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Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 | ANKZF1 |
Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation. The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist_MOI' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.; to: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation. The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist_moi' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease. |
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Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 | ANKZF1 |
Achchuthan Shanmugasundram changed review comment from: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation. The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease.; to: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation. The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist_MOI' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease. |
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Primary immunodeficiency or monogenic inflammatory bowel disease v4.174 | ANKZF1 |
Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are three unrelated cases reported with monoallelic ANKZF1 variants and infantile-onset inflammatory bowel disease. However, there are only two unrelated cases reported with biallelic variants, of which one has homozygous variant and other has compound heterozygous variants. The homozygous variant (p.Arg585Gln) is very common in gnomAD. Functional studies show that R585Q variant causes reduced ANKZF1 mRNA and protein expression and leads to reduced stress-induced mitochondrial translocation. The MOI should therefore be set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" with the current evidence. In addition, 'watchlist' tag has been added to review any new evidence in support of the association of biallelic variants to inflammatory bowel disease. |
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Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 | ANKZF1 |
Hannah Knight gene: ANKZF1 was added gene: ANKZF1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: ANKZF1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: ANKZF1 were set to PMID: 28302725; PMID: 36857589 Phenotypes for gene: ANKZF1 were set to Inflammatory bowel disease Review for gene: ANKZF1 was set to AMBER Added comment: PMID: 28302725 (2017) identified two infantile-onset IBD patients with biallelic ANKZF1 variants + some functional work: One homozygous for R585Q - although this variant is very common in gnomAD One compound heterozygous for E152K and V32_Q87del Also two patients with one heterozygous variants PMID: 36857589 (2023) also identified a de novo variant (p.Leu415Val) in a young patient with IBD Sources: Literature |
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Primary immunodeficiency or monogenic inflammatory bowel disease v4.125 | DUT |
Hannah Knight gene: DUT was added gene: DUT was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: DUT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DUT were set to Bone marrow failure and diabetes mellitus syndrome Review for gene: DUT was set to AMBER Added comment: PMID: 28073829 (2017) - two unrelated consanguineous families with diabetes and bone marrow aplasia, both homozygous for p.Y142C PMID: 35611808 (2022) - another family, two affected children with thrombocytopenia, macrocytosis, with or without anemia, followed by non-autoimmune diabetes. Same homozygous missense variant identified as before PMID: 35931051 (2022) - identified probands who came from two independent families, had bi-allelic DUT variants, and presented with severe pancytopenia and mucocutaneous skin features. Information in supplementary materials. One patient homozygous for p.Tyr142Cys and the other compound het for p.Arg173Trp and p.Tyr227Cys Sources: Literature |
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Primary immunodeficiency or monogenic inflammatory bowel disease v2.526 | CRACR2A |
Zornitza Stark gene: CRACR2A was added gene: CRACR2A was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: CRACR2A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRACR2A were set to PMID:34908525 Phenotypes for gene: CRACR2A were set to late onset combined immunodeficiency Review for gene: CRACR2A was set to RED Added comment: PMID:34908525 - one patient compound het (missense and PTC) with late onset combined immunodeficiency (current chest infections, panhypogammaglobulinemia and CD4+T cell lymphopenia). Functional studies showed defective JNK phosphorylation, defective SOCE and impaired cytokine production. Sources: Literature |
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Primary immunodeficiency or monogenic inflammatory bowel disease v2.454 | RGS10 |
