Comprehensive Genetic Assessment Research Articles

Genomic Insights and Conservation Priorities for Kongshan Cattle: A Whole-Genome Resequencing Approach.

Kongshan Cattle, indigenous to Sichuan Province and recognized as China's 56th local cattle breed in 2024, exhibit unique adaptations including superior resistance to harsh conditions. Despite a declining population due to the influx of foreign breeds, there is a significant focus on preserving their genetic diversity through advanced genomic techniques. This study utilized whole-genome resequencing, a cost-effective and information-rich method, to perform a comprehensive genetic assessment of the Kongshan Cattle. High-quality resequencing data yielded an average of 17.5 billion clean bases per sample, with high proportions of Q20 and Q30 bases and a balanced GC content. SNP analysis revealed an average of 14 million SNPs per sample, with a notable transition-to-transversion ratio and a significant portion of heterozygosity. Further analysis of genomic and coding regions identified substantial insertions and deletions, particularly in coding sequences affecting gene functionality. A detailed examination of these genetic variations highlighted genes, including NEIL2 and PNKP, which are integral to stress resistance pathways, indicating potential adaptive advantages. This study not only underscores the genetic diversity of Kongshan Cattle but also contributes to broader efforts in germplasm conservation.

Germline variant profiling of CHEK2 sequencing variants in breast cancer patients

The cell cycle checkpoint kinase 2 (CHEK2) is a tumor suppressor gene coding for a protein kinase with a role in the cell cycle and DNA repair pathways. Variants within CHEK2 are associated with an increased risk of developing breast, colorectal, prostate and several other types of cancer. Comprehensive genetic risk assessment leads to early detection of hereditary cancer and provides an opportunity for better survival. Multigene panel screening can identify the presence of pathogenic variants in hereditary cancer predisposition genes (HCPG), including CHEK2. Multigene panels, however, also result in large quantities of genetic data some of which cannot be interpreted and are classified as variants of uncertain significance (VUS). A VUS provides no information for use in medical management and leads to ambiguity in genetic counseling. In the absence of variant segregation data, in vitro functional analyses can be used to clarify variant annotations, aiding in accurate clinical management of patient risk and treatment plans. In this study, we performed whole exome sequencing (WES) to investigate the prevalence of germline variants in 210 breast cancer (BC) patients and conspicuously among the many variants in HCPGs that we found, we identified 16 individuals with non-synonymous or frameshift CHEK2 variants, sometimes along with additional variants within other BC susceptibility genes. Using this data, we investigated the prevalence of these CHEK2 variants in African American (AA) and Caucasian (CA) populations identifying the presence of two novel frameshift variants, c.1350delA (p.Val451Serfs*18) and c.1528delC (p.Gln510Argfs*3) and a novel missense variant, c262C>T (p.Pro88Ser). Along with the current clinical classifications, we assembled available experimental data and computational predictions of function for these CHEK2 variants, as well as explored the role these variants may play in polygenic risk assessment.

Loneliness as neurobehavioral issue in amyotrophic lateral sclerosis.

In elderly people loneliness represents a risk factor for dementia and may negatively impact on mental and physical health. The specific contribute of loneliness to cognitive and behavioral functioning have not yet been determined in amyotrophic lateral sclerosis (ALS). Our hypothesis was that loneliness may be related to motor dysfunction with a negative impact on cognitive and behavioral decline, possibly related to specific cortical involvement. In 200 ALS patients (ALSpts) and 50 healthy controls (HCs) we measured loneliness, mood, and quality of life (QoL). ALSpts underwent comprehensive clinical, genetic, and neuropsychological assessment to define phenotypes. Seventy-seven ALSpts performed 3T MRI scans to measure cortical thickness. Between-group, partial correlation and regression analyses were used to examined clinical, neuropsychological, and cortical signatures of loneliness. Feelings of loneliness were documented in 38% of ALSpts (ALS/L+pts) and in 47% of HCs. In both groups loneliness was associated with anxiety (P < 0.001), depression (P ≤ 0.005), and poor QoL (P < 0.001). ALS/L+pts had similar motor dysfunctions and cognitive abilities than non-lonely ALSpts, but distinct behavioral profiles (P ≤ 0.005) and frontoparietal involvement (P < 0.05). Loneliness in ALS is related to behavioral changes, apathy, and emotional dysregulation (P < 0.001). Our cross-sectional study indicates that, in ALS, the satisfaction of social environment is associated with a sense of life well-being that is not limited to the motor status, proving instead that loneliness can impact on disease-related neurobehavioral changes with a possible flashback on brain architecture. This suggests that sociality could promote personal resilience against behavioral and affective decline in ALS.

