changing Red Genes to Expert Review Green (https://panelapp.genomicsengland.co.uk/panels/398/gene/DBR1/), other examples are POLE2, BRCA1, BRCA2, ERCC4 etc unless there is evidence missed from the upload?; to: PanelApp curators : you might need to re-review all the Green genes on this panel that were previously rated as Red on the PID panel, there may have been an error with the automatic upload changing Red Genes to Expert Review Green (https://panelapp.genomicsengland.co.uk/panels/398/gene/DBR1/), other examples are POLE2, BRCA1, BRCA2, ERCC4 etc unless there is evidence missed from the upload?
COVID-19 research v0.60 DBR1 Louise Daugherty changed review comment from: PanelApp curators : you might need to all the Green genes on this panel that were previously rated as Red on the PID panel, there may have been an error with the automatic upload changing Red Genes to Expert Review Green (https://panelapp.genomicsengland.co.uk/panels/398/gene/DBR1/), other examples are POLE2, BRCA1, BRCA2, ERCC4 etc unless there as evidence missed from the upload?; to: PanelApp curators : you might need to all the Green genes on this panel that were previously rated as Red on the PID panel, there may have been an error with the automatic upload changing Red Genes to Expert Review Green (https://panelapp.genomicsengland.co.uk/panels/398/gene/DBR1/), other examples are POLE2, BRCA1, BRCA2, ERCC4 etc unless there is evidence missed from the upload?
COVID-19 research v0.60 DBR1 Louise Daugherty reviewed gene: DBR1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.60 MPO Sarah Leigh Classified gene: MPO as Amber List (moderate evidence)
COVID-19 research v0.60 MPO Sarah Leigh Added comment: Comment on list classification: PMID 3208230 outlines the role of neutrophil extracellular traps (NETs) in the control of some pathogens including viruses, by virus capture and neutralization. In vivo treatment of the mice with DNase resulted in the enhanced susceptibility of IFNAR-/- mice to the CHIKV virus. Furthermore, the levels of MPO-DNA complex in acutely CHIKV-infected patients, were correlated with the levels of NETs and the viral load in the blood, suggesting that NETs are also released in natural human infection cases. Therefore, variants that result in myeloperoxidase deficiency, may well contribute to an increased susceptiblity to viral infection.
At least 9 variants have been reported in Myeloperoxidase deficiency 254600 and these could well be contributing to increased viral susceptibily.
COVID-19 research v0.60 MPO Sarah Leigh Gene: mpo has been classified as Amber List (Moderate Evidence).
Fanconi anaemia or Bloom syndrome v1.5 XRCC2 Tom Cullup reviewed gene: XRCC2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22232082, 27208205; Phenotypes: Fanconi anaemia complementation group U; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Familial pulmonary fibrosis v1.9 SFTPB Helen Savage reviewed gene: SFTPB: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 8163685, 15331184; Phenotypes: Surfactant metabolism dysfunction, pulmonary, 1, 265120; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
COVID-19 research v0.59 C17orf62 Abdelazeem Elhabyan Deleted their review
COVID-19 research v0.59 C17orf62 Abdelazeem Elhabyan reviewed gene: C17orf62: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.59 DBR1 Abdelazeem Elhabyan reviewed gene: DBR1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.59 IL17A Abdelazeem Elhabyan commented on gene: IL17A: I agree that the level should be reviewed for being increased to Green especially the association of SNPs with H1N1 (influenza A) and influenza B.


Association with CNVs with pathology has been confirmed but the disease state was not revealed in any of the patients
https://www.ncbi.nlm.nih.gov/clinvar?LinkName=gene_clinvar&from_uid=3605
COVID-19 research v0.59 IL17A Abdelazeem Elhabyan edited their review of gene: IL17A: Changed rating: GREEN
COVID-19 research v0.59 IL17A Abdelazeem Elhabyan Deleted their comment
COVID-19 research v0.59 IL17A Abdelazeem Elhabyan changed review comment from: I agree that the level should be reviewed for being increased to Green especially the association of SNPs with H1N1 (influenza A) and influenza B.


Association with CNVs with pathology has been confirmed but the disease state was not revealed in any of the patients
https://www.ncbi.nlm.nih.gov/clinvar?LinkName=gene_clinvar&from_uid=3605; to: I agree that the level should be reviewed for being increased to Green especially the association of SNPs with H1N1 (influenza A) and influenza B.


Association with CNVs with pathology has been confirmed but the disease state was not revealed in any of the patients
https://www.ncbi.nlm.nih.gov/clinvar?LinkName=gene_clinvar&from_uid=3605
COVID-19 research v0.59 IL17A Abdelazeem Elhabyan commented on gene: IL17A
COVID-19 research v0.59 IRF9 Abdelazeem Elhabyan commented on gene: IRF9
COVID-19 research v0.59 ACP5 Abdelazeem Elhabyan reviewed gene: ACP5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Skeletal dysplasia v2.6 NXN Ellen McDonagh Deleted their comment
Skeletal dysplasia v2.6 NXN Ellen McDonagh Deleted their comment
Skeletal dysplasia v2.6 NXN Ellen McDonagh Deleted their comment
Skeletal dysplasia v2.6 NXN Ellen McDonagh Classified gene: NXN as Amber List (moderate evidence)
Skeletal dysplasia v2.6 NXN Ellen McDonagh Added comment: Comment on list classification: Two family reports and mouse model...should this be promoted to Green?
Skeletal dysplasia v2.6 NXN Ellen McDonagh Gene: nxn has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.6 NXN Ellen McDonagh Classified gene: NXN as Amber List (moderate evidence)
Skeletal dysplasia v2.6 NXN Ellen McDonagh Added comment: Comment on list classification: Two family reports and mouse model...should this be promoted to Green?
Skeletal dysplasia v2.6 NXN Ellen McDonagh Gene: nxn has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.5 NXN Ellen McDonagh Classified gene: NXN as Amber List (moderate evidence)
Skeletal dysplasia v2.5 NXN Ellen McDonagh Added comment: Comment on list classification: Two family reports and mouse model...should this be promoted to Green?
Skeletal dysplasia v2.5 NXN Ellen McDonagh Gene: nxn has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.5 NXN Ellen McDonagh Classified gene: NXN as Amber List (moderate evidence)
Skeletal dysplasia v2.5 NXN Ellen McDonagh Added comment: Comment on list classification: Two family reports and mouse model...should this be promoted to Green?
