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| Inherited bleeding disorders v1.178 | RNU4ATAC | Arina Puzriakova Phenotypes for gene: RNU4ATAC were changed from Platelet disorder; Roifman Syndrome with thrombocytopenia and Primary immunodeficiency to Roifman syndrome, OMIM:616651; Roifman Syndrome with thrombocytopenia and Primary immunodeficiency | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.177 | GP6 | Arina Puzriakova Phenotypes for gene: GP6 were changed from Bleeding diathesis due to glycoprotein VI deficiency to Bleeding disorder, platelet-type, 11, OMIM:614201 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.173 | TBXA2R | Arina Puzriakova Phenotypes for gene: TBXA2R were changed from Thromboxane A2 receptor defect to {Bleeding disorder, platelet-type, 13, susceptibility to}, OMIM:614009 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.168 | GP1BB | Arina Puzriakova Phenotypes for gene: GP1BB were changed from Bernard-Soulier syndrome, type B (BIALLELIC, autosomal or pseudoautosomal); Giant platelet disorder, isolated (AR); 231200; Bernard-Soulier syndrome; Macrothrombocytopenia (MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown) to Bernard-Soulier syndrome, type B, OMIM:231200; Giant platelet disorder, isolated, OMIM:231200; Macrothrombocytopenia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.166 | F12 | Arina Puzriakova Phenotypes for gene: F12 were changed from Coagulaton disorder; Angioedema, hereditary, type 3 (AD); Angioedema, hereditary, type III; Factor 12 deficiency (AR); Factor XII deficiency to Angioedema, hereditary, type III, OMIM:610618; Factor XII deficiency, OMIM:234000 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.165 | TBXAS1 | Arina Puzriakova Phenotypes for gene: TBXAS1 were changed from Ghosal syndrome to Ghosal hematodiaphyseal syndrome, OMIM:231095; ?Thromboxane synthase deficiency, OMIM:614158; Bleeding disorder, platelet-type, 14, OMIM:614158 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.164 | VKORC1 | Ivone Leong Phenotypes for gene: VKORC1 were changed from Multiple coagulation factor deficiency type 2 to Vitamin K-dependent clotting factors, combined deficiency of, 2, OMIM:607473 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.161 | FLNA |
Arina Puzriakova Added comment: Comment on mode of inheritance: Changed MOI from 'X-LINKED... biallelic mutations in females' to 'X-LINKED... monoallelic mutations in females may cause disease'. FLNA-related periventricular nodular heterotopia (MIM# 300049) can be associated with macrothrombocytopenia and a bleeding tendency in some cases (PMID: 16684786; 21960593; 29449050; 32299270). Affected females with heterozygous variants in FLNA have been identified indicating XLD inheritance. The association with macrothrombocytopenia has been supported by in vitro assays and animal model (PMID: 21652675; 21960593; 30602618; 31471375) |
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| Inherited bleeding disorders v1.161 | FLNA | Arina Puzriakova Mode of inheritance for gene: FLNA was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.159 | ARPC1B | Arina Puzriakova Phenotypes for gene: ARPC1B were changed from Platelet disorder; Thrombocytopenia and Immune Deficiency to Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia, OMIM:617718; Combined immune deficiency with or without thrombocytopenia; Inflammatory predisposition | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.155 | IKZF5 |
Louise Daugherty gene: IKZF5 was added gene: IKZF5 was added to Inherited bleeding disorders. Sources: Literature Mode of inheritance for gene: IKZF5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: IKZF5 were set to 31217188 Phenotypes for gene: IKZF5 were set to Thrombocytopenia Review for gene: IKZF5 was set to GREEN Added comment: From abstract Lentaigne C et al (2019) PMID: 31217188: To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing (WGS) data from 13,037 individuals enrolled in the NIHR BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor (TF)-encoding gene IKZF5 and thrombocytopenia. We report five causal missense variants in or near IKZF5 zinc fingers (Znfs), of which two occurred de novo and three co-segregated in three pedigrees. A canonical DNA-Znf binding model predicts that three of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared to wild-type (WT) IKZF5 and electron microscopy (EM) revealed a reduced quantity of alpha granules in normally sized platelets. Proplatelet formation (PPF) was reduced in megakaryocytes (MKs) from seven cases relative to six controls. Comparison of RNA-seq data from platelets, monocytes, neutrophils and CD4+ T-cells from three cases and 14 healthy controls showed 1,194 differentially expressed genes (DEGs) in platelets but only four DEGs in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans. Sources: Literature |