Subspecies inflation hampers conservation efforts: a case study on wall lizards

Abstract The common practice of using subspecies as conservation targets raises the question of whether efforts are focused on preserving conspicuous components of the species’ phenotypic variability rather than evolutionarily significant units. To address this question, in this study we performed a comprehensive morphological and genetic assessment on all the subspecies of wall lizard described for the Aeolian Archipelago (Italy) to determine whether they represent distinct evolutionary lineages and/or discrete phenotypic partitions. Further, we applied a monophyly test to 70 subspecies belonging to seven wall lizard species occurring in Italy, based on our results and on previous phylogeographic studies. We found that none of the Aeolian subspecies represents a distinct evolutionary lineage, despite some morphological differentiation of island populations across the archipelago, suggesting a very recent origin of island populations and of the observed phenotype variation. Across seven wall lizard species, tests revealed that lizard subspecies rarely (&amp;lt; 9% of cases) match evolutionary units. This study demonstrates that intraspecific taxonomy of wall lizards is a poor predictor of phylogeographic partitions and evolutionary units, and therefore of limited use (if not dangerous) for defining conservation and management units. A better approach would be relying on the integration of genomic and phenotypic data to assess the evolutionary significance and conservation value of phenotypic and genetic units within species.

Occult Macular Dysfunction Syndrome: Identification of Multiple Pathologies in a Clinical Spectrum of Macular Dysfunction with Normal Fundus in East Asian Patients: EAOMD Report No. 5.

Occult macular dystrophy (OMD) is the most prevalent form of macular dystrophy in East Asia. Beyond RP1L1, causative genes and mechanisms remain largely uncharacterised. This study aimed to delineate the clinical and genetic characteristics of OMD syndrome (OMDS). Patients clinically diagnosed with OMDS in Japan, South Korea, and China were enrolled. The inclusion criteria were as follows: (1) macular dysfunction and (2) normal fundus appearance. Comprehensive clinical evaluation and genetic assessment were performed to identify the disease-causing variants. Clinical parameters were compared among the genotype groups. Seventy-two patients with OMDS from fifty families were included. The causative genes were RP1L1 in forty-seven patients from thirty families (30/50, 60.0%), CRX in two patients from one family (1/50, 2.0%), GUCY2D in two patients from two families (2/50, 4.0%), and no genes were identified in twenty-one patients from seventeen families (17/50, 34.0%). Different severities were observed in terms of disease onset and the prognosis of visual acuity reduction. This multicentre large cohort study furthers our understanding of the phenotypic and genotypic spectra of patients with macular dystrophy and normal fundus. Evidently, OMDS encompasses multiple Mendelian retinal disorders, each representing unique pathologies that dictate their respective severity and prognostic patterns.

Assessment of Genetic Diversity and Genetic Structure of Saussurea medusa (Asteraceae), a "Sky Island" Plant in the Qinghai-Tibet Plateau, Using SRAP Markers.

Saussurea medusa Maxim. is a typical "sky island" species and one with the highest altitude distributions among flowering plants. The present study aimed at analyzing the genetic diversity and population structure of 300 S. medusa accessions collected from 20 populations in the Qilian Mountains in the northeastern Qinghai-Tibet Plateau (QTP), using sequence-related amplified polymorphism (SRAP) markers. A total of 14 SRAP primer combinations were employed to analyze genetic diversity and population structure across all accessions. Out of 511 amplified bands, 496 (97.06%) were polymorphic. The populations in the eastern Qilian Mountains had significantly higher genetic diversity than those in the central and western groups. Population structure analysis revealed greater genetic differentiation among populations with a Gst of 0.4926. UPGMA-based clustering classified the 300 S. medusa accessions into 3 major clusters, while the Bayesian STRUCTURE analysis categorized them into 2 groups. Correlation analyses showed that the genetic affinity of the populations was based on differences in geographical distance, moisture conditions, and photothermal conditions between the habitats. This study represents the first comprehensive genetic assessment of S. medusa and provides important genetic baseline data for the conservation of the species.

