Genetic Testing

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. A total of 30 international groups were engaged. The entries reveal a general convergence of practices on mo...

The Homologous Recombination Deficiency (HRD) Score, determined by evaluating genomic instability through the assessment of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST), serves as a crucial biomarker for identifying patients who might benefit from targeted therapies, such as PARP inhibitors (PARPi). This study aimed to investigate the efficacy of HRD testing in high-grade serous ovarian carcinoma, tubal, and peritoneal cancer patients who are negative for somatic BRCA1 and BRCA2 mutations and to evaluate the impact of HRD status on Bevacizumab and PARPi therapy response. A cohort of 100 Romanian female patients, aged 42–77, was initially selected. Among them, 30 patients had unsuitable samples for HRD testing due to insufficient tumor content or DNA integrity. Using the OncoScan C.N.V. platform, HRD testing was successfully performed on the remaining 70 patients, with 20 testing negative and 50 testing positive for HRD. Amo...

Differences in sex development (DSD) are often correlated with a genetic etiology. This study aimed to assess the etiology of DSD patients following a protocol of genetic testing. Materials and methods. This study prospectively investigated a total of 267 patients with DSD who presented to Clinical Emergency Hospital for Children Cluj-Napoca between January 2012 and December 2019. Each patient was clinically, biochemically, and morphologically evaluated. As a first intervention, the genetic test included karyotype + SRY testing. A high value of 17-hydroxyprogesterone was found in 39 patients, in whom strip assay analysis of the CYP21A2 gene was subsequently performed. A total of 35 patients were evaluated by chromosomal microarray technique, and 22 patients were evaluated by the NGS of a gene panel. Results. The karyotype analysis established the diagnosis in 15% of the patients, most of whom presented with sex chromosome abnormalities. Genetic testing of CYP21A2 established a confi...

Lysosomal storage diseases (LSDs) are genetic disorders, clinically heterogeneous, mainly caused by defects in genes encoding lysosomal enzymes that degrade macromolecules. Several LSDs already have specific therapies that may improve clinical outcomes, especially if introduced early in life. With this aim, screening methods have been established and newborn screening (NBS) for some LSDs has been developed. Such programs should include additional procedures for the confirmation (or not) of the cases that had an abnormal result in the initial screening. We present here the methods and results of the additional investigation performed in four babies with positive initial screening results in a program of NBS for LSDs performed by a private laboratory in over 10,000 newborns in Brazil. The suspicion in these cases was of Mucopolysaccharidosis I - MPS I (in two babies), Pompe disease and Gaucher disease (one baby each). One case of pseudodeficiency for MPS I, 1 carrier for MPS I, 1 case...

ABSTRACTMaternal plasma contains circulating cell‐free DNA fragments originating from both the mother and the placenta. The proportion derived from the placenta is known as the fetal fraction. When measured between 10 and 20 gestational weeks, the average fetal fraction in the maternal plasma is 10% to 15% but can range from under 3% to over 30%. Screening performance using next‐generation sequencing of circulating cell‐free DNA is better with increasing fetal fraction and, generally, samples whose values are less than 3% or 4% are unsuitable. Three examples of the clinical impact of fetal fraction are discussed. First, the distribution of test results for Down syndrome pregnancies improves as fetal fraction increases, and this can be exploited in reporting patient results. Second, the strongest factor associated with fetal fraction is maternal weight; the false negative rate and rate of low fetal fractions are highest for women with high maternal weights. Third, in a mosaic, the de...

Spondyloarthritides represents a group of inflammatory disorders that have in common a correlation with the MHC class I molecule, HLA-B27. Having the knowledge of this correlation, these diseases are
traditionally believed to represent aberrations of adaptive immunity. Nevertheless, recent data are questioning this presumption and evoking the probability that innate immunity might be more significant as far as etiopathogenesis is considered as compared to earlier researchers (Figure 1). Here we present a case report of a patient who had persistent pains with rheumatoid factor (RF) negative but HLAB27 positive who responded to bolus methyl prednisolone after depotmedral and then responded
to wysolne with hydroxychloroquine 400 mg bd along with dabigartan.

Anatomically modern humans replaced Neanderthals in Europe around 40,000 years ago. The demise of the Neanderthals and the nature of the possible relationship with anatomically modern humans has captured our imagination and stimulated research for more than a century now. Recent chronological studies suggest a possible overlap between Neanderthals and anatomically modern humans of more than 5,000 years. Analyses of ancient genome sequences from both groups have shown that they interbred multiple times, including in Europe. A potential place of interbreeding is the notable Palaeolithic site of Riparo Mezzena in Northern Italy. In order to improve our understanding of prehistoric occupation at Mezzena, we analysed the human mandible and several cranial fragments from the site using radiocarbon dating, ancient DNA, ZooMS and isotope analyses. We also performed a more detailed investigation of the lithic assemblage of layer I. Surprisingly we found that the Riparo Mezzena mandible is no...

