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| Mendeliome v2.0 | PLAU | Gene migrated from ENSG00000122861 to ENSG00000122861 (gene set migration) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.5025 | CLUAP1 |
Sarah Milton changed review comment from: CLUAP1 encodes Clusterin-associated protein 1 which localizes to the base and tip of cilia and associates with the intraflagellar transport (IFT) complex B group of proteins. Leber congenital amaurosis (LCA) PMID: 26820066 and 34209753 report biallelic variants in CLUAP1 in individuals with Leber congenital amaurosis including severe visual dysfunction from birth and nystagmus. Missense and splice variants were reported with functional studies to support a deleterious nature (Cell models/Zebrafish transfection and minigene splice assays). Other causative LCA genes are known to be involved in intraflagellar transport. Biallelic zebrafish and mouse result in lethality in utero, zebrafish embryos at 5 days post fertilisation demonstrate lack of photoreceptor cells. Amber for this association. Ciliopathy PMID 28679688 reports one individual with biallelic variants in CLUAP1 with a syndromic phenotype reminiscent of Joubert/orofaciodigital syndrome including dysmorphic features, rhizomelic limb shortening, polydactyly, molar tooth sign, midline teeth, oculomotor apraxia. One missense and one nonsense variant were noted with functional studies to support the deleterious nature. Red for this association. It is plausible the LCA and ciliopathy phenotypes are a spectrum of disease however there is insufficient evidence to indicate this currently. Sources: Literature; to: CLUAP1 encodes Clusterin-associated protein 1 which localizes to the base and tip of cilia and associates with the intraflagellar transport (IFT) complex B group of proteins. Leber congenital amaurosis (LCA) PMID: 26820066 and 34209753 report biallelic variants in CLUAP1 in 2 individuals with Leber congenital amaurosis including severe visual dysfunction from birth and nystagmus. Missense and splice variants were reported with functional studies to support a deleterious nature (Cell models/Zebrafish transfection and minigene splice assays). Other causative LCA genes are known to be involved in intraflagellar transport. Biallelic zebrafish and mouse result in lethality in utero, zebrafish embryos at 5 days post fertilisation demonstrate lack of photoreceptor cells. Amber for this association. Ciliopathy PMID 28679688 reports one individual with biallelic variants in CLUAP1 with a syndromic phenotype reminiscent of Joubert/orofaciodigital syndrome including dysmorphic features, rhizomelic limb shortening, polydactyly, molar tooth sign, midline teeth, oculomotor apraxia. One missense and one nonsense variant were noted with functional studies to support the deleterious nature. Red for this association. It is plausible the LCA and ciliopathy phenotypes are a spectrum of disease however there is insufficient evidence to indicate this currently. Sources: Literature |
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| Mendeliome v1.5024 | CLUAP1 |
Sarah Milton gene: CLUAP1 was added gene: CLUAP1 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: CLUAP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CLUAP1 were set to 34209753; 28679688; 26820066 Phenotypes for gene: CLUAP1 were set to Leber congenital amaurosis, MONDO:0018998, CLUAP1-related; Ciliopathy, MONDO:0005308, CLUAP1-related Review for gene: CLUAP1 was set to AMBER Added comment: CLUAP1 encodes Clusterin-associated protein 1 which localizes to the base and tip of cilia and associates with the intraflagellar transport (IFT) complex B group of proteins. Leber congenital amaurosis (LCA) PMID: 26820066 and 34209753 report biallelic variants in CLUAP1 in individuals with Leber congenital amaurosis including severe visual dysfunction from birth and nystagmus. Missense and splice variants were reported with functional studies to support a deleterious nature (Cell models/Zebrafish transfection and minigene splice assays). Other causative LCA genes are known to be involved in intraflagellar transport. Biallelic zebrafish and mouse result in lethality in utero, zebrafish embryos at 5 days post fertilisation demonstrate lack of photoreceptor cells. Amber for this association. Ciliopathy PMID 28679688 reports one individual with biallelic variants in CLUAP1 with a syndromic phenotype reminiscent of Joubert/orofaciodigital syndrome including dysmorphic features, rhizomelic limb shortening, polydactyly, molar tooth sign, midline teeth, oculomotor apraxia. One missense and one nonsense variant were noted with functional studies to support the deleterious nature. Red for this association. It is plausible the LCA and ciliopathy phenotypes are a spectrum of disease however there is insufficient evidence to indicate this currently. Sources: Literature |
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| Mendeliome v1.4918 | IL12RB2 |
