Importance of Family History in the Era of Exome Analysis: A Report of a Family with Multiple Concurrent Genetic Diseases

2021 ◽  
Vol 86 (1-4) ◽  
pp. 28-33
Author(s):  
Karishma Mahtani ◽  
Diana Park ◽  
Jessica Abbott ◽  
Pavalan Panneer Selvam ◽  
Paldeep S. Atwal
Keyword(s):  
Prostate Cancer ◽  
Family History ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Pedigree Analysis ◽  
Single Patient ◽  
Disease Etiology ◽  
Whole Exome ◽  
Exome Analysis ◽  
Dependent Processes

Multiple familial diseases in a single patient often present with overlapping symptomatology that confers difficulty in delineating a clinical diagnosis. Pedigree analysis has been a long-standing practice in the field of medical genetics to discover familial diseases. In recent years, whole exome sequencing (WES) has proven to be a useful tool for aiding physicians in diagnosing and understanding disease etiology. This report shows that pedigree analysis and WES are co-dependent processes in establishing diagnoses in a family with 4 different genetic disorders: Birt-Hogg-Dubé Syndrome, <i>RRM2B</i>-related mitochondrial disease, <i>CDC73</i>-related primary hyperparathyroidism, and familial prostate cancer.

scholarly journals Pilot study of EVIDENCE: High diagnostic yield and clinical utility of whole exome sequencing using an automated interpretation system for patients with suspected genetic disorders

2019 ◽  
Author(s):  
Go Hun Seo ◽  
Taeho Kim ◽  
Jung-young Park ◽  
Jungsul Lee ◽  
Sehwan Kim ◽  
...  
Keyword(s):  
Family Member ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Whole Exome ◽  
Interpretation System ◽  
Automated Interpretation ◽  
Age Range

AbstractPurposeEVIDENCE, an automated interpretation system, has been developed to facilitate the entire process of whole exome sequencing (WES) analyses. This study investigated the diagnostic yield of EVIDENCE in patients suspected genetic disorders.MethodsDNA from 330 probands (age range, 0–68 years) with suspected genetic disorders were subjected to WES. Candidate variants were identified by EVIDENCE and confirmed by testing family members and/or clinical reassessments.ResultsThe average number of overlapping organ categories per patient was 4.5 ± 5.0. EVIDENCE reported a total 244 variants in 215 (65.1%) of the 330 probands. After clinical reassessment and/or family member testing, 196 variants were identified in 171 probands (51.8%), including 115 novel variants. These variants were confirmed as being responsible for 146 genetic disorders. One hundred-seven (54.6%) of the 196 variants were categorized as pathogenic or likely pathogenic before, and 146 (74.6%) after, clinical assessment and/or family member testing. Factors associated with a variant being confirmed as causative include rules, such as PVS1, PS1, PM1, PM5, and PP5, and similar symptom scores between that variant and a patient’s phenotype.ConclusionThis new, automated variant interpretation system facilitated the diagnosis of various genetic diseases with a 51% improvement in diagnostic yield.

Variation p.R1045H in MYH7 correlated with hypertrophic cardiomyopathy in a Chinese pedigree

2020 ◽  
Author(s):  
Yan Zhang ◽  
Shang Yiyi ◽  
Luo Liu ◽  
Xiaoxue Ding ◽  
Haiyan Wu ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Family History ◽  
Genetic Factors ◽  
Genetic Variant ◽  
Heart Function ◽  
Pedigree Analysis ◽  
Genetic Defects ◽  
Fatal Disease ◽  
Whole Exome

Abstract Objective: Inherited hypertrophic cardiomyopathy (HCM) is s a fatal disease that damages heart function and may cause the heart to stop beating suddenly. The genetic factors play an important role in HCM. Pedigree analysis is a good way to identify the genetic defects that cause disease. Methods: A HCM pedigree was found in Yunnan of China. Whole-exome sequencings were performed for finding the genetic variant of HCM. Another 30 HCM patients and 200 health controls were also used to investigate the frequency of variation by TaqMan-MGB method. Results: The variation NM_000257.4:c.3134G>A (NP_000248.2:p.Arg1045His, rs397516178, short as c.3134G>A) was found to co-segregate with the symptoms of HCM. Meanwhile, the variation was not found in 200 controls. After genotyping the variation in 30 HCM patients, one patient carried the variation and had a family history. Conclusion: Our findings support that this variation may be closely related to the occurrence of the disease. According the ACMG guideline, the c. 3134G>A should be classified as " Likely pathogenic".

