ZNF445: a homozygous truncating variant in a patient with Temple syndrome and multilocus imprinting disturbance

Abstract Background ZNF445, as well as ZFP57, is involved in the postfertilization methylation maintenance of multiple imprinting-associated differentially methylated regions (iDMRs). Thus, ZNF445 pathogenic variants are predicted to cause multilocus imprinting disturbances (MLIDs), as do ZFP57 pathogenic variants. In particular, the MEG3/DLK1:IG-DMR would be affected, because the postzygotic methylation imprint of the MEG3/DLK1:IG-DMR is maintained primarily by ZNF445, whereas that of most iDMRs is preserved by both ZFP57 and ZNF445 or primarily by ZFP57. Results We searched for a ZNF445 variant(s) in six patients with various imprinting disorders (IDs) caused by epimutations and MLIDs revealed by pyrosequencing for nine iDMRs, without a selection for the original IDs. Re-analysis of the previously obtained whole exome sequencing data identified a homozygous ZNF445 variant (NM_181489.6:c.2803C>T:p.(Gln935*)) producing a truncated protein missing two of 14 zinc finger domains in a patient with Temple syndrome and MLID. In this patient, array-based genomewide methylation analysis revealed severe hypomethylation of most CpGs at the MEG3:TSS-DMR, moderate hypomethylation of roughly two-thirds of CpGs at the H19/IGF2:IG-DMR, and mild-to-moderate hypomethylation of a few CpGs at the DIRAS3:TSS-DMR, MEST:alt-TSS-DMR, IGF2:Ex9-DMR, IGF2:alt-TSS, and GNAS-AS1:TSS-DMR. Furthermore, bisulfite sequencing analysis for the MEG3/DLK1:IG-DMR delineated a markedly hypomethylated segment (CG-A). The heterozygous parents were clinically normal and had virtually no aberrant methylation pattern. Conclusions We identified a ZNF445 pathogenic variant for the first time. Since ZNF445 binds to the MEG3/DLK1:IG-DMR and other iDMRs affected in this patient, the development of Temple syndrome and MLID would primarily be explained by the ZNF445 variant. Furthermore, CG-A may be the target site for ZNF445 within the MEG3/DLK1:IG-DMR.

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Whole-Exome Sequencing and C9orf72 Analysis in Primary Progressive Aphasia

Journal of Alzheimer s Disease ◽

10.3233/jad-201310 ◽

2021 ◽

pp. 1-6

Author(s):

Vanesa Pytel ◽

Laura Hernández-Lorenzo ◽

Laura Torre-Fuentes ◽

Raúl Sanz ◽

Nieves González ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Primary Progressive Aphasia ◽

Sequencing Data ◽

Progressive Aphasia ◽

Primary Progressive ◽

Pathogenic Variants ◽

Whole Exome ◽

Whole Exome Sequencing Data ◽

Sporadic Disease

Primary progressive aphasia (PPA) is mainly considered a sporadic disease and few studies have systematically analyzed its genetic basis. We here report the analyses of C9orf72 genotyping and whole-exome sequencing data in a consecutive and well-characterized cohort of 50 patients with PPA. We identified three pathogenic GRN variants, one of them unreported, and two cases with C9orf72 expansions. In addition, one likely pathogenic variant was found in the SQSTM1 gene. Overall, we found 12%of patients carrying pathogenic or likely pathogenic variants. These results support the genetic role in the pathophysiology of a proportion of patients with PPA.

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Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants

Cells ◽

10.3390/cells9112368 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2368

Author(s):

Heidi G. Sutherland ◽

Neven Maksemous ◽

Cassie L. Albury ◽

Omar Ibrahim ◽

Robert A. Smith ◽

...

Keyword(s):

Genetic Testing ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Factors ◽

Sequencing Data ◽

Hemiplegic Migraine ◽

Pathogenic Variants ◽

Targeted Analysis ◽

Whole Exome ◽

Whole Exome Sequencing Data

Hemiplegic migraine (HM) is a rare migraine disorder with aura subtype including temporary weakness and visual, sensory, and/or speech symptoms. To date, three main genes—CACNA1A, ATP1A2, and SCN1A—have been found to cause HM. These encode ion channels or transporters, important for regulating neuronal ion balance and synaptic transmission, leading to HM being described as a channelopathy. However, <20% of HM cases referred for genetic testing have mutations in these genes and other genes with roles in ion and solute transport, and neurotransmission has also been implicated in some HM cases. In this study, we performed whole exome sequencing for 187 suspected HM probands referred for genetic testing, but found to be negative for CACNA1A, ATP1A2, and SCN1A mutations, and applied targeted analysis of whole exome sequencing data for rare missense or potential protein-altering variants in the PRRT2, PNKD, SLC1A3, SLC2A1, SLC4A4, ATP1A3, and ATP1A4 genes. We identified known mutations and some potentially pathogenic variants in each of these genes in specific cases, suggesting that their screening improves molecular diagnosis for the disorder. However, the majority of HM patients were found not to have candidate mutations in any of the previously reported HM genes, suggesting that additional genetic factors contributing to the disorder are yet to be identified.