Arina Puzriakova Added comment: Comment on list classification: New gene added by Boaz Palterer. Single family with 3 affected sibs reported (PMID:34315806), who presented with short stature and immunodeficiency and harboured compound het variants in RGS10 that segregated with disease. However, the sibs also carried a heterozygous PIK3CD (E525K) variant that has previously been deemed pathogenic in Activated PI3 Kinase Delta Syndrome (APDS), a primary immunodeficiency. The variant was excluded as the father also carried the PIK3CD variant but was mostly healthy and none of the 3 affected sibs displayed the full spectrum of symptoms associated with APDS. Nonetheless, APDS is a clinically heterogeneous condition with variable penetrance among affected individuals and so the contribution of PIK3CD to the patients immune dysregulation cannot be completely ruled out. There are no further reports of an association between RGS10 variants and immunodeficiency to date, and therefore rating Red until further evidence emerges. |
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Primary immunodeficiency or monogenic inflammatory bowel disease v2.424 | STXBP3 |
Arina Puzriakova changed review comment from: Ouahed et al. 2021 (PMID: 33891011) report 5 unrelated families with 10 patients who presented with a similar phenotype including medically refractory infantile-onset IBD (10/10), severe bilateral sensorineural hearing loss (8/10), and, in the majority, recurrent infections (6/10). Heterozygous variants in STXBP3 were identified in 3 families (2 de novo, 1 paternally transmitted); while 5 sibs from 2 unrelated families harboured different compound het variants. Variants interfered with either intron splicing or protein stability and all were shown to reduce STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. Additional variants not thought to be independently deleterious by the authors, but in pathways of interest or in known VEOIBD genes, were identified in 4/5 families. * Note the previous review submitted by Kelsey Jones (GOSH) references an abstract briefly reporting on 4/5 of the families from PMID:33891011; to: Ouahed et al. 2021 (PMID: 33891011) report 5 unrelated families with 10 patients who presented with a similar phenotype including medically refractory infantile-onset IBD (10/10), severe bilateral sensorineural hearing loss (8/10), and, in the majority, recurrent infections (6/10). Heterozygous variants in STXBP3 were identified in 3 families (2 de novo, 1 paternally transmitted); while 5 sibs from 2 unrelated families harboured different compound het variants. Variants interfered with either intron splicing or protein stability and all were shown to reduce STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. Additional variants not thought to be independently deleterious by the authors, but in pathways of interest or in known VEOIBD genes, were identified in 4/5 families. * Note the previous review submitted by Kelsey Jones (GOSH) references an abstract briefly reporting on 4 of the families from PMID:33891011 |
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Primary immunodeficiency or monogenic inflammatory bowel disease v2.423 | LRRC32 |
Boaz Palterer gene: LRRC32 was added gene: LRRC32 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: LRRC32 was set to Unknown Publications for gene: LRRC32 were set to 34059789 Phenotypes for gene: LRRC32 were set to Common variable immunodeficiency; Enteropathy; Lymphopenia; Reduced Tregs Penetrance for gene: LRRC32 were set to unknown Review for gene: LRRC32 was set to RED Added comment: Lehmkuhl et al. described two patients with immune dysregulation and mutations of LRRC32. Both patients carried two rare variants, however, patient 1 has both variants in cis, while patient 2 was a compound heterozygote. Reduced protein expression ex-vivo was demonstrated. Conditional mice KO model recapitulated the phenotype. Sources: Literature |
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Primary immunodeficiency or monogenic inflammatory bowel disease v2.412 | PRIM1 |
Arina Puzriakova gene: PRIM1 was added gene: PRIM1 was added to Primary immunodeficiency. Sources: Literature Q2_21_rating tags were added to gene: PRIM1. Mode of inheritance for gene: PRIM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRIM1 were set to 33060134 Phenotypes for gene: PRIM1 were set to Microcephalic primordial dwarfism, MONDO:0017950 Review for gene: PRIM1 was set to GREEN Added comment: PRIM1 is currently not associated with any phenotype in OMIM (last edited in 2004) or Gene2Phenotype. - PMID: 33060134 (2020) - From a cohort of 220 families with microcephalic dwarfism spectrum disorders (OFC ≤−4 SD; height ≤−2 SD), three families (4 individuals) were identified with the same homozygous intronic variant (c.638+36C>G) in PRIM1. This variant was present in gnomAD in 2 individuals across all populations, but only in a heterozygous state. Haplotype analysis indicated that all three families share a distant common ancestor - i.e. confirmed founder variant. Authors subsequently identified a single individual with compound heterozygous PRIM1 variants (c.103+1G>T, c.901T>C) from the DDD study, who also presented microcephaly and short stature (OFC ≤−3 SD; height ≤−3 SD). Clinical overlap was evident in all 5 individuals, presenting extreme pre- and postnatal growth restriction, severe microcephaly (OFC −6.0 ± 1.5 SD) with simplified gyri appearance, hypothyroidism, hypo/agammaglobulinemia, and lymphopenia accompanied by intermittent anaemia/thrombocytopenia. All had chronic respiratory symptoms, and four died in early childhood from respiratory or GI infections. Functional studies demonstrated reduced PRIM1 protein levels, replication fork defects and prolonged S-phase duration in PRIM1-deficient cells. The resulting delay to the cell cycle and inability to sustain sufficient cell proliferation provides a likely mechanism for the presenting phenotype. Sources: Literature |
