Faculty Opinions recommendation of Allele frequency analysis of variants reported to cause autosomal dominant inherited retinal diseases question the involvement of 19% of genes and 10% of reported pathogenic variants.

2019 ◽  
Author(s):  
Laurent Villard
Keyword(s):  
Allele Frequency ◽  
Frequency Analysis ◽  
Autosomal Dominant ◽  
Retinal Diseases ◽  
Pathogenic Variants

Allele frequency analysis of variants reported to cause autosomal dominant inherited retinal diseases question the involvement of 19% of genes and 10% of reported pathogenic variants

2019 ◽  
Vol 56 (8) ◽  
pp. 536-542 ◽  
Author(s):  
Mor Hanany ◽  
Dror Sharon
Keyword(s):  
Allele Frequency ◽  
Autosomal Dominant ◽  
Warning Sign ◽  
Retinal Diseases ◽  
Inheritance Pattern ◽  
Pathogenic Variants ◽  
Mutation Database ◽  
Next Generation Sequencing Ngs ◽  
Functional Analyses ◽  
Ngs Data

BackgroundNext generation sequencing (NGS) generates a large amount of genetic data that can be used to better characterise disease-causing variants. Our aim was to examine allele frequencies of sequence variants reported to cause autosomal dominant inherited retinal diseases (AD-IRDs).MethodsGenetic information was collected from various databases, including PubMed, the Human Genome Mutation Database, RETNET and gnomAD.ResultsWe generated a database of 1223 variants reported in 58 genes, including their allele frequency in gnomAD that contains NGS data of over 138 000 individuals. While the majority of variants are not represented in gnomAD, 138 had an allele count of >1 and were examined carefully for various aspects including cosegregation and functional analyses. The analysis revealed 122 variants that were reported pathogenic but unlikely to cause AD-IRDs. Interestingly, in some cases, these unlikely pathogenic variants were the only ones reported to cause disease in AD inheritance pattern for a particular gene, therefore raising doubt regarding the involvement of 11 (19%) of the genes in AD-IRDs.ConclusionWe predict that these data are not limited to a specific disease or inheritance pattern since non-pathogenic variants were mistakenly reported as pathogenic in various diseases. Our results should serve as a warning sign for geneticists, variant database curators and sequencing panels’ developers not to automatically accept reported variants as pathogenic but cross-reference the information with large databases.

scholarly journals Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency

2021 ◽  
Author(s):  
Hrafnhildur L. Runolfsdottir ◽  
John A. Sayer ◽  
Olafur S. Indridason ◽  
Vidar O. Edvardsson ◽  
Brynjar O. Jensson ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Autosomal Recessive Disorder ◽  
European Population ◽  
Adenine Phosphoribosyltransferase ◽  
Genomic Databases ◽  
Pathogenic Variants ◽  
Adenine Phosphoribosyltransferase Deficiency ◽  
Variation Database ◽  
The Uk ◽  
Aprt Deficiency

AbstractAdenine phosphoribosyltransferase deficiency is a rare, autosomal recessive disorder of purine metabolism that causes nephrolithiasis and progressive chronic kidney disease. The small number of reported cases indicates an extremely low prevalence, although it has been suggested that missed diagnoses may play a role. We assessed the prevalence of APRT deficiency based on the frequency of causally-related APRT sequence variants in a diverse set of large genomic databases. A thorough search was carried out for all APRT variants that have been confirmed as pathogenic under recessive mode of inheritance, and the frequency of the identified variants examined in six population genomic databases: the deCODE genetics database, the UK Biobank, the 100,000 Genomes Project, the Genome Aggregation Database, the Human Genetic Variation Database and the Korean Variant Archive. The estimated frequency of homozygous genotypes was calculated using the Hardy-Weinberg equation. Sixty-two pathogenic APRT variants were identified, including six novel variants. Most common were the missense variants c.407T>C (p.(Met136Thr)) in Japan and c.194A>T (p.(Asp65Val)) in Iceland, as well as the splice-site variant c.400 + 2dup (p.(Ala108Glufs*3)) in the European population. Twenty-nine variants were detected in at least one of the six genomic databases. The highest cumulative minor allele frequency (cMAF) of pathogenic variants outside of Japan and Iceland was observed in the Irish population (0.2%), though no APRT deficiency cases have been reported in Ireland. The large number of cases in Japan and Iceland is consistent with a founder effect in these populations. There is no evidence for widespread underdiagnosis based on the current analysis.

scholarly journals αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0235136
Author(s):  
Sara Morais ◽  
Jorge Oliveira ◽  
Catarina Lau ◽  
Mónica Pereira ◽  
Marta Gonçalves ◽  
...  
Keyword(s):  
Binding Sites ◽  
Autosomal Dominant ◽  
Transmembrane Domain ◽  
Laboratory Data ◽  
Atp Release ◽  
Cytoplasmic Domains ◽  
Pathogenic Variants ◽  
Distinct Disease ◽  
And Function ◽  
First Time