Исследования потомства плюсовых деревьев Pinus sylvestris L. в испытательных культурах первой генерации

The article describes the characteristics of the seed progeny of plus trees Pinus sylvestris L. at the age of 37, he was born in the Akmola region of Northern Kazakhstan. The purpose of the study is to carry out a preliminary selection and genetic assessment of the plus pine trees based on the results of testing their semi-plus offspring of the first generation. The safety of test cultures is 57.5%. The research covered 73 families of half-sibs, the total sample was 5,553 trees. It was found that in terms of height, more than half of the families (56.2%) had an excess over the control. However, only 28.8% of families were significantly higher than the control, the breeding effect of which was within 6.0%. The average trunk diameter of these families exceeded the control by 3.9%. Of these families, less than a quarter (23.8%) significantly exceeded the control value by 14.9%. As a result, 5 families (1k, 13k, 42, 38, 3k) were classified as the most productive. When assessing the sanitary condition of half-siblings, 2 families (51k and 16k) were classified as weakened, and the remaining families were classified as healthy. When assessing qualitative characteristics, clustering was carried out, with the help of which the studied families were divided into 3 main groups. The weakened families were united into a separate cluster. According to the results of score assessments, the trees of these families had poor trunk quality and weak stability. The second and third clusters are formed from families with high average grades and good condition. However, the families of the third cluster, according to the results of ball scores, are the most stable, differ in greater straightness and dense bifurcation. It was found that according to the results of a comprehensive selection and genetic assessment of the offspring of P. sylvestris plus trees of the first generation, 6.9% of families (1k, 13k, 42, 38, 3k) were classified as promising.

Population structure and genetic connectivity reveals distinctiveness of Irish harbour seals (Phoca vitulina) and implications for conservation management

Abstract The identification of discrete intraspecific units, such as genetically informed management units (MUs), is important to effectively develop and implement conservation strategies for protected species. Harbour seals (Phoca vitulina) occurring in Irish waters are currently viewed as a single nationwide panmictic population (and hence MU), although this assumption is not based on any knowledge of population structure because of the lack of available genetic data. Thus, the present study used mitochondrial control region sequences and between nine and 11 microsatellite loci from harbour seals from Ireland and Northern Ireland (up to n = 123) and adjacent UK/European waters (up to n = 289) to provide insights into the genetic population structure and diversity of harbour seals in the areas studied. Within the island of Ireland, genetic analyses revealed the presence of three genetically distinct local populations, characterized by high genetic diversity, hereby defined as: East Ireland (EI), North‐west &amp; Northern Ireland (NWNI), and South‐west Ireland (SWI). Using previously published and newly generated data, a subsequent wider scale analysis revealed that the EI and SWI local populations were genetically distinct from neighbouring UK/European areas, whereas seals from the NWNI area could not be distinguished from a previously identified Northern UK metapopulation. Migration rate estimates showed that NWNI receives migrants from North‐west Scotland, with NWNI acting as a genetic source for both SWI and EI. The present study provides the most comprehensive genetic assessment of harbour seals in European waters to date, with findings indicating that conservation strategies for harbour seals in Irish waters should be amended to accommodate at least three genetically distinct local populations/MUs. The use of approaches considering both ecological and genetic parameters is recommended for future assessments and delineation of units of ecological relevance for conservation management purposes.