Skeletal dysplasia v2.5 NXN Ellen McDonagh Gene: nxn has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v2.4 NXN Ellen McDonagh changed review comment from: Gene suggested by Sian Ellard (Royal Devon & Exeter NHS Foundation Trust, South West Genomic Laboratory Hub) to be added to this panel. PMID: 29276006 reports three individuals from two families with biallelic vairants in this gene that co-segregate with the disease. All three patients have typical facial characteristics of Robinow syndrome, mesomelia, brachydactyly, and broad thumbs/toes NXN knockout mice have craniofacial defects which is hypothesized to be caused by abnormal Wnt/Beta-catenin signalling.
Sources: Literature, Expert Review; to: Gene suggested by Sian Ellard (Royal Devon & Exeter NHS Foundation Trust, South West Genomic Laboratory Hub) to be added to this panel. PMID: 29276006 reports three individuals from two families with biallelic vairants in this gene that co-segregate with the disease. All three patients have typical facial characteristics of Robinow syndrome, mesomelia, brachydactyly, and broad thumbs/toes. NXN knockout mice have craniofacial defects which is hypothesized to be caused by abnormal Wnt/Beta-catenin signalling.
Skeletal dysplasia v2.4 NXN Ellen McDonagh gene: NXN was added
gene: NXN was added to Skeletal dysplasia. Sources: Literature,Expert Review
Mode of inheritance for gene: NXN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NXN were set to 29276006
Phenotypes for gene: NXN were set to Robinow syndrome, autosomal recessive 2 618529
Review for gene: NXN was set to AMBER
Added comment: Gene suggested by Sian Ellard (Royal Devon & Exeter NHS Foundation Trust, South West Genomic Laboratory Hub) to be added to this panel. PMID: 29276006 reports three individuals from two families with biallelic vairants in this gene that co-segregate with the disease. All three patients have typical facial characteristics of Robinow syndrome, mesomelia, brachydactyly, and broad thumbs/toes NXN knockout mice have craniofacial defects which is hypothesized to be caused by abnormal Wnt/Beta-catenin signalling.
Sources: Literature, Expert Review
COVID-19 research v0.59 IGHG2 Ivone Leong reviewed gene: IGHG2: Rating: ; Mode of pathogenicity: None; Publications: 16092453; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.59 HLA-B Ivone Leong Publications for gene: HLA-B were set to 12969506
COVID-19 research v0.58 IL17A Ivone Leong Classified gene: IL17A as Amber List (moderate evidence)
COVID-19 research v0.58 IL17A Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber. There appears to be enough evidence for this gene to be promoted Green; however, will wait for expert review before promoting to Green.
COVID-19 research v0.58 IL17A Ivone Leong Gene: il17a has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.57 IL17A Ivone Leong Phenotypes for gene: IL17A were changed from Arthritis; Immunodeficiency 5 to Arthritis; Immunodeficiency 5; Susceptibility to influenza
COVID-19 research v0.56 IL17A Ivone Leong Mode of inheritance for gene: IL17A was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
COVID-19 research v0.55 IL17A Ivone Leong Publications for gene: IL17A were set to
COVID-19 research v0.54 IL17A Ivone Leong reviewed gene: IL17A: Rating: ; Mode of pathogenicity: None; Publications: 28860146, 31196204, 27890033, 21703407, 27155288, 29530464; Phenotypes: ; Mode of inheritance: Unknown
COVID-19 research v0.54 GAD1 Catherine Snow Classified gene: GAD1 as Red List (low evidence)
COVID-19 research v0.54 GAD1 Catherine Snow Added comment: Comment on list classification: GAD1 has no relationship to virus susceptibility.
COVID-19 research v0.54 GAD1 Catherine Snow Gene: gad1 has been classified as Red List (Low Evidence).
COVID-19 research v0.53 EPCAM Catherine Snow Classified gene: EPCAM as Red List (low evidence)
COVID-19 research v0.53 EPCAM Catherine Snow Added comment: Comment on list classification: No gene disease association.
COVID-19 research v0.53 EPCAM Catherine Snow Gene: epcam has been classified as Red List (Low Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.43 MPO Sarah Leigh Publications for gene: MPO were set to 15108282; 9354683; 9637725
COVID-19 research v0.52 IFNAR1 Sarah Leigh Classified gene: IFNAR1 as Green List (high evidence)
COVID-19 research v0.52 IFNAR1 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. However, the publications listed below give evidence that the three LOF variants in two unrelated cases are associated with an adverse reaction to attenuated virus vaccines, which are rescued by wt IFNAR1 protein in vitro.
COVID-19 research v0.52 IFNAR1 Sarah Leigh Gene: ifnar1 has been classified as Green List (High Evidence).
COVID-19 research v0.51 IFNAR1 Sarah Leigh Added comment: Comment on publications: PMID 31270247: reports three variants in two cases of healthy children with adverse reactions to live attuated virus vaccines. Each had biallelic loss-of-function IFNAR1 variations and the effects of these was demonstrated by the patient-derived fibroblasts being susceptible to viruses. This effect was recused by the WT IFNAR1.
PMID 26676772: reports the tageted degradation of IFNAR1 protein by
Influenza A virus (IAV), allowing the virus to escape the powerful innate immune system. Thus the loss of function of IFNAR1 would increase the susceptability to viral infection.
PMID 20020050: reports the tageted degradation of IFNAR1 protein by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells.
COVID-19 research v0.51 IFNAR1 Sarah Leigh Publications for gene: IFNAR1 were set to 31270247; 26676772; 20020050
Primary immunodeficiency or monogenic inflammatory bowel disease v2.42 IFNAR1 Sarah Leigh Classified gene: IFNAR1 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.42 IFNAR1 Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. However, the publications listed below give evidence that the three LOF variants in two unrelated cases are associated with an adverse reaction to attenuated virus vaccines, which are rescued by wt IFNAR1 protein in vitro.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.42 IFNAR1 Sarah Leigh Gene: ifnar1 has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.50 UNC119 Eleanor Williams commented on gene: UNC119: Checked OMIM and literature (through PubMed) for updates in April 2020 - no new cases reported. Keep red.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.41 IFNAR1 Sarah Leigh Added comment: Comment on publications: PMID 31270247: reports two cases of healthy children with adverse reactions to live attuated virus vaccines. Each had biallelic loss-of-function IFNAR1 variations and the effects of these was demonstrated by the patient-derived fibroblasts being susceptible to viruses. This effect was recused by the WT IFNAR1.
PMID 26676772: reports the tageted degradation of IFNAR1 protein by
Influenza A virus (IAV), allowing the virus to escape the powerful innate immune system. Thus the loss of function of IFNAR1 would increase the susceptability to viral infection.