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Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

Pediatric Research ◽

10.1038/s41390-021-01509-3 ◽

2021 ◽

Author(s):

Adam L. Numis ◽

Gilberto da Gente ◽

Elliott H. Sherr ◽

Hannah C. Glass

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

De Novo ◽

List Type ◽

Sequencing Analysis ◽

Neonatal Seizures ◽

Pathogenic Variants ◽

Targeted Analysis ◽

Whole Exome ◽

Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

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Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome

Human Genome Variation ◽

10.1038/s41439-021-00149-7 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Jong Seop Kim ◽

Hyoungseok Jeon ◽

Hyeran Lee ◽

Jung Min Ko ◽

Yonghwan Kim ◽

...

Keyword(s):

Hip Dysplasia ◽

Large Deletion ◽

Compound Heterozygous ◽

Radial Head Dislocation ◽

Sequencing Data ◽

Novel Mutations ◽

Exome Sequencing Data ◽

Whole Exome ◽

Whole Exome Sequencing Data ◽

Carpal Coalition

AbstractAn 11-year-old Korean boy presented with short stature, hip dysplasia, radial head dislocation, carpal coalition, genu valgum, and fixed patellar dislocation and was clinically diagnosed with Steel syndrome. Scrutinizing the trio whole-exome sequencing data revealed novel compound heterozygous mutations of COL27A1 (c.[4229_4233dup]; [3718_5436del], p.[Gly1412Argfs*157];[Gly1240_Lys1812del]) in the proband, which were inherited from heterozygous parents. The maternal mutation was a large deletion encompassing exons 38–60, which was challenging to detect.

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ETumorMetastasis: A Network-based Algorithm Predicts Clinical Outcomes Using Whole-exome Sequencing Data of Cancer Patients

Genomics Proteomics & Bioinformatics ◽

10.1016/j.gpb.2020.06.009 ◽

2021 ◽

Cited By ~ 1

Author(s):

Jean-Sébastien Milanese ◽

Chabane Tibiche ◽

Naif Zaman ◽

Jinfeng Zou ◽

Pengyong Han ◽

...

Keyword(s):

Exome Sequencing ◽

Cancer Patients ◽

Clinical Outcomes ◽

Whole Exome Sequencing ◽

Sequencing Data ◽

Exome Sequencing Data ◽

Whole Exome ◽

Whole Exome Sequencing Data

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Long runs of homozygosity are associated with Alzheimer’s disease

Translational Psychiatry ◽

10.1038/s41398-020-01145-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sonia Moreno-Grau ◽

◽

Maria Victoria Fernández ◽

Itziar de Rojas ◽

Pablo Garcia-González ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

European Ancestry ◽

Runs Of Homozygosity ◽

Sequencing Data ◽

Outbred Population ◽

Whole Exome ◽

Whole Exome Sequencing Data ◽

Outbred Populations ◽

Recessive Effects

AbstractLong runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer’s disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [βAVROH (CI 95%) = 0.070 (0.037–0.104); P = 3.91 × 10−5; βFROH (CI95%) = 0.043 (0.009–0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10−16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10−4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.

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A Survey of Computational Tools to Analyze and Interpret Whole Exome Sequencing Data

International Journal of Genomics ◽

10.1155/2016/7983236 ◽

2016 ◽

Vol 2016 ◽

pp. 1-16 ◽

Cited By ~ 16

Author(s):

Jennifer D. Hintzsche ◽

William A. Robinson ◽

Aik Choon Tan

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sequencing Data ◽

Disease Treatment ◽

Computational Tools ◽

Whole Exome ◽

Data Production ◽

Whole Exome Sequencing Data ◽

Computationally Intensive ◽

Generation Technology

Whole Exome Sequencing (WES) is the application of the next-generation technology to determine the variations in the exome and is becoming a standard approach in studying genetic variants in diseases. Understanding the exomes of individuals at single base resolution allows the identification of actionable mutations for disease treatment and management. WES technologies have shifted the bottleneck in experimental data production to computationally intensive informatics-based data analysis. Novel computational tools and methods have been developed to analyze and interpret WES data. Here, we review some of the current tools that are being used to analyze WES data. These tools range from the alignment of raw sequencing reads all the way to linking variants to actionable therapeutics. Strengths and weaknesses of each tool are discussed for the purpose of helping researchers make more informative decisions on selecting the best tools to analyze their WES data.

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