Purpose The purpose of this research is to study the clinical outcomes using a next-generation sequencing-based protocol allowing for simultaneous testing of mutations in the beta thalassemia (HBB) gene, including single nucleotide polymorphism (SNP) markers for PGT-M along with low-pass whole genome analysis of chromosome aneuploidies for PGT-A. Methods A combined PGT-M (thalassemia) plus PGT-A system was developed for patients undergoing IVF in Vietnam. Here we developed a system for testing numerous thalassemia mutations plus SNP-based testing for backup mutation analysis and contamination control using next-generation sequencing (NGS). Low -pass next-generation sequencing was used to assess aneuploidy in some of the clinical PGT cases. Patients underwent IVF followed by embryo biopsy at the blastocyst stage for combined PGT-A/M. Results Two cases have completed the entire process including transfer of embryos, while a further nine cases have completed the IVF and PGT-M/A analysi...

Public attitudes about genetics appear to depend on the local context. We analyzed survey responses obtained in 2015 from 293 residents of Luján, a city in the province of Buenos Aires, Argentina, who self-assessed their knowledge about genetics and their trust in genetic tests. The survey integrated a larger research project for which consenting adult participants shared demographic and genealogical information and provided saliva samples for genetic ancestry analyses. Participants reported little knowledge but high trust in genetic testing when questioned about knowledge and trust. Well-known media stories of DNA-based forensic genetic investigations to identify the victims of state repression during the military dictatorship may have contributed to the high self-assessment of their genetic knowledge expressed by some participants, regardless of educational attainment. Our analysis provides information that could be used as a baseline to begin unraveling the current level of publi...

Opitz G/BBB syndrome is a heterogeneous disorder characterised by variable expression of midline defects including cleft lip and palate, hypertelorism, laryngealtracheoesophageal anomalies, congenital heart defects, and hypospadias. The X-linked form of the condition has been associated with mutations in the MID1 gene on Xp22. The autosomal dominant form has been linked to chromosome 22q11.2, although the causative gene has yet to be elucidated. In this study, we performed whole exome sequencing on DNA samples from a three-generation family with characteristics of Opitz G/BBB syndrome with negative MID1 sequencing. We identified a heterozygous missense mutation c.1189A>C (p.Thr397Pro) in SPECC1L, located at chromosome 22q11.23. Mutation screening of an additional 19 patients with features of autosomal dominant Opitz G/BBB syndrome identified a…

Pre-implantation genetic diagnosis (PGD) has changed the landscape of clinical genetics by helping families reduce the transmission of monogenic disorders. However, given the high prevalence of embryonic aneuploidy, particularly in patients of advanced reproductive age, unaffected embryos remain at high risk of implantation failure or pregnancy loss due to aneuploidy. 24-chromosome aneuploidy screening has become widely utilized in routine in vitro fertilization (IVF) to pre-select embryos with greater pregnancy potential, but concurrent 24-chromosome aneuploidy screening has not become standard practice in embryos biopsied for PGD. We performed a retrospective cohort study of patients who underwent PGD with or without 24-chromosome aneuploidy screening to explore the value of concurrent screening. Among the PGD + aneuploidy-screened group (n = 355 blastocysts), only 25.6 % of embryos were both Single Gene Disorder (SGD)-negative (or carriers) and euploid; thus the majority of embry...

Létrehoztunk egy olyan internetes adatbázist, mellyel a tremorral járó idegrendszeri betegségekben szenvedők adatainak feldolgozását követően homogén betegcsoportok alakíthatók ki. Tremorometriás vizsgálatokkal igazoltuk, hogy a tremor frekvencia-paraméterei Parkinson-betegségben jellegzetesen aszimmetrikusak, míg esszenciális tremorban (ET) mindkét oldalon hasonló eltérést mutatnak, függetlenül a tremor intenzitásától. Ez arra utal, hogy Parkinson-kórban a két féltekében egymástól függetlenül, míg ET-ban egymással kapcsoltan működő tremorgenerátorkör feltételezhető. Kimutattuk, hogy ET-ban az kézmozgások ritmusossága mindkét oldalon zavart szenved, mely cerebelláris működészavart igazol, és alátámasztja, hogy az ET nem monoszimptómás betegség, hanem több funkcionális rendszert érintő komplex kórkép. Bizonyítottuk, hogy a krónikus valproát kezelés még azokban a betegekben is módosítja a tremor frekvencia-teljesítmény spektrumot, akiknél nincsen klinikailag kimutatható intenzitású tr...