PMID 20020050: reports the tageted degradation of IFNAR1 protein by Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.41 IFNAR1 Sarah Leigh Publications for gene: IFNAR1 were set to 31270247; 26676772; 20020050
COVID-19 research v0.50 STAT5A Eleanor Williams Publications for gene: STAT5A were set to 16418296
COVID-19 research v0.49 STAT5A Eleanor Williams edited their review of gene: STAT5A: Added comment: April 2020
- no association with any human disease phenotype in OMIM (page last updated Feb 2020).
- no associations in Gene2Phenotype.
- PubMed search - no publications describing reports of variants in STAT5 and PID/viral susceptibility but :

PMID: 26541527- Leahy et al 2016 - mention that STAT5 mRNA (which is in the IL-15 pathway) is differentially expressed in children with severe bronchiolitis compared with those with moderate severity bronchiolitis.
PMID: 23593005- Hong et al 2013 - in human papillomavirus (HPV) infections STAT-5 is activated as part of the process to regulate genome amplification in suprabasal cells.
PMID: 22520852 - Li et al - show in mouse studies that tetramerization of STAT5 is critical for cytokine responses and normal immune function; Changed publications: 16418296, 26541527, 23593005, 22520852
COVID-19 research v0.49 IRF9 Catherine Snow Classified gene: IRF9 as Green List (high evidence)
COVID-19 research v0.49 IRF9 Catherine Snow Added comment: Comment on list classification: Rating Green on this panel following feedback with Genomics England clinical team, as this is a research panel and IRF9 has two unrelated cases and an animal model.
COVID-19 research v0.49 IRF9 Catherine Snow Gene: irf9 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.40 IFNAR1 Sarah Leigh gene: IFNAR1 was added
gene: IFNAR1 was added to Primary immunodeficiency. Sources: Expert Review,Literature
Mode of inheritance for gene: IFNAR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IFNAR1 were set to 31270247; 26676772; 20020050
Phenotypes for gene: IFNAR1 were set to IFNAR1 associated adverse reactions to certain live attenuated viral vaccines
Review for gene: IFNAR1 was set to AMBER
Added comment: Hypothesis from Abdelazeem Elhabyan (Tanta University Hospitals): this gene is involved in the interferon-mediated immune response to viruses of those is SARS Coronavirus (2003) which down-regulates the IFNAR1 receptors through its 3a protein. Additionally, Influenzavirus A suppress immune response by downregulation of this gene. It has been also linked to adverse reactions to measles and yellow fever vaccines in healthy individuals.
Sources: Expert Review, Literature
COVID-19 research v0.48 HLA-B Ivone Leong reviewed gene: HLA-B: Rating: ; Mode of pathogenicity: None; Publications: 15243926, 18186801; Phenotypes: ; Mode of inheritance: None
COVID-19 research v0.48 CCL2 Rebecca Foulger Publications for gene: CCL2 were set to 25818534; 26687605; 16916890; 24788844
COVID-19 research v0.47 CCL2 Rebecca Foulger commented on gene: CCL2: PMID:27260136 (Kim et al., 2016) report that CCL2 ablation highly increased susceptibility to Japanese encephalitis, indicating that CCL2 plays an essential role in conferring protection against JE caused by JE virus (JEV) infection. They also note a surprising opposite effect for ablation of the CCR2 (the corresponding receptor).
COVID-19 research v0.47 CCL2 Rebecca Foulger Publications for gene: CCL2 were set to 25818534; 26687605; 16916890
COVID-19 research v0.46 CCL2 Rebecca Foulger commented on gene: CCL2: PMID:24788844 (Han et al., 2014) studied 36 Chines patients and report that the CCL2-2510G allele is associated with susceptibility to EV71 encephalitis in Chinese patients.
COVID-19 research v0.46 CCL2 Rebecca Foulger Phenotypes for gene: CCL2 were changed from Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection; Susceptibility to SARS-CoV to {HIV-1, resistance to}, 609423; Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection; Susceptibility to SARS-CoV
COVID-19 research v0.45 CCL2 Rebecca Foulger commented on gene: CCL2: PMID:16916890 (Ansari et al.) report increased CCL2 levels in HIV-1 patients, and suggest inhibition of CCL2 production could provide a therapeutic intervention in HIV infection.
COVID-19 research v0.45 CCL2 Rebecca Foulger Publications for gene: CCL2 were set to 25818534
COVID-19 research v0.44 CCL2 Rebecca Foulger commented on gene: CCL2
COVID-19 research v0.44 IRF2BP2 Zornitza Stark reviewed gene: IRF2BP2: Rating: RED; Mode of pathogenicity: None; Publications: 27016798; Phenotypes: Immunodeficiency, common variable, 14, MIM# 617765; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
COVID-19 research v0.44 MPO Sarah Leigh Publications for gene: MPO were set to 9354683; 15108282; 9637725
COVID-19 research v0.43 ACE Rebecca Foulger Marked gene: ACE as ready
COVID-19 research v0.43 ACE Rebecca Foulger Gene: ace has been classified as Red List (Low Evidence).
COVID-19 research v0.43 KRAS Rebecca Foulger Added comment: Comment on mode of inheritance: Autosomal (AD) inheritance listed in OMIM for MIM:614470.
COVID-19 research v0.43 KRAS Rebecca Foulger Mode of inheritance for gene: KRAS was changed from Unknown to Unknown
COVID-19 research v0.42 KRAS Rebecca Foulger commented on gene: KRAS
COVID-19 research v0.42 KRAS Rebecca Foulger Phenotypes for gene: KRAS were changed from RAS associated lymphoproliferative disease, 614470; RALD to RALD; RAS-associated autoimmune leukoproliferative disorder, 614470
COVID-19 research v0.41 IRF8 Ellen McDonagh Classified gene: IRF8 as Green List (high evidence)
COVID-19 research v0.41 IRF8 Ellen McDonagh Gene: irf8 has been classified as Green List (High Evidence).
COVID-19 research v0.40 KDM6A Ellen McDonagh Source Expert Review Green was added to KDM6A.
Added phenotypes Combined immunodeficiencies with associated or syndromic features; Kabuki Syndrome 2 due to KDM6A deficiency; Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present for gene: KDM6A
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 SH3KBP1 Ellen McDonagh Source Expert Review Green was added to SH3KBP1.
Added phenotypes Predominantly Antibody Deficiencies; Severe bacterial infections; SH3KBP1 (CIN85) deficiency; Immunodeficiency 61, 300310 for gene: SH3KBP1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 IRAK1 Ellen McDonagh Source Expert Review Green was added to IRAK1.