The clinical spectrum and diagnosis of Rubenstein-Taybi syndrome

Genomic medicine has enabled molecular diagnosis for a variety of conditions, however the question of who and when to sequence continues to evolve. In this volume of The Journal, Levetan et al. report an international cross-sectional analysis from 311 individual with a diagnosis of Rubenstein-Taybi syndrome (RSTS), a rare genetic disorder typically characterized by short stature, broad thumbs, and distinctive facial features. As the features of RSTS may not be obvious during the neonatal period, the authors investigated when and how a diagnosis was made and assessed associated systemic involvement in the newborn period. Their analysis revealed several important features. First, prenatal ultrasound findings were present in 94 (30%) cases, including non-specific findings such as polyhydramnios and growth restriction, yet only two participants received prenatal molecular diagnoses. This portends the potential utility of a comprehensive prenatal screen for genetic conditions, the results of which could modulate pregnancy and postnatal care. Second, in 59 (22.1%) of cases, concerns were first noted by parents, not healthcare providers. This highlights the importance of a family-centered approach and basic familiarity with the spectrum of rare disorders that can present in the neonatal period. Third, the study revealed that most RSTS in this cohort was diagnosed in the first month of life (85.9%), even though <1% of cases were diagnosed prenatally. This manuscript exemplifies how data aggregation in rare disorders elucidates the spectrum of clinical presentations and provides evidence for the utility of comprehensive genetic assessment, especially in the prenatal period. Article page 106 ▸ Rubinstein-Taybi Syndrome: Presentation in the First Month of LifeThe Journal of PediatricsVol. 249PreviewThis web-based survey of 311 respondents from 25 countries provides additional information about the early presentation of Rubinstein–Taybi syndrome. Most (86%) infants present during the neonatal period, with 69% of these within 24 hours of life. Prolonged hospital stay is common (61%). Full-Text PDF

Phylogeographic and phenotypic divergence between two subspecies of Testudo graeca (T. g. buxtoni and T. g. zarudnyi) across their contact zone in Iran

Contact zones are considered as windows into the evolutionary process, allowing identification of factors influencing the evolutionary forces. Here, we combined phylogenetic and morphometric analyses to explore the evolutionary process affecting the taxonomic pattern of two subspecies of Testudo graeca (T. g. buxtoni and T. g. zarudnyi) across their contact zone in Central Iran. Our results showed high levels of phylogeographic and phenotypic variation in the contact zone. Two monophyletic clades including, clade 1 (T. g. zarudnyi) and clade 2 (T. g. buxtoni) were identified. Furthermore, four distinct subclades were found in T. g. buxtoni, across a wide geographic range. Divergence time analysis suggests that the two subspecies diverged from one another after the uplifting of the Zagros Mountains during the early Pliocene. Using neutrality tests and mismatch distribution analysis, we found no evidence of recent population expansion. Morphological associations among geographical populations in the contact zone found more distinctions, with some significant adaptive and non-adaptive morphological variations in these populations. These distinctive morphological populations can be considered as management units (MUs) to conserve the evolutionary potential of this species. Finer scale evolutionary studies are required to address the southern part of the Zagros mountain range, where the overlapping of mitochondrial clades and subclades has occurred. Such information is essential for effective conservation of T. graeca populations, preventing translocation or mixing of individuals without comprehensive genetic and morphological assessment.

Whole-genome risk prediction of common diseases in human preimplantation embryos

Preimplantation genetic testing (PGT) of in-vitro-fertilized embryos has been proposed as a method to reduce transmission of common disease; however, more comprehensive embryo genetic assessment, combining the effects of common variants and rare variants, remains unavailable. Here, we used a combination of molecular and statistical techniques to reliably infer inherited genome sequence in 110 embryos and model susceptibility across 12 common conditions. We observed a genotype accuracy of 99.0–99.4% at sites relevant to polygenic risk scoring in cases from day-5 embryo biopsies and 97.2–99.1% in cases from day-3 embryo biopsies. Combining rare variants with polygenic risk score (PRS) magnifies predicted differences across sibling embryos. For example, in a couple with a pathogenic BRCA1 variant, we predicted a 15-fold difference in odds ratio (OR) across siblings when combining versus a 4.5-fold or 3-fold difference with BRCA1 or PRS alone. Our findings may inform the discussion of utility and implementation of genome-based PGT in clinical practice.

