Role Of Genetic Testing Research Articles

In-Stent Thrombosis after Antiplatelet Therapy Conversion while Awaiting Coronary Bypass

In-stent thrombosis (IST) is a rare yet dangerous complication that may occur despite optimized coronary intervention in the cardiac catheterization laboratory. This is a case of an 81-year-old man who presented with ST-elevation myocardial infarction. Right coronary artery (RCA) occlusion was suspected. RCA angiography and percutaneous coronary intervention were performed. Complicated left coronary artery disease was subsequently discovered. Per cardiothoracic surgeon request, the patient was transitioned from ticagrelor to clopidogrel therapy in preparation for coronary artery bypass grafting. The patient experienced IST the day before surgery while receiving clopidogrel. We examine this case, which highlights the complexity of antiplatelet therapy choice and the role of genetic testing in evaluation of IST risk.

The Role of Genetic Testing in the Clinical Practice and Research of Early-Onset Parkinsonian Disorders in a Hungarian Cohort: Increasing Challenge in Genetic Counselling, Improving Chances in Stratification for Clinical Trials.

The genetic analysis of early-onset Parkinsonian disorder (EOPD) is part of the clinical diagnostics. Several genes have been implicated in the genetic background of Parkinsonism, which is clinically indistinguishable from idiopathic Parkinson’s disease. The identification of patient’s genotype could support clinical decision-making process and also track and analyse outcomes in a comprehensive fashion. The aim of our study was to analyse the genetic background of EOPD in a Hungarian cohort and to evaluate the clinical usefulness of different genetic investigations. The age of onset was between 25 and 50 years. To identify genetic alterations, multiplex ligation-dependent probe amplification (n = 142), Sanger sequencing of the most common PD-associated genes (n = 142), and next-generation sequencing (n = 54) of 127 genes which were previously associated to neurodegenerative disorders were carried out. The genetic analysis identified several heterozygous damaging substitutions in PD-associated genes (C19orf12, DNAJC6, DNAJC13, EIF4G1, LRRK2, PRKN, PINK1, PLA2G6, SYNJ1). CNVs in PRKN and SNCA genes were found in five patients. In our cohort, nine previously published genetic risk factors were detected in three genes (GBA, LRRK2, and PINK1). In nine cases, two or three coexisting pathogenic mutations and risk variants were identified. Advances of sequencing technologies make it possible to aid diagnostics of PD by widening the scope of analysis to genes which were previously linked to other neurodegenerative disorders. Our data suggested that rare damaging variants are enriched versus neutral variants, among PD patients in the Hungarian population, which raise the possibility of an oligogenic effect. Heterozygous mutations of multiple recessive genes involved in the same pathway may perturb the molecular process linked to PD pathogenesis. Comprehensive genetic assessment of individual patients can rarely reveal monogenic cause in EOPD, although it may identify the involvement of multiple PD-associated genes in the background of the disease and may facilitate the better understanding of clinically distinct phenocopies. Due to the genetic complexity of the disease, genetic counselling and management is getting more challenging. Clinical geneticist should be prepared for counselling of patients with coexisting disease-causing mutations and susceptibility factors. At the same time, genomic-based stratification has increasing importance in future clinical trials.

P4797Genetic testing in 101 consecutive lone atrial fibrillation patients is able to identify a subgroup with increased severity