The contribution of germline DNA damage response mutations on prostate cancer risk and prognosis: A UK Biobank whole-exome analysis.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 67-67
Author(s):  
Niedzica Camacho ◽  
Athena Matakidou
Keyword(s):  
Prostate Cancer ◽  
Family History ◽  
Cancer Risk ◽  
Dna Damage Response ◽  
Prostate Cancer Risk ◽  
Population Based ◽  
Uk Biobank ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Damage Response

67 Background: Germline mutations in DNA Damage Response (DDR) genes such as BRCA2 and ATM have been associated with prostate cancer risk and aggressiveness. These associations are largely based on studies that ascertain for cancer diagnosis and family history and provide risk estimates with limited population-level accuracy. Here we evaluate the clinical significance of germline pathogenic variants in 20 DDR genes and a high-risk susceptibility coding variant in HOXB13 using whole exome sequences from (1) the UK Biobank (UKBB), a population-based cohort (300,000 participants) and (2) patients recruited in AZ clinical trials. Methods: Whole exomes from 6,987 prostate cancer patients (5,921 UKBB and 1,066 AZ) and 88,499 cancer-free males were analysed. Known and novel pathogenic variants were identified and associations with disease risk, age of onset, family history, response to hormonal therapy and overall survival were estimated (multiplicity corrected P value < 0.005). Results: HOXB13 G48E (1.36%), ATM (1.03%) and BRCA2 (0.99%) were the largest contributors to prostate cancer risk, each conferring an increase of ~4-fold, followed by CHEK2 with a moderate contribution (0.46%). No significant contributions to prostate cancer risk were observed for any of the other genes analysed. Family history of prostate cancer was not significantly enriched in any of the gene subpopulations of prostate cancer carriers and compared with non-carriers, there was no significant difference in the median age of disease onset. Analysis of clinical outcomes showed that BRCA2 carriers had a 4-fold increased risk of death (Cox PH HR p = 4.11E-12) and poorer overall survival (Log-Rank p = 4.60E-14), with 88% dying from prostate cancer compared to 49% of non- BRCA2 carriers (UKBB analysis). BRCA2 pathogenic mutations were also associated with early failure to hormonal therapy (Cox PH HR 2.38; p = 9.48E-04; AZ cohort analysis). HOXB13, ATM and CHEK2 mutations were not significantly associated with clinical outcomes. Conclusions: This is the largest study to date providing population-based estimates of prostate cancer risk and prognosis, highlighting BRCA2 carriers as a population in clinical need of early identification and targeted intervention. Updated analyses with data from the full 450,000 UKBB participants (9,000 prostate cancers) will be presented.

scholarly journals Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases

2017 ◽  
Vol 25 (4) ◽  
pp. 404-409 ◽  
Author(s):  
Jacqueline Neubauer ◽  
Maria Rita Lecca ◽  
Giancarlo Russo ◽  
Christine Bartsch ◽  
Argelia Medeiros-Domingo ◽  
...  
Keyword(s):  
Sudden Infant Death Syndrome ◽  
Infant Death ◽  
Genetic Diseases ◽  
Sudden Infant Death ◽  
Sudden Infant ◽  
Post Mortem ◽  
Whole Exome ◽  
Exome Analysis

scholarly journals A Novel Frameshift Homozygous Mutation in DHCR7 with a Known Missense Homozygous Mutation in the PROC in a 6-Year-Old Boy: A Child with Two Rare Genetic Diseases

2019 ◽  
Vol 08 (03) ◽  
pp. 168-171
Author(s):  
Evren Gumus
Keyword(s):  
Genetic Disorders ◽  
Genetic Diseases ◽  
Laboratory Data ◽  
Valuable Insight ◽  
Homozygous Mutation ◽  
Homozygous Variant ◽  
Whole Exome ◽  
Rare Genetic Diseases ◽  
Proc Gene ◽  
Autosomal Recessive Diseases

AbstractIn the present case report, we described a 6-year-old-boy with developmental delay, mental retardation, lack of speech, skin scars, and 2 to 3 toe syndactyly from healthy consanguineous Turkish parents. The whole exome sequencing (WES) analysis of this patient showed homozygous variant c.418T > C p.(Cys140Arg) in PROC gene and novel homozygous variant c.57dupC p.(Asn20Glnfs*2) in the DHCR7 gene. This finding demonstrated that WES is of great value for the diagnosis of two separate genetic disorders in a patient with multiple dysmorphic and other clinical features. It should also be kept in mind that the coexistence of two autosomal recessive diseases could be observed in highly related consanguineous marriages. The combined evaluation of clinical and laboratory data provided extremely valuable insight into the diagnosis of this unique case.