Comprehensive Genetic Assessment from Genetic Diagnosis to Prognostic Prediction in Small for Gestational Age Newborns: A Retrospective Cohort Study

Comprehensive Genetic Assessment from Genetic Diagnosis to Prognostic Prediction in Small for Gestational Age Newborns: A Retrospective Cohort Study

Polygenic risk scores predict cognitive impairment as measured by the Preclinical Alzheimer Cognitive Composite (PACC) score in the ADNI cohort

AbstractBackgroundThe development of diagnostic tools to identify disease risk is critical to enable selection of suitable individuals for inclusion in clinical trials and cohort studies. The utility of Polygenic Risk Scores (PRS) is gaining increasing attention for generating an individual genetic risk profile and subsequent estimation of future disease risk in Alzheimer’s Disease. We have previously reported on the performance of our PRS to differentiate Alzheimer Disease cases from healthy controls in the ADNI cohort and also cognitive decline using ADAS‐Cog13 and CDR‐SB scales. In this work we have analysed whether the PRS is able to predict more subtle changes in cognition by using PACC scores of ADNI cohort participants. The aim being to demonstrate the utility of PRS approaches in longitudinal studies and future clinical practice.MethodThis study explored the performance of the Cytox genoSCORE™ PRS algorithm as measured using a receiver operating characteristic curve (ROC) curve to predict a PACC score of &lt;‐1, as measured upon entry into the study. 724 subjects who entered the study as either cognitively normal, or with a diagnosis of mild cognitive impairment are included in the analysis based on availability of PACC scores and of genetic data in the ADNI database. Further analyses to predict longitudinal changes in PACC have also been performed.ResultIn a population of 724 individuals genoSCORE™ has an accuracy as measured by area under the curve (AUC) of 65.6% in predicting those individuals with cognitive impairment as measured by the PACC scale (threshold &lt;‐1). A similar analysis performed using age as the predictor in the same group showed no discernible correlation with lower PACC scores.ConclusionIdentifying individuals of higher risk for cognitive decline due to Alzheimer’s Disease irrespective of their baseline cognitive performance will allow clinical trialists to enrich their studies with more appropriate patients. In addition, use of such risk evaluation techniques in clinical practice will enable clinicians to make more informed decisions on how to manage their patients. Cytox is able to provide a robust end‐to‐end process to provide this comprehensive genetic risk assessment.

Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing

BackgroundDespite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking. ObjectiveTo define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing. Design, setting, and participantsWe retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020. Outcome measurement and statistical analysisThe frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher’s exact or χ2 test). Results and limitationsOf 232 patients with early-onset RCC, 50% had non–clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non–RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non–clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non–RCC-associated genes was 0% and 9.9%, respectively. ConclusionsPatients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing. Patient summaryIn this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.

Population Genetics of a Translocated Population of Mottled Ducks and Allies

ABSTRACTTranslocating species is an important management tool to establish or expand the range of species. Success of translocations requires an understanding of potential consequences, including whether a sufficient number of individuals were used to minimize founder effects and if interspecific hybridization poses a threat. We provide an updated and comprehensive genetic assessment of a 1970s–1980s translocation and now established mottled duck (Anas fulvigula) population in South Carolina, USA. In addition to examining the population genetics of these mottled ducks, we simulated expected genetic assignments for generational hybrids (F1–F10), permitting formal purity assignment across samples to identify true hybrids and establish hybridization rates. In addition to wild mallards (A. platyrhynchos), we tested for presence of hybrids with migrant American black ducks (A. rubripes) and released domestic game‐farm mallards (A. p. domesticus). We used wild reference populations of North American mallard‐like ducks and sampled game‐farm mallards from 2 sites in South Carolina that could potentially interbreed with mottled ducks. Despite 2 different subspecies of mottled duck (Florida [A. f. fulvigula] and the Western Gulf Coast [A. f. maculatlus]) used in original translocations, we determined the gene pool of the Western Gulf Coast mottled duck was overwhelmingly represented in South Carolina's current population. We found no evidence of founder effects or inbreeding and concluded the original translocation of 1,285 mottled ducks was sufficient to maintain current genetic diversity. We identified 7 hybrids, including an F1 and 3 late‐staged (i.e., F2–F3 backcrosses) mottled duck × black duck hybrids, 1 F2‐mottled duck backcrossed with a wild mallard, and 2 F3‐mottled ducks introgressed with game‐farm mallard. We estimated a 15% hybridization rate in our mottled duck dataset; however, the general lack of F1 and intermediate hybrids were inconsistent with scenarios of high hybridization rates or presence of a hybrid swarm. Instead, our results suggested a scenario of infrequent interspecific hybridization between South Carolina's mottled ducks and congeners. We concluded that South Carolina's mottled duck population is sufficiently large now to absorb current hybridization rates because 85% of sampled mottled ducks were pure. These results demonstrate the importance in managing and maintaining large parental populations to counter hybridization. As such, future population management of mottled ducks in South Carolina will benefit from increased geographical and continued sampling to monitor hybridization rates with closely related congeners. We also suggest that any future translocations of mottled ducks to coastal South Carolina should originate from the Western Gulf Coast. © 2021 The Wildlife Society.