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two‐sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom) = 1.78, 95% confidence interval (CI) = 1.26–2.52, p = 1.19 × 10−3 and ORdom = 1.74, 95% CI = 1.15–2.63, p = 8.57 × 10−3, respectively). Neit...

There are several instruments to assess how patients evaluate their medical treatment choice. These are used to evaluate decision aids. Our objective is to investigate which psychological factors play a role when patients evaluate their medical treatment choices. A pool of 36 items was constructed, covering concepts such as uncertainty about and satisfaction with the decision, informed choice, effective decision making, responsibility for the decision, perceived riskiness of the choice, and social support regarding the decision. This pool was presented to patients at high risk for breast and ovarian cancer, awaiting a genetic test result, and facing the choice between prophylactic surgery or screening. Additional measures were assessed for validation purposes. Factor and Rasch analyses were used for factor and item selection. Construct validity of emerging scales was assessed by relating them with the additional measures. Three factors summarised the psychological factors concerning...

We use novel data to study genetic testing among individuals at risk for Huntington disease (HD), a hereditary disease with limited life expectancy. Although genetic testing is perfectly predictive and carries little economic cost, presymptomatic testing is rare. Testing rates increase with increases in ex ante risk of having HD. Untested individuals express optimistic beliefs about their health and make decisions (e.g., retirement) as if they do not have HD, even though individuals with confirmed HD behave differently. We suggest that these facts can be reconciled by an optimal expectations model (Brunnermeier and Parker 2005). (JEL D84, I12)

The basic aim of this study was to evaluate the current accepted standard clinical endpoint for the earliest-studied HD participants likely to be recruited into clinical trials. As the advent of genetic testing for HD, it is possible to identify gene carriers before the diagnosis of disease, which opens up the possibility of clinical trials of disease-modifying treatments in clinically asymptomatic persons. Current accepted standard clinical endpoints were examined as part of a multinational, 32-site, longitudinal, observational study of 786 research participants currently in the HD prodrome (gene-positive but not clinically diagnosed). Clinical signs and symptoms were used to prospectively predict functional loss as assessed by current accepted standard endpoints over 8 years of follow-up. Functional capacity measures were not sensitive for HD in the prodrome; over 88% scored at ceiling. Prospective evaluation revealed that the first functional loss was in their accustomed work. In...

Potential discrimination from genetic testing may undermine technological advances for health care. Researching long‐term consequences of testing for genetic conditions that may lead to discrimination is a public health priority. The consequences of genetic discrimination generate social, health, and economic burdens for society by diminishing opportunities for at‐risk individuals in a range of contexts. The current study objective was to investigate perceptions of genetic stigmatization and discrimination among persons who completed predictive testing for Huntington's disease (HD). Using semi‐structured interviews and computerized qualitative analysis, the perceptions of 15 presymptomatic persons with a positive gene test predicting HD were examined with regard to differential treatment following testing. The sample comprised 11 women and 4 men, mostly married (73%), aged between 22 and 62 years, with an average education of 14.6 years (SD ± 2.57) and residing in urban, rural a...

Genetic discrimination—defined as the denial of rights, privileges, or opportunities or other adverse treatment based solely on genetic information (including family history)—is an important concern to patients, healthcare professionals, lawmakers, and family members at risk for carrying a deleterious gene. Data from the United States, Canada, and Australia were collected from 433 individuals at risk for Huntington disease (HD) who have tested either positive or negative for the gene that causes HD and family members of affected individuals who have a 50% risk for developing the disorder but remain untested. Across all three countries, a total of 46.2% of respondents report genetic discrimination or stigma based on either their family history of HD or genetic testing for the HD gene mutation. We report on the overall incidence of discrimination and stigma in the domains of insurance (25.9%), employment (6.5%), relationships (32.9%), and other transactions (4.6%) in the United States...

Genetic discrimination may be experienced in the day‐to‐day lives of people at risk for Huntington disease (HD), encompassing occurrences in the workplace, when seeking insurance, within social relationships, and during other daily encounters. At‐risk individuals who have tested either positive or negative for the genetic expansion that causes HD, as well as at‐risk persons with a 50% chance for developing the disorder but have not had DNA testing completed the International RESPOND‐HD (I‐RESPOND‐HD) survey. One of the study's purposes was to examine perceptions of genetic stigmatization and discrimination. A total of 412 out of 433 participants provided narrative comments, and 191 provided related codable narrative data. The core theme, Information Control, refers to organizational policies and interpersonal actions. This theme was found in narrative comments describing genetic discrimination perceptions across employment, insurance, social, and other situations. These reports ...