Abstract Introduction Atrial fibrillation (AF) is the most common arrhythmia and the cause of 15% of all strokes and up to 6% of medical admissions. It is estimated that currently about 2.0 million Brazilians, and 30 million individuals worldwide, are affected by the disease. It is a complex and multifactorial disease, and the mechanisms are still not well understood. Between 10–20% of AF patients do not have any known predisposing factors, a condition once called “lone AF”. The role of genetic testing still remains controversial in this clinical scenario. Purpose The aim of this study was to identify the occurrence of pathogenic genetic variants in patients with atrial fibrillation without known risk factors. Methods In a tertiary hospital, 101 young patients with apparent “lone AF” were screened with genetic testing by NGS using a custom genetic panel with 159 channelopathy and cardiomyopathy related genes. Variants found were classified according to the American College of Genetic and Genomic (ACMG) criteria. Subjects were evaluated with clinical and familial history, electrocardiogram, 24 hours Holter monitoring, echocardiogram, cardiac MRI and treatment response. Multivariate analyses were performed by logistic linear regression model. Results During an inclusion period of 4 years, 101 consecutive patients, with mean age of 38.6 years old, were classified as “lone AF” (78% male); 76% presented paroxysmal AF and 24% persistent/permanent AF. Family history of early sudden death (bellow 60 years old) was reported in 37% of cases (78% below 50 years old); 10% had family members with pacemakers; and 44% reported having family members with early AF onset. Genetic testing demonstrated that 14/101 (13.8%) of patients presented genetic variants classified as pathogenic or likely pathogenic (P/LP) according to ACMG criteria. The genes most frequently affected were LMNA (3/101), ANK2 (3/101) and truncating variants in TTN (3/101). Two variables were significantly associated with harboring a pathogenic mutation: family history of sudden death (OR: 5.58; 1,19–26,12 CI; p=0.029) and pacemaker reported in the family history (OR: 6.83; 1.11–42.04 CI; p=0.038). Conclusion Our data showed that approximately 15% of “lone AF” patients are carriers of known pathogenic mutations in genes associated with inherithed cardiomyopathy. In addition, we show that being a carrier is potentially associated with a more severe phenotype. These findings suggest that genetic testing in “lone AF” patients may be able to identify a subgroup with a more severe phenotype are for whom a different management strategy might be indicated. Acknowledgement/Funding National Council for Scientific and Technological Development (CNPq)

SAT-232 Is There a Role for Genetic Testing in Guiding the Management of Primary Hyperparathyroidism in Pregnancy?

Introduction Primary hyperparathyroidism (PHPT) in pregnancy is rare, with a reported incidence of <1%. It is associated with serious maternal and foetal complications, and is genetically determined in ~10% of cases. Confirming a genetic diagnosis can guide management of inherited PHPT, and enables screening for syndrome-related diseases. This case series highlights the role of genetic testing in the tailored management of patients with PHPT in pregnancy. Clinical cases Case 1 is a 20 year old female who was diagnosed with PHPT at 5 weeks gestation after presentation with nausea. She was hypercalcaemic (2.78 mmol/L at diagnosis; 2.98 mmol/L pre-parathyroidectomy), had negative neck ultrasonography and a MEN1 mutation (exon 2, c.236_237del, p.(Pro79fs)) on genetic testing in pregnancy. After initial management with oral and IV rehydration, her severe symptomatic hypercalcaemia required treatment with open neck exploration and a 3 gland parathyroidectomy in the 2nd trimester. The standard surgical approach of a 3.5 gland parathyroidectomy was avoided due to the risk of inducing hypoparathyroidism. Intra-operative PTH dropped 53.8% post 3 gland parathyroidectomy. Parathyroid hyperplasia on histology was consistent with the diagnosis of MEN1 syndrome. The patient’s symptoms resolved post-operatively and foetal investigations are normal at 28 weeks gestation. She is receiving close obstetric follow-up including 3-weekly foetal growth scans due to the increased risk of IUGR. She was counseled on her increased risk of pancreatic and pituitary tumours and her 1st degree relatives are undergoing genetic screening. Case 2 is a 40 year old female with a known diagnosis of PHPT who was awaiting parathyroidectomy prior to pregnancy. She was hypercalcaemic (2.78 mmol/L at 7 weeks; 2.99 mmol/L pre-parathyroidectomy), and had a lower left parathyroid adenoma on ultrasound and pre-pregnancy SPECT-CT. Genetic testing was not performed as she was 40 at diagnosis and had no contributory family history. After failure of conservative management, parathyroidectomy of the left superior parathyroid gland was performed in the 2nd trimester. Histology results confirmed a left inferior parathyroid adenoma, concordant with the radiological findings. Her symptoms improved post-operatively; she is receiving close obstetric follow-up. Clinical lessons Genetic testing enables the management of PHPT to be tailored appropriately. It can better inform the surgical approach; including the need for subtotal parathyroidectomy and bilateral neck exploration in those cases at risk of multiple parathyroid gland disease, as demonstrated in our case with MEN1. Finally this case series demonstrates that surgical management of PHPT should be considered for select cases in pregnancy and thus far no maternal or foetal complications have arisen in these featured cases following surgical intervention.