scholarly journals A Bioinformatics Pipeline for Whole Exome Sequencing: Overview of the Processing and Steps from Raw Data to Downstream Analysis

2017 ◽  
Author(s):  
Narendra Meena ◽  
Praveen Mathur ◽  
Krishna Mohan Medicherla ◽  
Prashanth Suravajhala
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Variant Calling ◽  
Genome Project ◽  
Bioinformatics Pipeline ◽  
Whole Exome ◽  
Ngs Data

AbstractRecent advances in next generation sequencing (NGS) technologies have given an impetus to find causality for rare genetic disorders. Since 2005 and aftermath of the human genome project, efforts have been made to understand the rare variants of genetic disorders. Benchmarking the bioinformatics pipeline for whole exome sequencing (WES) has always been a challenge. In this protocol, we discuss detailed steps from quality check to analysis of the variants using a WES pipeline comparing them with reposited public NGS data and survey different techniques, algorithms and software tools used during each step. We observed that variant calling performed on exome and whole genome datasets have different metrics generated when compared to variant callers, GATK and VarScan with different parameters. Furthermore, we found that VarScan with strict parameters could recover 80-85% of high quality GATK SNPs with decreased sensitivity from NGS data. We believe our protocol in the form of pipeline can be used by researchers interested in performing WES analysis for genetic diseases and by large any clinical phenotypes.

649: Prostate Cancer Screening in Persons with a Positive Family History

2004 ◽  
Vol 171 (4S) ◽  
pp. 172-173
Author(s):  
Kathleen Herkommer ◽  
Juergen E. Gschwend ◽  
Martina Kron ◽  
Richard E. Hautmann ◽  
Thomas Paiss
Keyword(s):  
Prostate Cancer ◽  
Cancer Screening ◽  
Family History ◽  
Prostate Cancer Screening ◽  
Positive Family History

Prostate Cancer

2018 ◽  
Author(s):  
Kathryn M. Wilson ◽  
Lorelei Mucci
Keyword(s):  
Prostate Cancer ◽  
Risk Factors ◽  
Family History ◽  
Prostate Specific Antigen ◽  
Advanced Prostate Cancer ◽  
Advanced Disease ◽  
African Ancestry ◽  
Specific Antigen ◽  
Dietary Factors ◽  
Increased Risk

Prostate cancer is among the most commonly diagnosed cancers among men, ranking second in cancer globally and first in Western countries. There are marked variations in incidence globally, and its incidence must be interpreted in the context of diagnostic intensity and screening. The uptake of prostate-specific antigen screening since the 1990s has led to dramatic increases in incidence in many countries, resulting in an increased proportion of indolent cancers that would never have come to light clinically in the absence of screening. Risk factors differ when studying prostate cancer overall versus advanced disease. Older age, African ancestry, and family history are established risk factors for prostate cancer. Obesity and smoking are not associated with risk overall, but are associated with increased risk of advanced prostate cancer. Several additional lifestyle factors, medications, and dietary factors are now emerging as risk factors for advanced disease.

scholarly journals Hunting for Familial Parkinson’s Disease Mutations in the Post Genome Era

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 430
Author(s):  
Steven R. Bentley ◽  
Ilaria Guella ◽  
Holly E. Sherman ◽  
Hannah M. Neuendorf ◽  
Alex M. Sykes ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Family History ◽  
Rare Variants ◽  
Strong Family History ◽  
Disease Mutations ◽  
Whole Exome ◽  
History Of ◽  
Functional Consequences ◽  
Multiplex Families

Parkinson’s disease (PD) is typically sporadic; however, multi-incident families provide a powerful platform to discover novel genetic forms of disease. Their identification supports deciphering molecular processes leading to disease and may inform of new therapeutic targets. The LRRK2 p.G2019S mutation causes PD in 42.5–68% of carriers by the age of 80 years. We hypothesise similarly intermediately penetrant mutations may present in multi-incident families with a generally strong family history of disease. We have analysed six multiplex families for missense variants using whole exome sequencing to find 32 rare heterozygous mutations shared amongst affected members. Included in these mutations was the KCNJ15 p.R28C variant, identified in five affected members of the same family, two elderly unaffected members of the same family, and two unrelated PD cases. Additionally, the SIPA1L1 p.R236Q variant was identified in three related affected members and an unrelated familial case. While the evidence presented here is not sufficient to assign causality to these rare variants, it does provide novel candidates for hypothesis testing in other modestly sized families with a strong family history. Future analysis will include characterisation of functional consequences and assessment of carriers in other familial cases.

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