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| Inherited bleeding disorders v1.153 | ACTB | Louise Daugherty Phenotypes for gene: ACTB were changed from Baraitser-Winter syndrome 1 with macrothrombocytopenia to Baraitser-Winter syndrome 1 with macrothrombocytopenia; Platelet disorder | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.151 | ACTB |
Louise Daugherty gene: ACTB was added gene: ACTB was added to Inherited bleeding disorders. Sources: Literature Mode of inheritance for gene: ACTB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ACTB were set to 30315159; 22366783 Phenotypes for gene: ACTB were set to Baraitser-Winter syndrome 1 with macrothrombocytopenia Review for gene: ACTB was set to GREEN Added comment: PMID: 30315159 describe six individuals from four unrelated families carrying de novo or co-segregating heterozygous variants in exons 5 and 6 of the ACTB gene. Patients are clinically distinct from those with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF), presenting with mild developmental disability, unspecific minor facial anomalies, microcephaly and thrombocytopenia with platelet anisotropy (variable size including normal and enlarged platelets). Sources: Literature |
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| Inherited bleeding disorders v1.149 | SLC35A1 |
Rebecca Foulger gene: SLC35A1 was added gene: SLC35A1 was added to Inherited bleeding disorders. Sources: Literature Mode of inheritance for gene: SLC35A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC35A1 were set to 15576474; 30115659 Phenotypes for gene: SLC35A1 were set to Congenital disorder of glycosylation, type IIf, 603585; severe thrombocytopenia; hemorrhages; macrothrombocytopenia Review for gene: SLC35A1 was set to AMBER Added comment: Added SLC35A1 to the 'Inherited bleeding disorders' panel with Amber rating as suggested by Helen Brittain, based on pattern of bleeding anomalies and macrothrombocytopaenia reported in PMID:15576474 (Martinez-Duncker, 2005. Note a 'leaky' polymorphism) and PMID:30115659 (Kauskot et al. 2018). More cases required for a diagnostic rating. Sources: Literature |
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| Inherited bleeding disorders v1.147 | PTPRJ |
Louise Daugherty gene: PTPRJ was added gene: PTPRJ was added to Inherited bleeding disorders. Sources: Literature watchlist tags were added to gene: PTPRJ. Mode of inheritance for gene: PTPRJ was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTPRJ were set to 30591527 Phenotypes for gene: PTPRJ were set to Thrombocytopenia; spontaneous bleeding, small-sized platelets, and impaired platelet responses to the GPVI agonists collagen and convulxin. Review for gene: PTPRJ was set to AMBER Added comment: Marconi C et al. Dec 2018 (PMID: 30591527) through exome sequencing of two siblings with autosomal recessive thrombocytopenia, identified two biallelic loss-of-function variants in the gene PTPRJ. They also investigated the pathogenic role of PTPRJ deficiency in hematopoiesis in vivo, carried out using CRISPR/Cas9-mediated ablation of ptprja (the ortholog of human PTPRJ) in zebrafish, which induced a significantly decreased number of CD41+ thrombocytes in vivo. Megakaryocytes of the patients showed impaired maturation and profound defects in SDF1-driven migration and formation of proplatelets in vitro. Silencing of PTPRJ in a human megakaryocytic cell line reproduced the functional defects observed in patients' megakaryocytes. The disorder caused by PTPRJ mutations presented as a non-syndromic thrombocytopenia characterized by spontaneous bleeding, small-sized platelets, and impaired platelet responses to the GPVI agonists collagen and convulxin. Sources: Literature |