The comparison of two whole genome amplification methods: A new method of pre-implantation genetic testing (PGT-M) for Southeast Asian deletion in alpha-thalassemia using high resolution melting analysis

Introduction In Southeast Asia, alpha-thalassemia with Southeast Asian (SEA) deletion type is the most common mutations of alpha-thalassemia-1 which can cause severe form known as Bart's hydrops fetalis. For couples which carrier of single gene defects, pre-implantation genetic testing for monogenic (PGT-M) plays a role in genetic testing for selecting of unaffected embryos prior implantation. Recently, high resolution melting (HRM) analysis is a simple, rapid and widely used for genotyping and gene scanning of genetic variation. In this study, we developed HRM analysis method for detection of SEA deletion in alpha-thalassemia and compared two WGA methods, SurePlex DNA Amplification System and REPLI-g Single Cell on the performance of HRM analysis and linkage analysis. Material and Methods Retrospective study was carried out in a single private fertility clinic from 2015 to 2017. The single cell embryos were biopsied on blastocyst stage from couples with disease- carrier of SEA deletion type. The trophectoderm biopsied cells were amplified by two whole genome amplification (WGA), SurePlex DNA Amplification System-PCR based method (Illumina, USA) and REPLI-g MDA Single Cell (QIAGEN, Germany). All WGA products were analyzed with two primer pairs of HRM analysis for detection of SEA deletion type in alpha-thalassemia disease and confirmed with the informative short tandem repeated (STRs) linkage analysis. Results A total of 53 single cell biopsied were amplified with SurePlex-WGA (n=33) and REPLI-g MDA (n=20) which used as template for HRM analysis. The HRM results revealed clearly distinguished between wild type and mutant type of SEA deletion mutation in alpha-thalassemia. Comparing between two WGA methods, the HRM amplification results efficiency and allele drop out (ADO) rate of REPLI- g MDA were 95% (19/20) and 31.57% (6/19), respectively. Meanwhile, for SurePlex-WGA showed 75.76% (25/33) and 28% (7/25), respectively. Furthermore, the HRM melting profile results of REPLI-g MDA showed higher concordance rate with the informative STRs linkage analysis results (63.16%, 12/18) than that of SurePlex-WGA (48%, 12/25). Conclusions HRM analysis is an alternative technique with high sensitivity and accuracy for detecting of alpha-thalassemia mutations. The REPLI-g MDA Single Cell method with HRM analysis is suitable for detection of alpha-thalassemia1 SEA type deletion in PGT-M and provided a good concordance with informative STRs linkage analysis. However, ADO from PCR amplification could be occurred and caused of misdiagnosis which might be affected to the interpretation results of the embryos disease- status. Thus, the mutation analysis method using HRM analysis combined with STRs linkage analysis are recommend in PGT-M to avoid the effected of ADO and increase the accuracy and reliable of the PGT-M results.

Partial lipodystrophy type 2: One case report and literature review

Familial partial lipodystrophy type 2 (FPLD2) is an autosomal dominant disorder caused by mutations in LMNA gene, which is characterized by adolescent onset selective subcutaneous fat loss with metabolic abnormalities such as insulin resistance. Severe insulin resistance can cause acanthosis nigricans, pseudoacromegaly, ovarian dysfunction, glucose, and lipid metabolism disorders. Therefore, it is often misdiagnosed as metabolic syndrome, type 2 diabetes, polycystic ovary syndrome, acromegaly, and Cushing′s syndrome. Through the analysis of the diagnosis and treatment of a case of FPLD2 with acromegaly, and the importance of tracing the origin of the disease is emphasized and also does the role of genetic testing in diagnosis. It suggests that clinicians should pay attention to the fat distribution of those similar patients, and make diagnosis and treatment timely. Key words: Lipodystrophy; LMNA gene; Fat distribution; Acromegaloidism

Diagnosis of monogenic chronic kidney diseases.