Added phenotypes Bacterial infections, X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1; Defects in Intrinsic and Innate Immunity for gene: IRAK1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TRAF3 Ellen McDonagh Added phenotypes Herpetic encephalitis (HSE); Herpes simplex virus 1 encephalitis; Defects in Intrinsic and Innate Immunity; Defects in intrinsic and innate immunity; {?Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 5},614849; Herpes simplex encephalitis, susceptibility to, 3 for gene: TRAF3
COVID-19 research v0.40 TOP2B Ellen McDonagh Source Expert Review Green was added to TOP2B.
Added phenotypes Recurrent infections, facial dysmorphism, limb anomalies; Hoffman syndrome/TOP2B deficiency; Predominantly Antibody Deficiencies for gene: TOP2B
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TNFSF12 Ellen McDonagh Source Expert Review Green was added to TNFSF12.
Added phenotypes Immunodeficiency, common variable with lack of anti-pneumococcal antibody; Common variable immunodeficiency disorders (CVID); Predominantly Antibody Deficiencies; Pneumonia, bacterial infections, warts, thrombocytopenia. neutropenia; Pneumonia, bacterial infections, warts, thrombocytopenia for gene: TNFSF12
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 THBD Ellen McDonagh Source Expert Review Green was added to THBD.
Added phenotypes Complement Deficiencies; Thrombomodulin deficiency; Hemolytic uremic syndrome, atypical, susceptibility to, 6; Atypical hemolytic-uremic syndrome for gene: THBD
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TGFBR2 Ellen McDonagh Source Expert Review Green was added to TGFBR2.
Added phenotypes Recurrent respiratory infections, eczema, food allergies, hyperextensible joints, scoliosis, retention of primary teeths, aortic anuerysms; Combined immunodeficiencies with associated or syndromic features; ALPS-FAS for gene: TGFBR2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TGFBR1 Ellen McDonagh Source Expert Review Green was added to TGFBR1.
Added phenotypes Loeys-Dietz syndrome 1, 609192; Loeys Dietz syndrome due to TGFBR1 deficiency; Combined immunodeficiencies with associated or syndromic features; Recurrent respiratory infectons, eczema, food allergies, hyperextensible joints, scoliosis, retention of primary teeths, aortic anuerysms for gene: TGFBR1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 SRP54 Ellen McDonagh Source Expert Review Green was added to SRP54.
Added phenotypes Schwachman Diamond features; Congenital defects of phagocyte number or function for gene: SRP54
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 SH3BP2 Ellen McDonagh Source Expert Review Green was added to SH3BP2.
Added phenotypes Other autoinflammatory diseases with known genetic defect; Autoinflammatory Disorders; Cherubism 118400; Bone degeneration in jaws for gene: SH3BP2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 SEMA3E Ellen McDonagh Source Expert Review Green was added to SEMA3E.
Added phenotypes CHARGE syndrome; immune-mediated cerebellar ataxia; Coloboma, heart anomaly, choanal atresia, intellectual retardation, genital and ear anomalies, CNS malformation, some are SCID-like and have low TRECs; Charge syndrome 214800; Combined immunodeficiencies with associated or syndromic features for gene: SEMA3E
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 SEC61A1 Ellen McDonagh Source Expert Review Green was added to SEC61A1.
Added phenotypes Severe recurrent respiratory tract infections; Predominantly Antibody Deficiencies; Hyperuricemic nephropathy, familial juvenile, 4, 617056; SEC61A1 deficiency for gene: SEC61A1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 RELA Ellen McDonagh Source Expert Review Green was added to RELA.
Added phenotypes RelA haplosufficiency; Mucosal ulceration, impaired NFkB activation; Mucocutaneous ulceration, chronic, 618287; Immunodeficiencies affecting cellular and humoral immunity for gene: RELA
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 RANBP2 Ellen McDonagh Source Expert Review Green was added to RANBP2.
Added phenotypes Fever induces acute encephalopathy; Defects in intrinsic and innate immunity; Defects in Intrinsic and Innate Immunity for gene: RANBP2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 PSEN1 Ellen McDonagh Source Expert Review Green was added to PSEN1.
Added phenotypes Hidradenitis suppurative with cutaneous hyperpigmentation; Acne inversa, familial, 3 613737; Defects in Intrinsic and Innate Immunity for gene: PSEN1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 OAS1 Ellen McDonagh Source Expert Review Green was added to OAS1.
Added phenotypes OAS1 GOF; Autoinflammatory Disorders; Pulmonary alveolar proteinosis, skin rash for gene: OAS1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 NFE2L2 Ellen McDonagh Source Expert Review Green was added to NFE2L2.
Added phenotypes Recurrent respiratory and skin infections, growth retardation, , developmental delay; increased expression of stress response genes; Immunodeficiency, developmental delay, and hypohomocysteinemia, 617744; white matter cerebral lesions, increased level of homocysteine; Combined immunodeficiencies with associated or syndromic features; NFE2L2 GOF for gene: NFE2L2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 NFAT5 Ellen McDonagh Source Expert Review Green was added to NFAT5.
Added phenotypes NFAT5 haploinsufficieny; IBD, recurrent sinopulmonary infections; Diseases of Immune Dysregulation for gene: NFAT5
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 KMT2D Ellen McDonagh Source Expert Review Green was added to KMT2D.
Added phenotypes Kabuki syndrome 1, 147920; Combined immunodeficiencies with associated or syndromic features; Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present for gene: KMT2D
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 KMT2A Ellen McDonagh Source Expert Review Green was added to KMT2A.
Added phenotypes Wiedemann-Steiner syndrome with Congenital immunodeficiency; Combined immunodeficiencies with associated or syndromic features; Unclassified antibody deficiency; Respiratory infections, short stature, hypertelorism, hairy elbows, developmental delay, intellectual disability for gene: KMT2A
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 JAK1 Ellen McDonagh Source Expert Review Green was added to JAK1.
Added phenotypes Hypereosinophilic syndrome; HSM, eosinophilia, eosinophilic enteritis, thyroid disease, poor growth, viral infections; Diseases of Immune Dysregulation; Susceptibility to mycobacteria and viruses, urothelial carcinoma; Defects in Intrinsic and Innate Immunity; HSM, eosinophilic enteritis, thyroid disease, poor growth, viral infections for gene: JAK1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 IRF2BP2 Ellen McDonagh Source Expert Review Green was added to IRF2BP2.
Added phenotypes Recurrent infections, possible autoimmunity and inflammatory disease; Predominantly Antibody Deficiencies; CVID for gene: IRF2BP2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 ERBIN Ellen McDonagh Source Expert Review Green was added to ERBIN.