Zornitza Stark edited their review of gene: IL12RB2: Added comment: PMID 31158284 reports single individual with high impact variant and Mendelian Susceptibility to Mycobacterial Disease (MSMD). PMID 42012883 reports two individuals with disseminated coccidioidomycosis and missense variants but one of these has an implausibly high population frequency.; Changed publications: 30578351, 31158284, 42012883; Changed phenotypes: Inborn error of immunity, MONDO:0003778, IL12RB2-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Mendeliome v1.4029 | SMC1B |
Zornitza Stark gene: SMC1B was added gene: SMC1B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SMC1B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SMC1B were set to 40180776; 27603904 Phenotypes for gene: SMC1B were set to Infertility disorder, MONDO:0005047, SMC1B-related Review for gene: SMC1B was set to RED Added comment: [PMID 27603904] reports 2 individuals from 2 families with heterozygous missense SMC1B variants (p.I221T, p.Q1177L) presenting with primary ovarian insufficiency. [PMID 40180776] reports 1 individual from 1 family with a heterozygous missense p.C619F variant causing severe necrozoospermia; the variant segregates from a carrier mother and functional assays show reduced SMC1B protein, indicating a loss‑of‑function mechanism. All three variants are present in the population, p.Q1177L at an implausibly high frequency. Sources: Literature |
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| Mendeliome v1.3897 | NSMF | Zornitza Stark edited their review of gene: NSMF: Added comment: PMIDs 31220265, 34348883, 35316923, 39010903, 39809967 report 10 unrelated families with heterozygous NSMF missense or truncating variants linked to functional hypogonadotropic hypogonadism, congenital hypogonadotropic hypogonadism, Kallmann syndrome, normosmic isolated HH, delayed‑puberty HH, and adult‑onset azoospermia. Variants are mostly classified as VUS; most are present in gnomAD, some at implausibly high frequencies; no functional assays or robust segregation data are provided. Therefore retain Red rating.; Changed publications: 39809967, 39010903, 35316923, 34348883, 31220265; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.3142 | ANLN |
Zornitza Stark edited their review of gene: ANLN: Added comment: Further reports but evidence is conflicting, including variants with implausibly high pop frequency. Gbadegesin et al (2014); Hall et al (2018) 2 x families reported with FSGS (USA) and missense variants G618C (v4: absent) and R431C (v4: 63 hets, 0 hom). R431C was identified in 6 affected family members and absent in 6 unaffected family members. G618C was present in the proband and absent in 4 unaffected family members, the other 2 affected individuals from this family were not genotyped (deceased). Missense demostrated as LoF with both in vitro and in vivo (zebrafish). R431C was shown to disrupt interaction with CD2AP (primarily LoF effect), causing downstream hyperactivation of the PI3K/AKT/mTOR/Rac1 signaling pathway, which drives podocytes hypermotility. Geminiganesan et al (2021) 1 x 2 year old child (India) with early-onset steroid resistant nephrotic syndrome, whole-exome sequencing and genome-wide linkage studies, a missense variant in ANLN was identified p.Thr821Met (v4: 508 hets, 0 hom). Zhang et al (2023) 3 x children with steroid resistant nephrotic syndrome (China). 2 x missense (p.M1099I - LP (v4:1 het, 0 hom), p.S140T - VUS (v4: 6 hets, 0 hom) and 1 x stop gain reported p.R39X - LP ( v4: 1 het, 0 hom). Lin et al (2023) 3 x unrelated individuals with missense E841K (China, v4: 618 hets, 2 hom). In famly A the variant was de novo, in family 2 only the proband as tested, in family 3 the variant was inherited from an affected father. 4 x unaffected individuals did not have the variant. Knockout mouse model inconclusive, did not show any effect until 36 weeks. Zebrafish model was also inconclusive.; Changed publications: 24676636, 30002222, 34819827, 38322629, 37957688 |
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| Mendeliome v1.2228 | P2RY8 |
Zornitza Stark gene: P2RY8 was added gene: P2RY8 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: P2RY8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: P2RY8 were set to 34889940 Phenotypes for gene: P2RY8 were set to Systemic lupus erythematosus, MONDO:0007915, P2RY8-related Review for gene: P2RY8 was set to AMBER Added comment: One de novo variant, p.Leu257Phe, absent from gnomAD v4 identified in an individual with early-onset SLE. Subsequent search for additional individuals in large cohorts identified: p. Asn97Lys, inherited from mother, present in 19 individuals in gnomADv4. p.Glu323Gly identified in 6 Chinese individuals, inheritance not determined, present in 51 individuals in gnomADv4. Functional data support the role of the gene in immune tolerance. Role in contributing to the development of SLE is plausible, though not necessarily under a monogenic model. Sources: Literature |
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| Mendeliome v1.1922 | OAS2 |
Zornitza Stark gene: OAS2 was added gene: OAS2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: OAS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: OAS2 were set to 36538032 Phenotypes for gene: OAS2 were set to Multisystem inflammatory syndrome, MONDO:0035375, OAS2-related Review for gene: OAS2 was set to GREEN Added comment: 3x unrelated patients with MIS-C after COVID infection. Patients displayed excessive inflammatory responses to intracellular dsRNA, SARS-CoV-2, SARS-CoV-2–infected cells, and their RNA, providing a plausible mechanism for MIS-C. Similar presentation to OAS1 and RNASEL. Functional data. Sources: Literature |