The purpose of this review is to emphasize that single gene disorders are an important and sometimes unrecognized cause of progressive chronic kidney disease. We provide an overview of the benefits of making a genetic diagnosis, the currently available genetic testing methods and examples of diseases illustrating the impact of a genetic diagnosis. Although there are now a number of monogenic renal diseases, only a few, such as autosomal dominant polycystic kidney disease (ADPKD), are generally diagnosable without genetic testing. Complicating clinical diagnosis is that many diseases that classically have characteristic renal or extrarenal findings, often present with an incomplete or overlapping phenotype that requires additional testing to be uncovered. Advances in sequencing technology and bioinformatic processing now give us the ability to screen the entire human genome or exome or an organ-limited subset of genes quickly and inexpensively permitting the unbiased interrogation of hundreds of genes, thus removing the need for precision in clinical diagnosis prior to testing. We provide an overview of the principal phenotypes seen in chronic kidney disease with a focus on the cystic diseases and ciliopathies, the glomerular diseases, disorders of renal development and the tubulointerstitial diseases. In each of these phenotypes, we provide a listing of some of the important genes that have been identified to date, a brief discussion of the clinical diagnosis, the role of genetic testing and the differentiation of distinct genetic disorders from acquired and genetic phenocopies.

Characterization of actionable genetic alterations to guide targeted therapy for metastatic urothelial carcinoma.

407 Background: Genetic alterations predicting response to targeted therapy are an area of active interest in developing novel therapies for patients with metastatic urothelial carcinoma (mUC). With the objective of characterizing the frequency of actionable alterations (AA) and the evidence supporting targeted therapy for these AAs, we report our experience with next-generation sequencing in mUC. Methods: Patients with sequenced mUC lesions were identified from our prospectively-maintained database. All AAs with clinical or biologic evidence supporting the alteration as predicting response to targeted therapy were identified and stratified by Oncology Knowledge Base (OncoKB) level of evidence (table). The relationship between strength of evidence and administration of targeted therapy was examined. Results: Ninety-nine of 134 patients (74%) harbored at least one AA, with 162 total AAs identified. Twenty level 2B AAs were identified, reflecting the highest level evidence in this cohort, with ERBB2 amplification (9), TSC1/TSC2 (6), and BRCA1/BRCA2 mutations (3) most common. Twenty-eight level 3A, 51 level 3B, and 62 level 4 AAs were also identified. Seventeen patients received targeted therapy, which was administered with greater frequency among patients with level 3B or higher AAs (21% vs 3%). Conclusions: Most patients with mUC harbor at least one AA, suggesting multiple targeted therapeutic opportunities in mUC. These findings highlight the need for additional clinical trials and the role of genetic testing in identifying candidates for targeted therapy. [Table: see text]

Abstract P2-14-04: Genetic testing and bilateral mastectomy for women with breast cancer: Does testing matter more than the test result?

Abstract Background: Genetic testing for hereditary breast cancer may allow women with breast cancer to make informed and individualized decisions regarding breast cancer treatment and strategies to reduce the risk of contralateral breast cancer. While rates of bilateral mastectomy (therapeutic mastectomy + contralateral prophylactic mastectomy) among women with unilateral breast cancers are known to be increasing, the factors influencing this decision and the role of genetic testing are poorly understood. We examined bilateral mastectomy rates and factors associated with bilateral mastectomy among women with unilateral breast cancer. Methods: We identified patients diagnosed with unilateral breast cancer from 2000-2015 from The Health of Women Study, a cohort study led by the Dr. Susan Love Research Foundation. We calculated rates of bilateral mastectomy among women who underwent surgical treatment for breast cancer. We used multivariable logistic regression models to evaluate factors associated with bilateral mastectomy. Results: Among 2,028 patients who underwent surgery for unilateral breast cancer, 19% underwent bilateral mastectomy. Forty-one percent (n= 84 of 205) of patients who underwent testing and tested positive for a deleterious mutation underwent bilateral mastectomy, compared to 26% (n= 439 of 1,689) of women who tested negative and 12.5% (n= 274 of 2,197) of those not tested. Among those with a negative genetic test, pre-test risk of harboring a genetic mutation (based on family history and age at diagnosis) was not associated with bilateral mastectomy (p=0.250). After adjusting for race, age, level of education, and pre-test mutation risk, the odds of bilateral mastectomy were 69% higher among patients who underwent genetic testing (OR 1.69, 95% CI 1.29–2.22, p&amp;lt;0.001) versus those who did not undergo genetic testing. This finding was consistent regardless of genetic test result. Multivariable analysis of factors associated with bilateral mastectomy Odds ratio95% Confidence Intervalp valueRisk Category Low riskReference--Moderate risk1.470.96 – 2.420.078High risk1.460.92 – 2.320.111 Genetic testing1.691.29 – 2.22&amp;lt;0.001 Genetic test result Not testedReference--Positive test2.711.66 – 4.46&amp;lt;0.001Negative test1.561.18 – 2.070.002*Adjusted for age, race, and level of education. Conclusions: Genetic testing among breast cancer patients, regardless of test result or pre-test mutation risk, is significantly associated with bilateral mastectomy. Many women (˜1/4) with a negative genetic test and at low risk of hereditary breast cancer, by family history and age at diagnosis, currently undergo bilateral mastectomy with unclear benefits. Further qualitative research will aim to elucidate reasons driving choice of bilateral mastectomy among women with breast cancer. Citation Format: Verdial FC, Bartek MA, Anderson BO, Javid SH. Genetic testing and bilateral mastectomy for women with breast cancer: Does testing matter more than the test result? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-04.