Added phenotypes ERBIN deficiency; Combined immunodeficiencies with associated or syndromic features; Recurrent respiratory infections, susceptibility to S. aureus, eczema, hyperextensible joints, scoliosis, arterial dilatation in some for gene: ERBIN
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 BCL11B Ellen McDonagh Source Expert Review Green was added to BCL11B.
Added phenotypes Combined immunodeficiencies with associated or syndromic features; leaky SCID; ?Immunodeficiency 49, 617237; Immunodeficiencies affecting cellular and humoral immunity; Congenital abnormalities, neonatal teeth, dysmorphic facies, absent corpus callosum, neurocognitive deficits for gene: BCL11B
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 APOL1 Ellen McDonagh Source Expert Review Green was added to APOL1.
Added phenotypes Defects in Intrinsic and Innate Immunity; Trypanosomiasis, susceptibility to; Trypanosomias; Trypanosomiasis for gene: APOL1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 ACTB Ellen McDonagh Source Expert Review Green was added to ACTB.
Added phenotypes Congenital defects of phagocyte number or function; neutrophil dysfunction; Mental retardation, short stature; Actin beta deficiency (ACTB); Phagocytic disorder; Poor neutrophil chemotaxis, oxidative burst and actin remodeling. Thrombocytopenia; Baraitser-Winter syndrome 1, 243310 for gene: ACTB
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TNFRSF13B Ellen McDonagh Source Expert Review Green was added to TNFRSF13B.
Added phenotypes IgA with IgG subclass deficiency; Immunodeficiency, common variable, 2; Immunodeficiency, common variable, 2, 240500; Variable clinical expression; Isolated IgG subclass deficiency; IGAD; Selective IgA deficiency; Common variable immunodeficiency disorders (CVID); Predominantly Antibody Deficiencies; Immunoglobulin A deficiency 2, 609529; CVID for gene: TNFRSF13B
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 CFHR2 Ellen McDonagh Source Expert Review Green was added to CFHR2.
Added phenotypes Complement Deficiencies; Age related macular degeneration; Atypical hemolytic uremic syndrome susceptibility; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections for gene: CFHR2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 ZNF341 Ellen McDonagh Source Expert Review Green was added to ZNF341.
Added phenotypes Hyper-IgE syndrome; Combined immunodeficiencies with associated or syndromic features; Bacterial infections, mild facial dysmorphism, pneumatoceles, hyperextensible joints, bone fractures, retention of primary teeth for gene: ZNF341
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 WRAP53 Ellen McDonagh Source Expert Review Green was added to WRAP53.
Added phenotypes Bone marrow failure; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; Combined immunodeficiencies with associated or syndromic features; Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/- recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson Syndrome (HHS) may occur in some DKC patients; microcephaly, neurodevelopmental delay for gene: WRAP53
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TRIM22 Ellen McDonagh Source Expert Review Green was added to TRIM22.
Added phenotypes TRIM22; Granulomatous colitis; Autoinflammatory Disorders; Diseases of Immune Dysregulation for gene: TRIM22
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TRAF3IP2 Ellen McDonagh Source Expert Review Green was added to TRAF3IP2.
Added phenotypes Defects in Intrinsic and Innate Immunity; Chronic mucocutaneous candidiasis (CMC); Defects in intrinsic and innate immunity; Candidiasis, familial, 8 615527; CMC, blepharitis, folliculitis and macroglossia for gene: TRAF3IP2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TNFSF11 Ellen McDonagh Source Expert Review Green was added to TNFSF11.
Added phenotypes Osteopetrosis with severe growth retardation; Defects in intrinsic and innate immunity; Defects in Intrinsic and Innate Immunity for gene: TNFSF11
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TNFRSF9 Ellen McDonagh Source Expert Review Green was added to TNFRSF9.
Added phenotypes EBV lymphoproliferation, B-cell lymphoma; CD137 deficiency (41BB) for gene: TNFRSF9
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TNFRSF4 Ellen McDonagh Source Expert Review Green was added to TNFRSF4.
Added phenotypes Kaposi's Sarcoma, impaired immunity to HHV8, OX40 deficiency; Immunodeficiencies affecting cellular and humoral immunity; Impaired immunity to HHV8, Kaposis sarcoma; Combined immunodeficiency for gene: TNFRSF4
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TIRAP Ellen McDonagh Source Expert Review Green was added to TIRAP.
Added phenotypes Staphylococcal disease during childhood; Defects of TLR/NFkappa-B signalling; TIRAP deficiency; Defects in intrinsic and innate immunity; Defects in Intrinsic and Innate Immunity for gene: TIRAP
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TGFB1 Ellen McDonagh Source Expert Review Green was added to TGFB1.
Added phenotypes Inflammatory bowel disease, immunodeficiency, and encephalopathy, 618213; IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy; TGFB1 deficiency; Diseases of Immune Dysregulation for gene: TGFB1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TFRC Ellen McDonagh Source Expert Review Green was added to TFRC.
Added phenotypes Recurrent infections, neutropenia, thrombocytopenia; Recurrent infections, thrombocytopenia; Immunodeficiencies affecting cellular and humoral immunity for gene: TFRC
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TCIRG1 Ellen McDonagh Source Expert Review Green was added to TCIRG1.
Added phenotypes Defects in intrinsic and innate immunity; Osteopetrosis with hypocalcemia; Defects in Intrinsic and Innate Immunity for gene: TCIRG1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 STN1 Ellen McDonagh Source Expert Review Green was added to STN1.
Added phenotypes Combined immunodeficiencies with associated or syndromic features; Bone marrow failure; Intrauterine growth retardation, premature aging, pancytopenia, hypocellular bone marrow, gastrointestinal hemorrhage due to vascular ectasia, intracranial calcification, abnormal telomeres for gene: STN1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 SNX10 Ellen McDonagh Source Expert Review Green was added to SNX10.
Added phenotypes Defects in intrinsic and innate immunity; Osteopetrosis with visual impairment; Defects in Intrinsic and Innate Immunity for gene: SNX10
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 SMARCD2 Ellen McDonagh Source Expert Review Green was added to SMARCD2.
Added phenotypes Congenital defects of phagocyte number or function; Neutropenia, developmental aberrations, skeletal abnormalities, hematopoietic stem cells, myelodysplasia for gene: SMARCD2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 SLC7A7 Ellen McDonagh Source Expert Review Green was added to SLC7A7.
Added phenotypes Lysinuric protein intolerance, 222700; Severe bacterial infections; Lysinuric protein intolerance SLC7A7 deficiency; Predominantly Antibody Deficiencies for gene: SLC7A7
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 SLC39A7 Ellen McDonagh Source Expert Review Green was added to SLC39A7.