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Primary immunodeficiency or monogenic inflammatory bowel disease v2.401 | RAD50 |
Boaz Palterer gene: RAD50 was added gene: RAD50 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: RAD50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RAD50 were set to 33378670 Phenotypes for gene: RAD50 were set to bone marrow failure; immunodeficiency; developmental defect Penetrance for gene: RAD50 were set to unknown Review for gene: RAD50 was set to RED Added comment: Chansel-Da Cruz et al. identified a single patient with bone marrow failure, immunodeficiency and developmental defect caused by compound heterozygous mutations in RAD50. The first mutations generate a null allele, the second is hypothesized to be hypomorphic because of the loss of a single amino acid residue in the coiled-coil domain of RAD50. Sources: Literature |
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Primary immunodeficiency or monogenic inflammatory bowel disease v2.392 | COL7A1 |
Kelsey Jones changed review comment from: Important monogenic cause of VEOIBD (recognised criteria for the R15 panel). In a retrospective case series, 9 of 57 (16%) children with recessive DEBP had diarrhoea with macroscopic/microscopic features of colitis (PMID: 18363753). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Not a recognised cause of immunodeficiency. Sources: Expert Review; to: Important monogenic cause of VEOIBD (recognised criteria for the R15 panel). In a retrospective case series, 9 of 57 (16%) children with recessive DEBP had diarrhoea with macroscopic/microscopic features of colitis (PMID: 18363753). There is additionally a recognised association between Epidermolysis Bullosa Acquisita (an autoimmune condition directed against Type VII Collagen (the COL7A1 protein product) (PMID: 23517353). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Not a recognised cause of immunodeficiency. Sources: Expert Review |
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Primary immunodeficiency or monogenic inflammatory bowel disease v2.392 | COL7A1 |
Kelsey Jones gene: COL7A1 was added gene: COL7A1 was added to Primary immunodeficiency. Sources: Expert Review Mode of inheritance for gene: COL7A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: COL7A1 were set to PMID: 18363753 Phenotypes for gene: COL7A1 were set to Very Early Onset Inflammatory Bowel Disease; Dystrophic Epidermolysis Bullosa Pruriginosa Penetrance for gene: COL7A1 were set to Incomplete Review for gene: COL7A1 was set to AMBER Added comment: Important monogenic cause of VEOIBD (recognised criteria for the R15 panel). In a retrospective case series, 9 of 57 (16%) children with recessive DEBP had diarrhoea with macroscopic/microscopic features of colitis (PMID: 18363753). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Not a recognised cause of immunodeficiency. Sources: Expert Review |
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Primary immunodeficiency or monogenic inflammatory bowel disease v2.392 | NPC1 |
Kelsey Jones changed review comment from: Important monogenic cause of VEOIBD (recognised criteria for the R15 panel). 14 patients with defects in NPC1 presenting with severe Crohn's-like intestinal inflammation described in PMID: 26953272. Mechanism suggested to involve defective bacterial handling by macrophages. Estimated 3-7% penetrance of intestinal inflammation in patients with Niemann-Pick type C disease (same reference). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Not a recognised cause of immunodeficiency. Sources: Expert list; to: Important monogenic cause of VEOIBD (recognised criteria for the R15 panel). 14 patients with defects in NPC1 presenting with severe Crohn's-like intestinal inflammation described in PMID: 26953272. Mechanism suggested to involve defective bacterial handling by macrophages. Estimated 3-7% penetrance of intestinal inflammation in patients with Niemann-Pick type C disease (same reference). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Not a recognised cause of immunodeficiency. Sources: Expert list |
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Primary immunodeficiency or monogenic inflammatory bowel disease v2.392 | NPC1 |