Emerging Implications of Genetic Testing in Inherited Primary Arrhythmia Syndromes.

Inherited primary arrhythmia syndromes are genetically determined disorders of cardiac ion channels or ion channel macromolecular complexes usually associated with a higher risk of sudden cardiac death. These conditions have a very broad spectrum of clinical manifestations, ranging from an asymptomatic course to syncope, atrial and ventricular arrhythmias, and conduction disturbances, but may produce sudden infant death syndrome and unexplained sudden cardiac death in apparently healthy individuals. During the last 20 years, the evolving knowledge on the genetic basis of inherited arrhythmia syndromes has dramatically reshaped our understanding of these conditions and, consequently, had a great impact on patient care. Based on the knowledge of the genetic substrates, specific risk factors for individual genotypes have been identified, and various investigations have been launched with the intention of developing a gene- and even mutation-specific therapy. Preliminary results from animal studies suggest that gene therapy rescues the normal ion channel function and thereby prevents cardiac events in some primary arrhythmia syndromes, which suggests that upon appropriate validation in a clinical setting, it may become available for affected patients. The purpose of this review is to provide clinicians with a contemporary insight into the role of genetic testing in the diagnosis, therapy, and prognosis of patients with primary arrhythmia syndromes, and the clinical implications of screening family members who are at risk of sudden cardiac death.

Extrathyroidal congenital defects in children with congenital hypothyroidism - observations from a single paediatric centre in Central Europe with a review of literature.

Patients with congenital hypothyroidism (CH) can have an increased risk of occurrence of extrathyroidal defects compared to the general population, which could influence their development. The abnormalities occur mainly in organ systems whose development and function is dependent on genes that are also responsible for proper organogenesis of the thyroid gland and thyroid hormone synthesis. The aim of the study was to evaluate the frequency of extrathyroidal defects in CH patients, taking into consideration the cause of this co-occurrence and the role of genetic tests. The study included 54 newborns with positive screening test for CH based on elevated TSH level, in the years 2010-2017, from South-Eastern Poland. The data was retrieved retrospectively from patients' medical records. Twenty of 54 newborns with CH (37%) had congenital defects of other organs. In 10 (18.5%) cardiac defects were found, in 5 (9.25%) abnormal symptoms of the respiratory system, 7 (12.96%) had abnormalities of the gastrointestinal system, five (9.25%) had genitouri-nary abnormalities, 3 (5.55%) had abnormalities of the nervous system, and 6 (11.1%) had musculoskeletal abnormalities. The analysis of our data and current literature suggests that genetic factors play the most important role in the development of extrathy-roidal abnormalities in newborns with CH. Identifying the mutation causing CH, the potential defects that can accompany newborns with CH, screening could be offered for these patients in order to obtain an earlier diagnosis and implement early and appropriate treat-ment.

Is routine genetic testing warranted in head and neck paragangliomas?