Added phenotypes Agammaglobulinemia; B cell deficiency; Early onset infections, blistering dermatosis, failure to thrive, thrombocytopenia; Predominantly Antibody Deficiencies for gene: SLC39A7
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 RNU4ATAC Ellen McDonagh Source Expert Review Green was added to RNU4ATAC.
Added phenotypes Recurrent bacterial infections, lymphadenopathy, Spondyloepiphyseal dysplasia, extreme intrauterine growth retardation, retinal dystrophy, facial dysmorphism, may present with microcephaly; Combined immunodeficiencies with associated or syndromic features; Recurrent bacterial infections, lymphadenopathy, Spondyloepiphyseal dysplasia, extreme intrauterine growth retardation, retinal dystrophy, facial dysmorphism, may present with microcephaly, short stature for gene: RNU4ATAC
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 RNF31 Ellen McDonagh Source Expert Review Green was added to RNF31.
Added phenotypes Polyglucosan body myopathy, early-onset, with or without immunodeficiency; Autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis; autoinflammation and combined immunodeficiency; Combined immunodeficiencies with associated or syndromic features; Bacterial infections, autoinflammation, amylopectinosis, lymphangiectasia for gene: RNF31
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 RELB Ellen McDonagh Source Expert Review Green was added to RELB.
Added phenotypes Immunodeficiencies affecting cellular and humoral immunity; Recurrent infectionsImmunodeficiencies affecting cellular and humoral immunity; Recurrent infections; ?Immunodeficiency 53, 617585 for gene: RELB
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 REL Ellen McDonagh Source Expert Review Green was added to REL.
Added phenotypes Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic infections; Immunodeficiencies affecting cellular and humoral immunity; c-Rel deficiency for gene: REL
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 PSMG2 Ellen McDonagh Source Expert Review Green was added to PSMG2.
Added phenotypes Panniculitis, lipodystrophy, autoimmune hemolytic anemia; CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy); Autoinflammatory Disorders for gene: PSMG2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 POLE2 Ellen McDonagh Source Expert Review Green was added to POLE2.
Added phenotypes Recurrent infections, disseminated BCG infections, autoimmunity (type 1 diabetes, hypothyroidism, facial dysmorphism); Combined immunodeficiencies with associated or syndromic features; Recurrent infections, disseminated BCG infections, autoimmunity (type 1 diabetes, hypothyroidism, facial dysmorphism for gene: POLE2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 POLD2 Ellen McDonagh Source Expert Review Green was added to POLD2.
Added phenotypes Immunodeficiencies affecting cellular and humoral immunity; Polymerase d 2 deficiency; Recurrent respiratory tract infections, skin infections, warts and molluscum, short stature, intellectual disability for gene: POLD2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 POLD1 Ellen McDonagh Source Expert Review Green was added to POLD1.
Added phenotypes Immunodeficiencies affecting cellular and humoral immunity; Recurrent respiratory tract infections, skin infections, warts and molluscum, short stature, intellectual disability; Polymerase d 1 deficiency for gene: POLD1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 PLEKHM1 Ellen McDonagh Source Expert Review Green was added to PLEKHM1.
Added phenotypes Osteopetrosis; Defects in intrinsic and innate immunity; Defects in Intrinsic and Innate Immunity for gene: PLEKHM1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 OSTM1 Ellen McDonagh Source Expert Review Green was added to OSTM1.
Added phenotypes Defects in intrinsic and innate immunity; Defects in Intrinsic and Innate Immunity; Osteopetrosis with hypocalcemia, neurologic features for gene: OSTM1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 NBAS Ellen McDonagh Source Expert Review Green was added to NBAS.
Added phenotypes Infantile liver failure syndrome 2, 616483; Defects in intrinsic and innate immunity; Fever induced liver failure; Defects in Intrinsic and Innate Immunity; Fever induces liver failure for gene: NBAS
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 MSH6 Ellen McDonagh Source Expert Review Green was added to MSH6.
Added phenotypes Colorectal cancer, hereditary nonpolyposis, type 5 614350; Endometrial cancer, familial 608089; Predominantly Antibody Deficiencies; Family or personal history of cancer; Mismatch repair cancer syndrome 276300 for gene: MSH6
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 MS4A1 Ellen McDonagh Source Expert Review Green was added to MS4A1.
Added phenotypes Predominantly Antibody Deficiencies; Recurrent infections; Common variable immunodeficiency disorders (CVID); Immunodeficiency, common variable, 5 613495 for gene: MS4A1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 MKL1 Ellen McDonagh Source Expert Review Green was added to MKL1.
Added phenotypes Susceptibility to severe bacterial infection; Mild thrombocytopenia; Congenital defects of phagocyte number or function for gene: MKL1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 MASP2 Ellen McDonagh Source Expert Review Green was added to MASP2.
Added phenotypes Complement Deficiencies; MASP2 deficiency 613791; Mannan-binding lectin serine protease (MASP) deficiency; Pyogenic infections, inflammatory lung disease, autoimmunity for gene: MASP2
Publications for gene MASP2 were updated from 24658431; 32086639; 32048120; 19405982 to 24658431; 32086639; 32048120; 19405982
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 LIG1 Ellen McDonagh Source Expert Review Green was added to LIG1.
Added phenotypes DNA ligase I deficiency; Combined immunodeficiencies with associated or syndromic features; DNA-ligase 1 ATP-dependent deficiency (LIG1); Recurrent respiratory infections, growth retardation, sun sensitivity, lymphoma, radiation sensitivity for gene: LIG1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 IL6ST Ellen McDonagh Source Expert Review Green was added to IL6ST.
Added phenotypes Eczema; Abnormal acute-phase responses; Recurrent infections; Bacterial infections, boiles, eczema, pulmonary abscesses, pneumatoceles, bone fractures, scoliosis, retention of primary teeth, craniosynostosis; Eosinophilia; Elevated IgE; Combined immunodeficiencies with associated or syndromic features for gene: IL6ST
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 IL6R Ellen McDonagh Source Expert Review Green was added to IL6R.
Added phenotypes Eczema; Recurrent infections; Recurrent pyogenic infections, cold abscesses, high circulating IL-6 levels; Hyper-IgE; Combined immunodeficiencies with associated or syndromic features for gene: IL6R
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 IL2RB Ellen McDonagh Source Expert Review Green was added to IL2RB.
Added phenotypes Lymphoproliferation, lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, dermatitis, enteropathy, recurrent viral (EBV, CMV) infections; Immunodeficiency 63 with lymphoproliferation and autoimmunity, 618495; CD122 deficiency for gene: IL2RB
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 IFNAR2 Ellen McDonagh Source Expert Review Green was added to IFNAR2.