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| Inherited bleeding disorders v1.146 | Ellen McDonagh List of related panels changed from Inherited platelet disorders; Monogenic thrombophilia; Bleeding and platelet disorders; Inherited bleeding and or platelet disorders; Unprovoked Thrombosis before 40; Monogenic venous thrombosis to Inherited platelet disorders; Monogenic thrombophilia; Inherited bleeding and or platelet disorders; Unprovoked Thrombosis before 40; Monogenic venous thrombosis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.145 | GBA | Louise Daugherty commented on gene: GBA: Update from NIHRRD-BR BRIDGE they will no longer be reporting on this gene on their platform. After discussion with Genomics England Clinical team, as the MOI is listed as biallelic so we would only prioritise variants that are homozygous or compound het. A parent might be found to be a carrier, when their child has the condition but that is to be expected and would be useful information. Gaucher is associated with haematological manifestations as part of the wider syndromic phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.144 | SMAD4 | Louise Daugherty Added comment: Comment on list classification: New gene from NIHRRD-BR BRIDGE Bleeding and Platelet Disorders project, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.143 | SMAD4 |
Louise Daugherty gene: SMAD4 was added gene: SMAD4 was added to Inherited bleeding disorders. Sources: Expert list Mode of inheritance for gene: SMAD4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: SMAD4 were set to Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, 175050; Bleeding disorder Review for gene: SMAD4 was set to GREEN Added comment: New bleeding, platelet, coagulation and thrombotic disorder Tier 1 reportable gene from NIHRRD-BR BRIDGE project, announced at ISTH-SSC meeting Dublin 2018. Sources: Expert list |
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| Inherited bleeding disorders v1.142 | ENG | Louise Daugherty Added comment: Comment on list classification: New gene from NIHRRD-BR BRIDGE Bleeding and Platelet Disorders project, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.139 | ENG |
Louise Daugherty gene: ENG was added gene: ENG was added to Inherited bleeding disorders. Sources: Expert list Mode of inheritance for gene: ENG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ENG were set to 9245986 Phenotypes for gene: ENG were set to Telangiectasia, hereditary hemorrhagic, type 1, 187300 Review for gene: ENG was set to GREEN Added comment: New bleeding, platelet, coagulation and thrombotic disorder Tier 1 reportable gene from NIHRRD-BR BRIDGE project, announced at ISTH-SCC meeting Dublin 2018. Sources: Expert list |
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| Inherited bleeding disorders v1.138 | ACVRL1 | Louise Daugherty Added comment: Comment on list classification: New gene from NIHRRD-BR BRIDGE Bleeding and Platelet Disorders project, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.136 | ACVRL1 | Louise Daugherty Added comment: Comment on publications: Added publications to support upgrading of the gene to Green. More than three unrelated cases in a range of ethnicities has been reported for HHT type 2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.133 | ACVRL1 |
Louise Daugherty gene: ACVRL1 was added gene: ACVRL1 was added to Inherited bleeding disorders. Sources: Expert list Mode of inheritance for gene: ACVRL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ACVRL1 were set to 8640225 Phenotypes for gene: ACVRL1 were set to Telangiectasia, hereditary hemorrhagic, type 2 Review for gene: ACVRL1 was set to GREEN Added comment: New bleeding, platelet, coagulation and thrombotic disorder Tier 1 reportable gene from NIHRRD-BR BRIDGE project, announced at ISTH-SCC meeting Dublin 2018. Sources: Expert list |
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| Inherited bleeding disorders v1.131 | SRC | Louise Daugherty Phenotypes for gene: SRC were changed from Thrombocytopenia, Bleeding and myelofibrosis; ?Thrombocytopenia 6,616937 to Thrombocytopenia, Bleeding and myelofibrosis; ?Thrombocytopenia 6,616937; Platelet disorder | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.130 | CDC42 | Louise Daugherty Added comment: Comment on list classification: New gene from NIHRRD-BR BRIDGE Bleeding and Platelet Disorders project, enough evidence in the literature to support gene-disease association and relevance to this panel to rate this gene Green. At least 17 unrelated individuals with de novo variants have been reported in the literature | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.129 | KLKB1 | Louise