Background Rare pathogenic variants in either the ITGA2B or ITGB3 genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia. Objectives To describe a series of patients with familial macrothrombocytopenia and decreased expression of αIIbβ3 integrin due to defects in the ITGA2B or ITGB3 genes. Methods We reviewed the clinical and laboratory records of 10 Portuguese families with GTLS (33 patients and 11 unaffected relatives), including the functional and genetic defects. Results Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP. Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls. We identified 7 missense variants: 3 in ITGA2B (5 families), and 4 in ITGB3 (5 families). Three variants (αIIb: p.Arg1026Trp and p.Arg1026Gln and β3: p.Asp749His) were previously reported. The remaining (αIIb: p.Gly1007Val and β3: p.Thr746Pro, p.His748Pro and p.Arg760Cys) are new, expanding the αIIbβ3 defects associated with GTLS. The integration of the clinical and laboratory data allowed the identification of two GTLS subgroups, with distinct disease severity. Conclusions Previously reported ITGA2B and ITGB3 variants related to thrombocytopenia were clustered in a confined region of the membrane-proximal cytoplasmic domains, the inner membrane clasp. For the first time, variants are reported at the outer membrane clasp, at the transmembrane domain of αIIb, and at the membrane distal cytoplasmic domains of β3. This is the largest single-center series of inherited macrothrombocytopenia associated with αIIbβ3 variants published to date.

scholarly journals Cantu syndrome and hypopituitarism: implications for endocrine monitoring

2019 ◽  
Vol 2019 ◽  
Author(s):  
Nicholas J Theis ◽  
Toby Calvert ◽  
Peter McIntyre ◽  
Stephen P Robertson ◽  
Benjamin J Wheeler
Keyword(s):  
Anterior Pituitary ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Facial Features ◽  
Pituitary Hormone ◽  
List Type ◽  
Pituitary Dysfunction ◽  
Pathogenic Variants ◽  
Clinical Surveillance ◽  
Learning Points

Summary Cantu syndrome, or hypertrichotic osteochondrodysplasia, is a rare, autosomal dominant genetically heterogeneous disorder. It is characterized by hypertrichosis, cardiac and skeletal anomalies and distinctive coarse facial features. We report a case where slowed growth velocity at 13 years led to identification of multiple pituitary hormone deficiencies. This adds to other reports of pituitary abnormalities in this condition and supports inclusion of endocrine monitoring in the clinical surveillance of patients with Cantu syndrome. Learning points: Cantu syndrome is a rare genetic disorder caused by pathogenic variants in the ABCC9 and KCNJ8 genes, which result in gain of function of the SUR2 or Kir6.1 subunits of widely expressed KATP channels. The main manifestations of the syndrome are varied, but most commonly include hypertrichosis, macrosomia, macrocephaly, coarse ‘acromegaloid’ facies, and a range of cardiac defects. Anterior pituitary dysfunction may be implicated in this disorder, and we propose that routine screening should be included in the clinical and biochemical surveillance of patients with Cantu syndrome.

A novel CRYBB2 mutation causes autosomal dominant cataract: A report from a Chinese family

2020 ◽  
pp. 112067212092645
Author(s):  
Li Juan Xu ◽  
Zhi Gang Lv ◽  
Ying Liu ◽  
Xiang Xiang Zhang ◽  
Yu Xin Cui ◽  
...  
Keyword(s):  
Axial Length ◽  
Healthy Subjects ◽  
Sanger Sequencing ◽  
Autosomal Dominant ◽  
Pathogenic Mutation ◽  
Chinese Family ◽  
Rare Mutation ◽  
Pathogenic Variants ◽  
Lens Opacities ◽  
Generation Sequencing

Purpose This study aimed to examine pathogenic mutation within one Chinese family of five-generations suffering from autosomal dominant cataract. Methods Next-generation sequencing and Sanger sequencing were used to find the pathogenic variants. Results A rare mutation, c.563G > A, in CRYBB2 gene was found in the proband that showed symptom of non-syndromic congenital autosomal dominant cataract. This mutation had been found in all affected individuals and in one healthy infant, but it did not exist between two individuals who did not develop such disease in that family, as well as in 100 healthy subjects who showed no relation with that family. Cataracts in this family varied with different severity of lens opacities and elongation of axial length. Conclusion One missense mutation c.563G > A is reported in the CRYBB2 gene among one Chinese family suffering from early-onset cataract, and associated novel phenotypes are the elongation of axial length and the types of cataract. Our results expand the spectrum of associated phenotypes of CRYBB2 mutation.

scholarly journals Novel COL11A2 Pathogenic Variants in a Child with Autosomal Recessive Otospondylomegaepiphyseal Dysplasia: A Review of the Literature

2019 ◽  
Vol 09 (02) ◽  
pp. 117-120
Author(s):  
Pavalan Selvam ◽  
Shekhar Singh ◽  
Angita Jain ◽  
Herjot Atwal ◽  
Paldeep S. Atwal
Keyword(s):  
Sequence Analysis ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Review Of The Literature ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum ◽  
Whole Exome ◽  
The Family ◽  
Type Xi Collagen ◽  
Exome Sequence

AbstractOtospondylomegaepiphyseal dysplasia (OSMED) is an inherited autosomal dominant and recessive skeletal dysplasia caused by both heterozygous and homozygous pathogenic variants in COL11A2 encoding the α2(XI) collagen chains, a part of type XI collagen. Here, we describe a 2-year-old girl presenting from birth with a phenotype suggestive of OSMED. On whole exome sequence analysis of the family via commercially available methods, we detected two novel heterozygous pathogenic variants in the proband. In addition, we reviewed the phenotype of autosomal recessive OSMED cases with COL11A2 pathogenic variants reported to date and quantitatively highlighted the phenotypic spectrum.

Sign in / Sign up

Export Citation Format

Share Document