Added phenotypes ?Immunodeficiency 45, 616669; Severe viral infections (disseminated vaccine-strain measles, HHV6); Defects in Intrinsic and Innate Immunity for gene: IFNAR2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 ICOSLG Ellen McDonagh Source Expert Review Green was added to ICOSLG.
Added phenotypes Immunodeficiencies affecting cellular and humoral immunity; Recurrent bacterial and viral infections for gene: ICOSLG
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 HYOU1 Ellen McDonagh Source Expert Review Green was added to HYOU1.
Added phenotypes Hypoglycemia, inflammatory complications; Congenital defects of phagocyte number or function for gene: HYOU1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 HMOX1 Ellen McDonagh Source Expert Review Green was added to HMOX1.
Added phenotypes amyloidosis; Hemolysis, nephritis, inflammation; Defects in Intrinsic and Innate Immunity for gene: HMOX1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 HAVCR2 Ellen McDonagh Source Expert Review Green was added to HAVCR2.
Added phenotypes T-cell lymphoma, subcutaneous panniculitis-like, 618398; Tim-3 deficiency; T-cell lymphoma, subcutaneous panniculitis-like, HLH; Autoinflammatory Disorders for gene: HAVCR2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 FERMT1 Ellen McDonagh Source Expert Review Green was added to FERMT1.
Added phenotypes FERMT1 deficiency (Kindler syndrome); Diseases of Immune Dysregulation; Kindler syndrome, 173650; Dermatosis characterized by congenital blistering, skin atrophy, photosensitivity, skin fragility, and scaling for gene: FERMT1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 FCN3 Ellen McDonagh Source Expert Review Green was added to FCN3.
Added phenotypes Respiratory infections, abscesses; Complement Deficiencies; Ficolin3 deficiency; Immunodeficiency due to ficolin 3 deficiency, 613860 for gene: FCN3
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 FCHO1 Ellen McDonagh Source Expert Review Green was added to FCHO1.
Added phenotypes Recurrent infections, lymphoproliferation, increased activation-induced T-cell death, defective clathrin-mediated endocytosis; FCHO1 deficiency; Immunodeficiencies affecting cellular and humoral immunity for gene: FCHO1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 FANCM Ellen McDonagh Source Expert Review Green was added to FANCM.
Added phenotypes Fanconi Anemia Type M; Bone marrow failure; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage for gene: FANCM
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 FANCI Ellen McDonagh Source Expert Review Green was added to FANCI.
Added phenotypes Fanconi anemia, complementation group I, 609053; Bone marrow failure; Fanconi Anemia Type I; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage for gene: FANCI
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 FANCF Ellen McDonagh Source Expert Review Green was added to FANCF.
Added phenotypes Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Fanconi anemia, complementation group F, 603467; Bone marrow failure; Fanconi Anemia Type F for gene: FANCF
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 FAAP24 Ellen McDonagh Source Expert Review Green was added to FAAP24.
Added phenotypes EBV infection-driven lymphoproliferative disease; Diseases of Immune Dysregulation for gene: FAAP24
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 ERCC4 Ellen McDonagh Source Expert Review Green was added to ERCC4.
Added phenotypes Fanconi anemia, complementation group Q, 615272; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Fanconi Anemia Type Q; Bone marrow failure for gene: ERCC4
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 DEF6 Ellen McDonagh Source Expert Review Green was added to DEF6.
Added phenotypes DEF6 deficiency; Diseases of Immune Dysregulation; Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections for gene: DEF6
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 DBR1 Ellen McDonagh Source Expert Review Green was added to DBR1.
Added phenotypes DBR1 deficiency; HSE of the brainstem. Other viral infections of the brainstem; Defects in intrinsic and innate immunity for gene: DBR1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 CLCN7 Ellen McDonagh Source Expert Review Green was added to CLCN7.
Added phenotypes Defects in Intrinsic and Innate Immunity; Osteopetrosis with hypocalcemia, neurologic features for gene: CLCN7
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 C8G Ellen McDonagh Source Expert Review Green was added to C8G.
Added phenotypes Complement Deficiencies; Complement factor 8 defect; Complement component 8 deficiency; Disseminated neisserial infections for gene: C8G
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 C17orf62 Ellen McDonagh Source Expert Review Green was added to C17orf62.
Added phenotypes Autosomal recessive CGD EROS; Congenital defects of phagocyte number or function for gene: C17orf62
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 BRCA2 Ellen McDonagh Source Expert Review Green was added to BRCA2.
Added phenotypes Fanconi anemia, complementation group D1, 605724; Normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Fanconi Anemia Type D1; Bone marrow failure for gene: BRCA2
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 BRCA1 Ellen McDonagh Source Expert Review Green was added to BRCA1.
Added phenotypes Fanconi Anemia Type S; Fanconi anemia, complementation group S, 617883; normal to low NK, CNS, skeletal, skin, cardiac, GI, urogenital anomalies, increased chromosomal breakage; Bone marrow failure for gene: BRCA1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 ARHGEF1 Ellen McDonagh Source Expert Review Green was added to ARHGEF1.
Added phenotypes Recurrent infections, bronchiectasis; Immunodeficiency 62, 618459; ARHGEF1 deficiency; Predominantly Antibody Deficiencies for gene: ARHGEF1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 AP3D1 Ellen McDonagh Source Expert Review Green was added to AP3D1.
Added phenotypes neutropenia; Immunodeficient HPS; seizures; Diseases of Immune Dysregulation; Hermansky-Pudlak syndrome with neutropenia; neuordevelopmental delay; albinism; ?Hermansky-Pudlak syndrome 10, 617050; Hermansky-Pudlak syndrome; Oculocutaneous albinism, recurrent infections, seizures, hearing loss and neurodevelopmental delay; Oculocutaneous albinism, severe neutropenia, recurrent infections, seizures, hearing loss and neurodevelopmental delay; HSP10 for gene: AP3D1
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 ALPI Ellen McDonagh Source Expert Review Green was added to ALPI.
Added phenotypes Inflammatory bowel disease; ALPI deficiency; Autoinflammatory Disorders for gene: ALPI
Rating Changed from Red List (low evidence) to Green List (high evidence)
COVID-19 research v0.40 TINF2 Ellen McDonagh Source Expert Review Green was added to TINF2.
Added phenotypes microcephaly, neurodevelopmental delay exudative retinopathy; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay for gene: TINF2
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 TERC Ellen McDonagh Source Expert Review Green was added to TERC.
Added phenotypes Dyskeratosis congenita; Bone marrow failure; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; Dyskeratosis congenita 1; Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/- recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson Syndrome (HHS) may occur in some DKC patients; Combined immunodeficiencies with associated or syndromic features; Hoyeraal-Hreidarsson syndrome; microcephaly, neurodevelopmental delay for gene: TERC
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 TBX1 Ellen McDonagh Source Expert Review Green was added to TBX1.