Is routine genetic testing warranted in head and neck paragangliomas?

A3401 A case report of a 33-year-old man with resistant hypertension and slightly elevated cortisol and aldosterone

Objectives: Describe a unusual case of familial glucocorticoid resistance (FGR). FGR, an autosomal dominant from of monogenic hypertension, is characterized by hypertension, hypokalemia, metabolic alkalosis but no Cushing syndrome. Here, we describe the case of a 33-year-old man patient with resistant hypertension (mean blood pressure above 180/120mmHg after administration six different classes of antihypertensive agents) and slightly elevated cortisol and aldosterone but no hypokalemia, metabolic alkalosis and Cushing syndrome. Our aim was to find the cause and to control the high blood pressure of the patients. Methods: We did a series of checks and excluded primary aldosteronism and hypercortisolism and other diseases. After the DNA sequencing, we found that the patient had a mutation Pro9Arg (c.26C > G) in the NR3C1 gene and the familial glucocorticoid resistance was diagnosed. Results: After taking 0.75 mg dexamethasone at 8 o’clock and 2 kinds of antihypertensive drugs (a calcium-channel blocker plus an angiotensin-II receptor blocker), the average blood pressure of the patient was below 140/90mmHg. Conclusion: The role of genetic testing and genetic counseling in establishing the early diagnosis of FGR is important. FGR can result in resistant hypertension. C.26C > G in the NR3C1 gene that caused p.Pro9Arg is a new mutation of FGR.

The role of genetics and genomics in clinical psychiatry

The enormous successes in the genetics and genomics of many diseases have provided the basis for the advancement of precision medicine. Thus, the detection of genetic variants associated with neuropsychiatric disorders, as well as treatment outcome, has raised growing expectations that these findings could soon be translated into the clinic to improve diagnosis, the prediction of disease risk and individual response to drug therapy. In this article, we will provide an introduction to the search for genes involved in psychiatric illness and summarize the present findings in major psychiatric disorders. We will review the genetic variants in genes encoding drug metabolizing enzymes and specific drug targets which were found to be associated with variable drug response and severe side effects. We will evaluate the clinical translatability of these findings, whether there is currently any role for genetic testing and in this context, make valuable sources of information available to the clinician seeking guidance and advice in this rapidly developing field of psychiatric genetics.

Sudden cardiac death in young athletes with long QT syndrome: the role of genetic testing and cardiovascular screening.

Sudden cardiac death (SCD) of young athletes during competition or training is a tragic event. The long QT syndrome (LQTS) is an arrythmogenic disorder characterized by prolonged ventricular repolarization leading to torsade de pointes evident at electrocardiogram (ECG). Implantable cardioverter defibrillator is an option to revert ventricular fibrillation to sinus rhythm, although the implantation may result in denial of sports participations to the athlete. The authors reviewed the current literature on LQTS in young athletes, to clarify the role of different screening technologies to prevent SCD. A systematic review of the literature was performed applying the PRISMA guidelines according to the PRISMA checklist and algorithm. A comprehensive search of PubMed, Medline, CINAHL, Cochrane, Embase and Google Scholar databases using various combinations of the keywords: 'QT', 'syndrome', 'screening', 'young', 'athletes', 'genetic', 'electrocardiogram', 'echocardiography' and 'prevention' were used. Young athletes with LQTS are at greater risk of SCD. Different detection screening technologies, including ECG monitoring and genetic testing, are recommended, even though their role is not fully understood. ECG and genetic testing screening programmes could reduce the incidence of SCD, and they may positively impact on the health and safety of young athletes during sport. Further studies should analyze other modalities of screening to allow early detection of cardiovascular conditions to prevent SCD in young athletes.

