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Molecular Diagnosis of Autosomal Dominant Polycystic Kidney Disease
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Matthew Lanktree, Amirreza Haghighi, Xueweng Song, York Pei
Truncating mutations (nonsense, frameshift, large deletions, or canonical splice site mutations) are generally considered pathogenic in ADPKD genes, but bioinformatic prediction algorithms can be helpful for assessing missense and noncanonical splicing variants.37 At least 15 different bioinformatic algorithms have been developed to assist in the prediction of the pathogenicity of rare variants. Popular tools include SIFT, PolyPhen2, MutationTaster, MutationAssessor, CADD, VEST, LRT, FATHMM, MetaSVM, METALR, GERP++, DANN, Eigen score, Max Entropy Scan (MES), and Human Splice Finder (HSF). Bioinformatic prediction algorithms generally work by examining evolutionary conservation of the mutated amino acid across many species, physiochemical properties of the induced amino acid change, database annotations, observed allele frequencies, and potential protein structural changes. Many algorithms provide quantitative outputs with user-defined thresholds for calling variants “pathogenic.” Newer algorithms (such as REVEL, VEST3, MetaLR, MetaSVM, Condel, Mcap, Eigen, and CADD) appear to have more reliable performance and are robust to underlying inheritance pattern and technical artifacts.38 The area under the receiver operator curve (AUC) for most algorithms compared to ClinVar assigned pathogenicity is about 0.8, with sensitivity and specificity ranging around 50%–90%.39 Ensuring agreement of multiple bioinformatics algorithms would be expected to increase specificity, but also reduces sensitivity. Overall, bioinformatics algorithms tend to overcall pathogenicity, and we recently found bioinformatic-predicted pathogenic variants in PKD1 and PKD2 had a cumulative prevalence of 1 in 222 in BRAVO and gnomad, above the epidemiologically observed prevalence of ADPKD.1 ANNOVAR (http://annovar.openbioinformatics.org/en/latest/) is an efficient tool that utilizes many bioinformatic prediction tools and annotates each variant.37
Traboulsi syndrome without features of Marfan syndrome caused by a novel homozygous ASPH variant associated with a heterozygous FBN1 variant
Published in Ophthalmic Genetics, 2023
Felipe L. Lima, Sebastião Cronemberger, Anna L. B. Albuquerque, Luciana F. Barbosa, Francine R. Cunha, Artur W. Veloso, Alberto Diniz-Filho, Eitan Friedman, luiz De Marco
Raw sequence files were prepared using the Genome Analysis Tool Kit (GATK) for the sequenced sample. The VCF file was analyzed using Mendel, MD software (http://mendel.medicina.ufmg.br) (18) as well as Ingenuity® Variant AnalysisTM software (www.ingenuity.com/variants) as previously described (19). Captured sequences were aligned with the human reference genome GRCh37 and a sequence of filters applied. Single-Nucleotide Variants annotation was made using Mutation Distiller, initially selecting ClinVar known disease mutations, non-synonymous variants deemed as pathogenic by MutationTaster and disease mutations near splice sites. They were ranked according to pathogenicity and correspondence with the phenotype “EL” (HPO: 0001083) and Autosomal Recessive EL type 2 (OMIM #225100). This analysis yielded two candidate variants in genes with 100% accordance with the selected phenotypes. The selected candidate variants were then validated in silico viewing the generated raw sequence BAM file in the IGV Java Desktop app 2.13.2 (https://software.broadinstitute.org/software/igv/home; accessed 4 August 2022) tool for visual exploration of genomic data, confirming variant zygosity, genomic coordinate and nomenclature.
Exome sequencing identified five novel USH2A variants in Korean patients with retinitis pigmentosa
Published in Ophthalmic Genetics, 2023
SeungHee Jung, Young Chan Park, DongHee Lee, SiYeon Kim, Sang-Mo Kim, YoungJin Kim, DongHyun Lee, JaeJoung Hyun, InSong Koh, Jong-Young Lee
This study predicted the effect of amino acid substitutions using three in silico software programs (SIFT, PolyPhen2, and MutationTaster). Missense variants identified in 10 probands with RP were predicted to be deleterious in at least two software programs (Table 1). SIFT predicts whether an amino acid substitution is likely to affect protein function as “tolerated” or “deleterious.” We considered “deleterious” as a clue to pathogenic variant. PolyPhen2 predicts the effect of an amino acid substitution on the structure and function of a protein as “probably damaging,” “possibly damaging,” “benign” or “unknown.” We considered “probably damaging” and “possibly damaging” as clues to pathogenic variant. MutationTaster predicts the deleteriousness of variants residing within protein coding genes as “disease causing,” “disease causing automatic,” “polymorphism” or “polymorphism automatic.” We considered “disease causing” and “disease causing automatic” as clues to pathogenic variant.
A novel variant in LCHGR gene in 3 siblings with type 1 Leydig cell hypoplasia
Published in Gynecological Endocrinology, 2020
Amine Aktar Karakaya, Edip Unal, Aslı Beştaş, Funda Taş, Hüseyin Onay, Yusuf Kenan Haspolat
As a result of the genetic analysis, a homozygous c.161 + 4 A > G mutation was detected in the LHCGR gene (Figure 1). The detected mutation has not been previously defined in either Human Gene Mutation Database Professional (HGMD; www.hgmd.cf.ac.uk) and ClinVar (www.ncbi.nlm.nih.gov/clinvar/) databases. In order to detect the effect of this novel splicing mutation, Mutation Taster and Human Splice Finder prediction tools which are commonly used to evaluate the effects of mutations on splice sites were used. MutationTaster modeling program predicts that this change may disrupt the protein structure. The splice region has changed according to the Human Splice Finder. Based on data came from these two web-based prediction softwares, this mutation was thought to be related to the disease. It was determined that the mother and father were heterozygous carriers for the same mutation.