Daugherty Phenotypes for gene: KLKB1 were changed from Fletcher factor (prekallikrein) deficiency, 612423; Fletcher syndrome to Fletcher factor (prekallikrein) deficiency, 612423; Fletcher syndrome; Coagulation disorder | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.128 | GBA | Louise Daugherty edited their review of gene: GBA: Changed phenotypes: Gaucher disease, Gaucher disease, perinatal lethal, 608013, Gaucher disease, type I, 230800, Gaucher disease, type II,230800, Gaucher disease, type III, 230800, Gaucher disease, type IIIC, 231005, Platelet disorder | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.128 | CDC42 | Louise Daugherty Phenotypes for gene: CDC42 were changed from to Takenouchi-Kosaki syndrome, 616737; Platelet disorder | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.126 | CDC42 |
Louise Daugherty gene: CDC42 was added gene: CDC42 was added to Inherited bleeding disorders. Sources: Expert list,Literature Mode of inheritance for gene: CDC42 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Review for gene: CDC42 was set to GREEN Added comment: New bleeding, platelet, coagulation and thrombotic disorder Tier 1 reportable gene from NIHRRD-BR BRIDGE project, announced at ISTH-SCC meeting Dublin 2018. Sources: Expert list, Literature |
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| Inherited bleeding disorders v1.122 | PIGA |
Louise Daugherty gene: PIGA was added gene: PIGA was added to Inherited bleeding disorders. Sources: Expert list Mode of inheritance for gene: PIGA was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Phenotypes for gene: PIGA were set to Paroxysmal nocturnal haemoglobinuria, somatic, 300818 Review for gene: PIGA was set to AMBER Added comment: New bleeding, platelet, coagulation and thrombotic disorder Tier 1 reportable gene from NIHRRD-BR BRIDGE project, announced at ISTH-SCC meeting Dublin 2018. Sources: Expert list |
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| Inherited bleeding disorders v1.121 | GBA | Louise Daugherty Added comment: Comment on list classification: New gene from NIHRRD-BR BRIDGE Bleeding and Platelet Disorders project, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.120 | GBA |
Louise Daugherty gene: GBA was added gene: GBA was added to Inherited bleeding disorders. Sources: Expert list Mode of inheritance for gene: GBA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GBA were set to 15813845 Phenotypes for gene: GBA were set to Gaucher disease; Gaucher disease, perinatal lethal, 608013; Gaucher disease, type I, 230800; Gaucher disease, type II,230800; Gaucher disease, type III, 230800; Gaucher disease, type IIIC, 231005 Review for gene: GBA was set to GREEN Added comment: New bleeding, platelet, coagulation and thrombotic disorder Tier 1 reportable gene from NIHRRD-BR BRIDGE project, announced at ISTH-SCC meeting Dublin 2018. Sources: Expert list |
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| Inherited bleeding disorders v1.119 | KLKB1 | Louise Daugherty Added comment: Comment on list classification: New gene from NIHRRD-BR BRIDGE Bleeding and Platelet Disorders project, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders v1.118 | KLKB1 |
Louise Daugherty gene: KLKB1 was added gene: KLKB1 was added to Inherited bleeding disorders. Sources: Expert list Mode of inheritance for gene: KLKB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KLKB1 were set to 17598838; 14652634; 11344577 Phenotypes for gene: KLKB1 were set to Fletcher factor (prekallikrein) deficiency, 612423; Fletcher syndrome Review for gene: KLKB1 was set to GREEN gene: KLKB1 was marked as current diagnostic Added comment: New bleeding, platelet, coagulation and thrombotic disorder Tier 1 reportable gene from NIHRRD-BR BRIDGE project, announced at ISTH-SCC meeting Dublin 2018. Sources: Expert list |
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| Inherited bleeding disorders | LAT | Rebecca Foulger classified LAT as amber | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders | LAT | Rebecca Foulger added LAT to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders | LAT | Rebecca Foulger reviewed LAT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders | PLAT | Louise Daugherty reviewed PLAT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inherited bleeding disorders | PLAT | BRIDGE consortium reviewed PLAT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||