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| Mendeliome v0.8824 | PLXNA2 |
Zornitza Stark gene: PLXNA2 was added gene: PLXNA2 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PLXNA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLXNA2 were set to 34327814 Phenotypes for gene: PLXNA2 were set to Intellectual disability; Abnormality of the face; Failure to thrive; Abnormal heart morphology Review for gene: PLXNA2 was set to AMBER Added comment: Altuame et al (2021 - PMID: 34327814) describe 3 individuals from 2 consanguineous Arab families with biallelic PLXNA2 variants. The index patient from the 1st family presented with CHD (hypoplastic right ventricle, ASD), DD and moderate ID (IQ of 40), failure to thrive as well as some dysmorphic features (obtuse mandibular angle, mild overbite, synophrys with downslanting p-f, strabismus, etc). There were additional features (eg. postaxial polydactyly) which were found in other affected and unaffected family members. Exome sequencing with autozygome analysis revealed homozygosity for a PLXNA2 stopgain variant (NM_025179:c.3603C>A / p.(Cys1201*)). Sanger confirmation was carried out and segregation analyses confirmed carrier status of the unaffected parents and a sib as well as a brother homozygous for the same variant. Clinical evaluation of the latter, following this finding revealed borderline intellectual functioning, ADHD, failure to thrive. There was no mandibular anomaly or overbite and no clinical evidence of CHD (no echo performed). The index patient from the 2nd consanguineous family was evaluated for ID (IQ of 63), with previous borderline motor development, ADHD and some dysmorphic features (obtuse mandibular angle and overbite). There was no clinical evidence of CHD (no echo performed). Exome sequencing with autozygosity mapping revealed a homozygous missense PLXNA2 variant (c.3073G>A / p.(Asp1025Asn), present only once in gnomAD (htz), with rather non-concordant in silico predictions SIFT 0.22, PolyPhen 0.682 and CADD 23.5. The aa was however highly conserved. Segregation analysis confirmed carrier state of the parents and 2 unaffected sibs, with a 3rd sib homozygous for the wt allele. As the authors discuss: *PLXNA2 belongs to the plexin family of genes, encoding transmbembrane proteins functioning as semaphorin receptors. It has predominant expression in neural tissue. The protein is thought to bind semaphorin-3A, -3C or -5 followed by plexin A2 dimerization, activation of its GTPase-activating protein domain, negative regulation of Rap1B GTPase and initiation of a signal transduction cascade mediating axonal repulsion/guidance, dendritic guidance, neuronal migration. *Murine Plxna2 knockout models display structural brain defects. In addition they display congenital heart defects incl. persistent truncus arteriosus and interrupted aortic arch. *Rare CNVs in adult humans with tetralogy of Fallot have suggested a potential role of PLXNA2 in cardiac development and CHD. *Expression and the role of PLXNA2 in human chondrocytes as well as a GWAS in 240 japanese patients with mandibular prognathism where PLXNA2 was suggested as a susceptibility locus. Overall, the authors recognize some common features (as for cognitive functioning, some dysmorphic features incl. obtuse mandibular angle and overbite in 2 unrelated subjects, failure to thrive 3/3) and provide plausible explanations for the variability / discordance of others eg: - Cyanotic heart disease explaining discordance in cognitive outcome among sibs - Incomplete penetrance for CHD (and/or ID or mandibular anomaly) as for few AR disorders and/or - Additional pathogenic variants possibly explaining the CHD in the first subject. There is no associated phenotype in OMIM or G2P. SysID includes PLXNA2 among the candidate ID genes. Sources: Literature |
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| Mendeliome v0.3788 | PLAU | Zornitza Stark Marked gene: PLAU as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3788 | PLAU | Zornitza Stark Gene: plau has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3788 | PLAU | Zornitza Stark Classified gene: PLAU as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3788 | PLAU | Zornitza Stark Gene: plau has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3787 | PLAU | Zornitza Stark Tag SV/CNV tag was added to gene: PLAU. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3787 | PLAU |
Zornitza Stark gene: PLAU was added gene: PLAU was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: PLAU was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PLAU were set to 20007542 Phenotypes for gene: PLAU were set to Quebec platelet disorder, MIM# 601709 Review for gene: PLAU was set to GREEN Added comment: Note this is a tandem 78kb duplication of the gene, multiple families reported. Sources: Expert list |
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