Added phenotypes Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability; DiGeorge syndrome 188400; Di George syndrome; T-B+ SCID; Severe combined immunodeficiency (SCID); Combined immunodeficiencies with associated or syndromic features for gene: TBX1
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 SAMD9L Ellen McDonagh Source Expert Review Green was added to SAMD9L.
Added phenotypes Cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction; Combined immunodeficiencies with associated or syndromic features; MDS, neurological features; Bone marrow failure for gene: SAMD9L
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 SAMD9 Ellen McDonagh Source Expert Review Green was added to SAMD9.
Added phenotypes IUGR with gonadal abnormalities, adrenal failure, MDS with chromosome 7 aberrations, predisposition to infections, enteropathy, absent spleen; MIRAGE syndrome (Myelodysplasia, Infection, Restriction of growth, Adrenal insufficiency, Genital phenotypes, and Enteropathy); ataxia-thrombocytopenia syndrome; Bone marrow failure; Combined immunodeficiencies with associated or syndromic features for gene: SAMD9
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 PTEN Ellen McDonagh Source Expert Review Green was added to PTEN.
Added phenotypes Recurrent infections, Lymphoproliferation, Autoimmunity; Lymphoproliferation, Autoimmunity; developmental delay; Predominantly Antibody Deficiencies for gene: PTEN
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 PSENEN Ellen McDonagh Source Expert Review Green was added to PSENEN.
Added phenotypes Acne inversa, familial, 2, with or without Dowling-Degos disease 613736; Defects in intrinsic and innate immunity; Defects in Intrinsic and Innate Immunity; Hidradenitis suppurativa for gene: PSENEN
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 NCSTN Ellen McDonagh Source Expert Review Green was added to NCSTN.
Added phenotypes Hidradenitis suppurativa with acne, 142690; Defects in intrinsic and innate immunity; familial hydradenitis suppurativa; Defects in Intrinsic and Innate Immunity; Hidradenitis suppurativa with acne for gene: NCSTN
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 IRF3 Ellen McDonagh Source Expert Review Green was added to IRF3.
Added phenotypes {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 7}, 616532; Herpes simplex virus 1 encephalitis; Defects in Intrinsic and Innate Immunity for gene: IRF3
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 IL17F Ellen McDonagh Source Expert Review Green was added to IL17F.
Added phenotypes CMC, folliculitis; Candidiasis, familial, 6, 613956; Defects in Intrinsic and Innate Immunity; Chronic mucocutaneous candidiasis (CMC) for gene: IL17F
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 TERT Ellen McDonagh Source Expert Review Green was added to TERT.
Added phenotypes Bone marrow failure; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay for gene: TERT
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 RAC2 Ellen McDonagh Source Expert Review Green was added to RAC2.
Added phenotypes Reticular dysgenesis; poststreptococcal glomerulonephritis; Congenital defects of phagocyte number or function; Neutrophil immunodeficiency syndrome; RAS-related C3 Bolutinum toxin substrate 2 deficiency (RAC2); T-B+ SCID; Neutrophil immunodeficiency syndrome 608203; Recurrent sinopulmonary infections, selective IgA defiency; urticaria; T-B- SCID; Poor wound healing, leukocytosis for gene: RAC2
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 NLRP1 Ellen McDonagh Source Expert Review Green was added to NLRP1.
Added phenotypes Dyskeratosis, autoimmunity and arthritis; Palmoplantar carcinoma, corneal scarring; Autoinflammation with arthritis and dyskeratosis; Autoinflammatory Disorders for gene: NLRP1
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 CFHR5 Ellen McDonagh Source Expert Review Green was added to CFHR5.
Added phenotypes Atypical hemolytic-uremic syndrome with anti-factor H antibodies; Atypical hemolytic uremic syndrome susceptibility; Nephropathy due to CFHR5 deficiency, 614809; Complement Deficiencies; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections for gene: CFHR5
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 CFHR4 Ellen McDonagh Source Expert Review Green was added to CFHR4.
Added phenotypes Complement Deficiencies; Age related macular degeneration; Atypical hemolytic uremic syndrome susceptibility; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections for gene: CFHR4
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 CFHR3 Ellen McDonagh Source Expert Review Green was added to CFHR3.
Added phenotypes Complement Deficiencies; Age related macular degeneration; Atypical hemolytic uremic syndrome susceptibility; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections for gene: CFHR3
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 CFHR1 Ellen McDonagh Source Expert Review Green was added to CFHR1.
Added phenotypes Complement Deficiencies; Age related macular degeneration; Atypical hemolytic uremic syndrome susceptibility; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections for gene: CFHR1
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 CFB Ellen McDonagh Source Expert Review Green was added to CFB.
Added phenotypes Infections with encapsulated organisms; Complement Deficiencies; complement factor B deficiency (AR); Atypical Hemolytic-uremic syndrome; Complement factor B deficiency, 615561; Susceptibility to atypical haemolytic uraemic syndrome 4 (AD) for gene: CFB
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 WDR1 Ellen McDonagh Source Expert Review Green was added to WDR1.
Added phenotypes Mild neutropenia, poor wound healing, severe stomatitis, neutrophil nuclei herniate; Congenital defects of phagocyte number or function for gene: WDR1
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 USP18 Ellen McDonagh Source Expert Review Green was added to USP18.
Added phenotypes Pseudo-TORCH syndrome 2, 617397; Autoinflammatory Disorders; TORCH like syndrome for gene: USP18
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 TNFRSF13C Ellen McDonagh Source Expert Review Green was added to TNFRSF13C.
Added phenotypes Immunodeficiency, common variable, 4; Variable clinical expression; Isolated IgG subclass deficiency; Common variable immunodeficiency disorders (CVID); Predominantly Antibody Deficiencies for gene: TNFRSF13C
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 TNFRSF11A Ellen McDonagh Source Expert Review Green was added to TNFRSF11A.
Added phenotypes Osteopetrosis; Defects in intrinsic and innate immunity; Defects in Intrinsic and Innate Immunity for gene: TNFRSF11A
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
COVID-19 research v0.40 TAPBP Ellen McDonagh Source Expert Review Green was added to TAPBP.
Added phenotypes Bare lymphocyte syndrome, type I 604571; Vasculitis, pyoderma gangrenosum; HLA class I deficiency; Immunodeficiencies affecting cellular and humoral immunity; Vasculitis,pyoderma gangrenosum for gene: TAPBP
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)