Erratum: Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer

Germline mutations in predisposition genes account for only 20% of all familial colorectal cancer (CRC) and the remaining genetic burden may be due to rare high-to-moderate-penetrance germline variants that are not explored. With the aim of identifying such potential cancer predisposing variants, we performed whole exome sequencing on three CRC cases and three unaffected members of a Polish family and identified two novel heterozygous variants; a coding variant in APC down-regulated 1 gene (APCDD1, p.R299H) and a non-coding variant in the 5’ untranslated region (UTR) of histone deacetylase 5 gene (HDAC5). Sanger sequencing confirmed the variants segregating with the disease and Taqman assays revealed 8 additional APCDD1 variants in a cohort of 1705 familial CRC patients and no further HDAC5 variants. Proliferation assays indicated an insignificant proliferative impact for the APCDD1 variant. Luciferase reporter assays using the HDAC5 variant resulted in an enhanced promoter activity. Targeting of transcription factor binding sites of SNAI-2 and TCF4 interrupted by HDAC5 variant showed a significant impact of TCF4 on promoter activity of mutated HDAC5. Our findings contribute not only to the identification of unrecognized genetic causes of familial CRC but also underline the importance of 5´UTR variants affecting transcriptional regulation and the pathogenesis of complex disorders.

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Using linkage studies combined with whole‐exome sequencing to identify novel candidate genes for familial colorectal cancer

International Journal of Cancer ◽

10.1002/ijc.32683 ◽

2019 ◽

Vol 146 (6) ◽

pp. 1568-1577 ◽

Cited By ~ 2

Author(s):

Claudio Toma ◽

Marcos Díaz‐Gay ◽

Sebastià Franch‐Expósito ◽

Coral Arnau‐Collell ◽

Bronwyn Overs ◽

...

Keyword(s):

Colorectal Cancer ◽

Exome Sequencing ◽

Candidate Genes ◽

Whole Exome Sequencing ◽

Linkage Studies ◽

Familial Colorectal Cancer ◽

Whole Exome

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Whole Exome Sequencing Identifies Novel Germline Variants of SLC15A4 Gene as Potentially Cancer Predisposing in Familial Colorectal Cancer

10.20944/preprints202103.0257.v1 ◽

2021 ◽

Author(s):

Diamanto Skopelitou ◽

Aayushi Srivastava ◽

Beiping Miao ◽

Abhishek Kumar ◽

Dagmara Dymerska ◽

...

Keyword(s):

Colorectal Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Familial Aggregation ◽

Familial Cancer ◽

Missense Variant ◽

Upstream Region ◽

Germline Variants ◽

Whole Exome ◽

Predisposition Genes

About 15% of colorectal cancer (CRC) patients have first-degree relatives affected by the same malignancy. However, for most families the cause of familial aggregation of CRC is unknown. In order to identify novel high-to-moderate penetrant germline variants underlying CRC susceptibility, we performed whole exome sequencing (WES) on four CRC cases and two unaffected family members of a Polish family without any mutation in known CRC predisposition genes. After WES, we used our in-house developed Familial Cancer Variant Prioritization Pipeline and identified two novel variants in the solute carrier family 15 member 4 (SLC15A4) gene. The heterozygous missense variant, p. Y444C, was predicted to affect the phylogenetically conserved PTR2/POT domain and to have a deleterious effect on the function of the encoded peptide/histidine transporter. The other variant was located in the upstream region of the same gene (GRCh37.p13, 12_129308531_C_T; 43bp upstream of transcription start site, ENST00000266771.5) and it was annotated to affect the promoter region of SLC15A4 as well as binding sites of 17 different transcription factors. Our findings of two distinct variants in the same gene may indicate a synergistic up-regulation of SLC15A4 as the underlying genetic cause and implicate this gene for the first time in genetic inheritance of familial CRC.

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Whole-exome sequencing of familial esophageal squamous cell carcinoma identified rare pathogenic variants in new predisposition genes

Clinical & Translational Oncology ◽

10.1007/s12094-019-02174-z ◽

2019 ◽

Vol 22 (5) ◽

pp. 681-693 ◽

Cited By ~ 1

Author(s):

F. F. Golyan ◽

T. E. Druley ◽

M. R. Abbaszadegan

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Squamous Cell ◽

Pathogenic Variants ◽

Whole Exome ◽

Predisposition Genes

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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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RHOBTB2 p.Arg511Trp Mutation in Early Infantile Epileptic Encephalopathy-64: Review and Case Report

Journal of Pediatric Genetics ◽

10.1055/s-0040-1722288 ◽

2021 ◽

Author(s):

J Fonseca ◽

C Melo ◽

C Ferreira ◽

M Sampaio ◽

R Sousa ◽

...

Keyword(s):

Case Report ◽

Intellectual Disability ◽

Status Epilepticus ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Epileptic Encephalopathy ◽

Btb Domain ◽

Pathogenic Variants ◽

Severe Intellectual Disability ◽

Whole Exome

AbstractEarly infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 (RHOBTB2) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

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Novel pathogenic variants and genes for myopathies identified by whole exome sequencing

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.142 ◽

2015 ◽

Vol 3 (4) ◽

pp. 283-301 ◽

Cited By ~ 23

Author(s):

Jesse M. Hunter ◽

Mary Ellen Ahearn ◽

Christopher D. Balak ◽

Winnie S. Liang ◽

Ahmet Kurdoglu ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Pathogenic Variants ◽

Whole Exome

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Whole-Exome Sequencing Identifies Pathogenic Variants in TJP1 Gene Associated With Arrhythmogenic Cardiomyopathy

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.118.002123 ◽

2018 ◽

Vol 11 (10) ◽

Cited By ~ 19

Author(s):

Marzia De Bortoli ◽

Alex V. Postma ◽

Giulia Poloni ◽

Martina Calore ◽

Giovanni Minervini ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Arrhythmogenic Cardiomyopathy ◽

Pathogenic Variants ◽

Whole Exome

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Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis

Journal of Dental Research ◽

10.1177/0022034517724149 ◽

2017 ◽

Vol 97 (1) ◽

pp. 49-59 ◽

Cited By ~ 16

Author(s):

N. Dinckan ◽

R. Du ◽

L.E. Petty ◽

Z. Coban-Akdemir ◽

S.N. Jhangiani ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Permanent Teeth ◽

Tooth Agenesis ◽

Disease Genes ◽

Nonsense Mediated Decay ◽

Pathogenic Variants ◽

Whole Exome ◽

Novel Variants ◽

Complex Inheritance

Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.

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