Kelsey Jones gene: NPC1 was added gene: NPC1 was added to Primary immunodeficiency. Sources: Expert list Mode of inheritance for gene: NPC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NPC1 were set to PMID: 26953272 Phenotypes for gene: NPC1 were set to Very Early Onset Inflammatory Bowel Disease Penetrance for gene: NPC1 were set to Incomplete Review for gene: NPC1 was set to GREEN Added comment: Important monogenic cause of VEOIBD (recognised criteria for the R15 panel). 14 patients with defects in NPC1 presenting with severe Crohn's-like intestinal inflammation described in PMID: 26953272. Mechanism suggested to involve defective bacterial handling by macrophages. Estimated 3-7% penetrance of intestinal inflammation in patients with Niemann-Pick type C disease (same reference). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Not a recognised cause of immunodeficiency. Sources: Expert list |
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Primary immunodeficiency or monogenic inflammatory bowel disease v2.369 | FAAP24 |
Eleanor Williams edited their review of gene: FAAP24: Added comment: Not associated with a phenotype in OMIM. PMID: 17289582 - Ciccia et al 2007 - report that FAAP24 (C19ORF40) is a component of the Fanconi anemia (FA) core complex and interacts with the C-terminal region of FANCM. FAAP24 is required for normal levels of FANCD2 monoubiquitylation following DNA damage. PMID: 27473539 - Daschkey et al 2016 - report a homozygous missense mutation in FAAP24 (cC635T, pT212M) in two siblings of a consanguineous Turkish family who died from an EBV-associated lymphoproliferative disease after infection with a variant EBV strain, expressing a previously unknown EBNA2 allele.; Changed rating: RED; Changed phenotypes: EBV-associated lymphoproliferative disease; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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Primary immunodeficiency or monogenic inflammatory bowel disease v2.184 | MCM10 |
Boaz Palterer gene: MCM10 was added gene: MCM10 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: MCM10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MCM10 were set to 32865517 Penetrance for gene: MCM10 were set to unknown Review for gene: MCM10 was set to AMBER Added comment: Compound heterozygous variants in minichromosomal maintenance complex member 10 (MCM10) were reported as a cause of NK-cell deficiency in a child with fatal susceptibility to CMV. Sources: Literature |
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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 |
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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. |
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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. |
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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). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Primary immunodeficiency or monogenic inflammatory bowel disease v2.43 | MPO | Sarah Leigh Publications for gene: MPO were set to 15108282; 9354683; 9637725 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 | USP18 |
Louise Daugherty commented on gene: USP18: Pseudo TORCH syndrome: Aicardi-Goutiere like - severe intracranial haemorrhage, thrombocytopaenia, seizures, liver failure caused by interferon activation - probable green association, is it a relevant phenotype? 2 families (one homozygous, one compound het where one variant was the same as the first family with possible common ancestor) - borderline, with lack of USP18 expression - abnormal activation of the immune system (interferon) - is this a likely presentation in immunology clinic? |
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Primary immunodeficiency or monogenic inflammatory bowel disease | MPO | Louise Daugherty marked gene: MPO as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Primary immunodeficiency or monogenic inflammatory bowel disease | MPO | Louise Daugherty classified MPO as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Primary immunodeficiency or monogenic inflammatory bowel disease | MPO | Sophie Hambleton reviewed gene: MPO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Primary immunodeficiency or monogenic inflammatory bowel disease | MPO | Sarah Leigh reviewed MPO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Primary immunodeficiency or monogenic inflammatory bowel disease | MPO | Louise Daugherty commented on MPO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Primary immunodeficiency or monogenic inflammatory bowel disease | MPO | Louise Daugherty commented on MPO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Primary immunodeficiency or monogenic inflammatory bowel disease | MPO | Louise Daugherty commented on MPO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Primary immunodeficiency or monogenic inflammatory bowel disease | MPO | Louise Daugherty reviewed MPO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Primary immunodeficiency or monogenic inflammatory bowel disease | MPO | Louise Daugherty Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Primary immunodeficiency or monogenic inflammatory bowel disease | MPO | Louise Daugherty Added gene to panel |