Breast care nurses– a pivotal role in genetic testing in the breast clinic

Breast care nurses– a pivotal role in genetic testing in the breast clinic

Role of Genetic Testing in Male Infertility

Male-factor infertility is responsible for 30-55% of all infertility cases. The causes of male infertility include varicocele, endocrine disorders, genital tract infections, genetic disorders and idiopathic. It is estimated that genetic abnormalities contribute to 50% of male infertility. In daily practice, the diagnosis of male infertility has been based on history taking, relevant physical examination, hormone tests and basic semen analysis with a strong emphasis on the assessment of sperm concentration, motility, and morphology. Although recent development in assisted-reproductive technologies such as in vitro fertilization and intrauterine insemination increases the chance of clinical pregnancy and live birth, genetic counseling and testing should always be performed whenever genetic risks are related to the cause of infertility for the identification of possible genetic abnormalities and to assess the risk of transmitting the genetic defects to future generations. Genetic defects affect male infertility by disrupting hormonal homeostasis, spermatogenesis, and sperm quality. These genetic defects include chromosomal abnormalities (e.g. Klinefelter Syndrome), Y chromosome deletions, and cystic fibrosis transmembrane conductance regulator gene mutations. The utilization of genetic counseling and testing is also important to predict the success of sperm retrieval in men with certain genetic abnormalities. To name a few, genetic analysis at the chromosomal level (karyotyping), androgen receptor gene mutations test, cystic fibrosis test, and Y chromosome microdeletions analysis should be considered in the diagnosis of male factor infertility where genetic risks are present.

The role of genetic testing in the prevention of acute aortic dissection.

Although much has been learned about disease of the thoracic aorta, most diagnosis of thoracic aortic aneurysm (TAA) is still incidental. The importance of the genetic aspects in thoracic aortic disease is overwhelming, and today different mutations which cause TAA or alter its natural history have been discovered. Technological advance has made available testing which detects genetic mutations linked to TAA. This article analyses the genetic aspects of TAA and describes the possible role of genetic tests in the clinical setting in preventing devastating complications of TAA.

Whole-exome sequencing improves genetic testing accuracy in pulmonary artery hypertension.

Sanger sequencing, the traditional “gold standard” for mutation detection, has been wildly used in genetic testing of pulmonary artery hypertension (PAH). However, with the advent of whole-exome sequencing (WES), few studies have compared the accuracy of WES and Sanger sequencing in routine genetic testing of PAH. PAH individuals were enrolled from Fu Wai Hospital and Shanghai Pulmonary Hospital. WES was used to analyze DNA samples from 120 PAH patients whose bone morphogenetic protein receptor type 2 (BMPR2) mutation statuses had been previously studied using Sanger sequencing. The Sanger sequencing and WES agreement was 98.3% (118/120) with near-perfect agreement (κ coefficient = 0.848). There was no significant difference between the two methods on the McNemar–Bowker test (P > 0.05). Twenty-one BMPR2 mutation carriers and 99 non-carriers were detected by Sanger sequencing. Among the 21 BMPR2 carriers detected by Sanger sequencing, one variant (c.1040 T > A) was not found by WES. Among the 99 BMPR2 non-carriers, WES detected an extra mutation carrier (c.76 + 1 G > C) missed by Sanger sequencing. Both false-positive and false-negative results were highly conserved and were re-analyzed by Sanger sequencing. WES improved the accuracy of Sanger sequencing and detected 1% (1/99) false-positive and 4.8% (1/21) false-negative results of Sanger sequencing. No false-positive and false-negative results of WES were identified in our analysis. WES is non-inferior to Sanger sequencing and may play a more important role in genetic testing of PAH patients in the future.

Inherited bone marrow failure syndrome: management and diagnostic advances utilizing next-generation sequencing

Inherited bone marrow failure syndromes (IBMFS) are part of a heterogeneous disease category in which at least one hematopoietic cell lineage is reduced in the bone marrow owing to a pathogenic genetic mutation. IBMFS comprise >25 defined disease entities, including Fanconi anemia (FA), Diamond-Blackfan anemia, and dyskeratosis congenita. The diagnosis is based on hematological and physical findings with the aid of several disease-specific diagnostic tests, such as the chromosomal breakage test for FA. With recent advances in clinical molecular studies that have revealed a considerable amount of pathognomonic molecular lesions in IBMFS, the role of genetic tests has become more important in the diagnosis of these diseases. Comprehensive genetic diagnostic systems using next-generation sequencing has been developed in Japan and other countries, making it technically possible to simultaneously analyze and evaluate >100 causative genes of IBMFS, and it is expected to be widely used in clinical settings.