scholarly journals Whole-genome Sequencing Reveals De-novo Mutations Associated with Nonsyndromic Cleft Lip/Palate

2021 ◽  
Author(s):  
Waheed Awotoye ◽  
Peter A. Mossey ◽  
Jacqueline B. Hetmanski ◽  
Lord Jephthah Joojo Gowans ◽  
Mekonen A. Eshete ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cleft Lip ◽  
De Novo ◽  
Association Studies ◽  
Whole Genome ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Pathogenic Variants ◽  
Cleft Lip Palate

Abstract The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact DNMs that contribute to the risk of nsCL/P, we conducted whole genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs that contribute to the risk of nsCL/P. These include novel loss-of-function DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Experimental evidence showed that ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, MINK1, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TTN genes contribute to facial development and mutations in these genes could contribute to CL/P. Association studies have identified TULP4 as a potential cleft candidate gene, while ARHGAP10 interacts with CTNNB1 to control WNT signaling. DLX6, EPHB2, SEMA3C and SEMA4D harbor novel damaging DNMs that may affect their role in neural crest migration and palatal development. This discovery of pathogenic DNMs also confirms the power of WGS analysis of trios in the discovery of potential pathogenic variants.

scholarly journals Detection and phasing of single base de novo mutations in biopsies from human in vitro fertilized embryos by advanced whole-genome sequencing

2015 ◽  
Vol 25 (3) ◽  
pp. 426-434 ◽  
Author(s):  
Brock A. Peters ◽  
Bahram G. Kermani ◽  
Oleg Alferov ◽  
Misha R. Agarwal ◽  
Mark A. McElwain ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
Whole Genome ◽  
De Novo Mutations ◽  
Single Base

scholarly journals Whole genome sequencing of apparently mutation-negative MEN1 patients

2020 ◽  
Vol 182 (1) ◽  
pp. 35-45 ◽  
Author(s):  
Samuel Backman ◽  
Duska Bajic ◽  
Joakim Crona ◽  
Per Hellman ◽  
Britt Skogseid ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Missense Variant ◽  
Endocrine Tumors ◽  
Whole Genome ◽  
Loss Of Function ◽  
Chromosome 1Q ◽  
Pathogenic Variants ◽  
Sporadic Disease ◽  
Tumor Dna

Objective Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1 gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1 mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1. Design Fourteen patients with a clinical diagnosis (n = 13) or suspicion (n = 1) of MEN1 who had negative genetic screening of the MEN1 gene were included. Methods Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model. Results Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson’s two-hit model. Conclusion These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation-negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.

Whole Genome Sequencing To Identify De Novo Mutations In Bipolar Disorder

2017 ◽  
Vol 27 ◽  
pp. S384
Author(s):  
Fernando Goes ◽  
Mehdi Pirooznia ◽  
Martin Tehan ◽  
Paula Wolyniec ◽  
John McGrath ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
Whole Genome ◽  
De Novo Mutations

scholarly journals Whole Genome Sequencing of a Vietnamese Family from a Dioxin Contamination Hotspot Reveals Novel Variants in the Son with Undiagnosed Intellectual Disability

2018 ◽  
Vol 15 (12) ◽  
pp. 2629 ◽  
Author(s):  
Dang Nguyen ◽  
Hai Nguyen ◽  
Thuy Nguyen ◽  
Thi Nguyen ◽  
Kaoru Nakano ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
Genetic Alterations ◽  
Whole Genome ◽  
Missense Mutations ◽  
De Novo Mutations ◽  
Bioinformatics Analyses ◽  
Dioxin Contamination

Although it has been a half-century since dioxin-contaminated herbicides were used to defoliate the landscape during the Vietnam War, dioxin contamination “hotspots” still remain in Vietnam. Environmental and health impacts of these hotspots need to be evaluated. Intellectual disability (ID) is one of the diseases found in the children of people exposed to the herbicides. This study aims to identify genetic alterations of a patient whose family lived in a dioxin hotspot. The patient’s father had a highly elevated dioxin concentration. He was affected with undiagnosed moderate ID. To analyze de novo mutations and genetic variations, and to identify causal gene(s) for ID, we performed whole genome sequencing (WGS) of the proband and his parents. Two de novo missense mutations were detected, each one in ETS2 and ZNF408 genes, respectively. Compound heterozygosity was identified in CENPF and TTN genes. Existing knowledge on the genes and bioinformatics analyses suggest that EST2, ZNF408, and CENPF might be promising candidates for ID causative genes.

scholarly journals A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies

2018 ◽  
Vol 102 (6) ◽  
pp. 1031-1047 ◽  
Author(s):  
Yuwen Liu ◽  
Yanyu Liang ◽  
A. Ercument Cicek ◽  
Zhongshan Li ◽  
Jinchen Li ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
Whole Genome ◽  
De Novo Mutations ◽  
Risk Genes ◽  
Statistical Framework ◽  
Sequencing Studies

scholarly journals Rare ABCA7 variants in 2 German families with Alzheimer disease

2018 ◽  
Vol 4 (2) ◽  
pp. e224 ◽  
Author(s):  
Patrick May ◽  
Sabrina Pichler ◽  
Daniela Hartl ◽  
Dheeraj R. Bobbili ◽  
Manuel Mayhaus ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Variants ◽  
Late Onset ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Pathogenic Variants ◽  
Genome Wide

ObjectiveThe aim of this study was to identify variants associated with familial late-onset Alzheimer disease (AD) using whole-genome sequencing.MethodsSeveral families with an autosomal dominant inheritance pattern of AD were analyzed by whole-genome sequencing. Variants were prioritized for rare, likely pathogenic variants in genes already known to be associated with AD and confirmed by Sanger sequencing using standard protocols.ResultsWe identified 2 rare ABCA7 variants (rs143718918 and rs538591288) with varying penetrance in 2 independent German AD families, respectively. The single nucleotide variant (SNV) rs143718918 causes a missense mutation, and the deletion rs538591288 causes a frameshift mutation of ABCA7. Both variants have previously been reported in larger cohorts but with incomplete segregation information. ABCA7 is one of more than 20 AD risk loci that have so far been identified by genome-wide association studies, and both common and rare variants of ABCA7 have previously been described in different populations with higher frequencies in AD cases than in controls and varying penetrance. Furthermore, ABCA7 is known to be involved in several AD-relevant pathways.ConclusionsWe conclude that both SNVs might contribute to the development of AD in the examined family members. Together with previous findings, our data confirm ABCA7 as one of the most relevant AD risk genes.

scholarly journals De novo mutations identified by whole-genome sequencing implicate chromatin modifications in obsessive-compulsive disorder

2022 ◽  
Vol 8 (2) ◽  
Author(s):  
Guan Ning Lin ◽  
Weichen Song ◽  
Weidi Wang ◽  
Pei Wang ◽  
Huan Yu ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
Chromatin Modification ◽  
Whole Genome ◽  
Chromatin Modifications ◽  
De Novo Mutations ◽  
Obsessive Compulsive ◽  
Compulsive Disorder

Trio-based whole-genome sequencing identified the role of chromatin modification in OCD pathology.

scholarly journals Effective variant filtering and expected candidate variant yield in studies of rare human disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Brent S. Pedersen ◽  
Joe M. Brown ◽  
Harriet Dashnow ◽  
Amelia D. Wallace ◽  
Matt Velinder ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Rare Disease ◽  
Genome Sequencing ◽  
Autosomal Dominant ◽  
De Novo ◽  
Autosomal Dominant Inheritance ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Dominant Inheritance ◽  
Family Based

AbstractIn studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.

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