HPO-driven virtual gene panel: a new efficient approach in molecular autopsy of sudden unexplained death

BackgroundMolecular autopsy represents an efficient tool to save the diagnosis in up to one-third of sudden unexplained death (SUD). A defined gene panel is usually used for the examination. Alternatively, it is possible to carry out a comprehensive genetic assessment (whole exome sequencing, WES), which also identifies rare, previously unknown variants. The disadvantage is that a dramatic number of variants must be assessed to identify the causal variant. To improve the evaluation of WES, the human phenotype ontology (HPO) annotation is used internationally for deep phenotyping in the field of rare disease. However, a HPO-based evaluation of WES in SUD has not been described before.MethodsWe performed WES in tissue samples from 16 people after SUD. Instead of a fixed gene panel, we defined a set of HPO terms and thus created a flexible “virtual gene panel”, with the advantage, that recently identified genes are automatically associated by HPO terms in the HPO database.ResultsWe obtained a mean value of 68,947 variants per sample. Stringent filtering ended up in a mean value of 276 variants per sample. Using the HPO-driven virtual gene panel we developed an algorithm that prioritized 1.4% of the variants. Variant interpretation resulted in eleven potentially causative variants in 16 individuals.ConclusionOur data introduce an effective diagnostic procedure in molecular autopsy of SUD with a non-specific clinical phenotype.

Identifying individuals with mild cognitive impairment who are at higher genetic risk of further substantial cognitive decline due to Alzheimer's disease

AbstractBackgroundThe development of tools to identify disease risk is critical to enable selection of suitable individuals for inclusion in clinical trials and cohort studies. The utility of Polygenic Risk Scores (PRS) is gaining increased attention for generating genetic risk profiles and subsequent estimation of future disease risk in Alzheimer’s Disease. We have previously reported on the performance of our PRS to differentiate AD cases from healthy controls in the ADNI cohort using individual's most recent diagnosis. In this work we have analysed whether the PRS is able to predict substantial cognitive decline towards an AD phenotype of individuals with MCI at the point of entering the study. The aim being to demonstrate the utility of PRS approaches in longitudinal studies and future clinical practice.MethodThis longitudinal study explored the performance of the Cytox genoSCORE™ PRS algorithm as measured using ROC, AUC analysis when predicting a change in ADAS‐Cog13 score of 5,10 and 15 points at 2, 3 and 4‐year assessment timepoints. Subjects are included in the analysis based on availability of ADAS‐Cog13 data at those timepoints and availability of genetic data in the ADNI database. Change in cognition as measured by ADAS‐Cog13 was used instead of change of diagnosis given the broad spectrum of baseline cognitive performance in those individuals with MCI.ResultIndividuals with low PRS clearly have a lower likelihood of experiencing substantial cognitive decline (&gt;10 points on the ADAS‐Cog13 scale over 4 years) than those individuals with higher PRS. In a population of 285 individuals with an MCI diagnosis at baseline genoSCORE™ has an accuracy as measured by area under the curve of 74% in predicting those individuals who declined substantially over 4 years, with very high negative predictive values.ConclusionIdentifying individuals of higher risk for substantial cognitive decline towards AD will allow clinical trialists to enrich their studies with more appropriate patients. In addition, use of such risk evaluation techniques in clinical practice will enable clinicians to make more informed decisions on how to manage their patients. Cytox is able to provide a robust end‐to‐end process to provide this comprehensive genetic risk assessment.

Genetic profiling of primary and secondary tumors from patients with lung adenocarcinoma and bone metastases reveals targeted therapy options

BackgroundPatients newly diagnosed with lung adenocarcinoma with bone metastases (LABM) have poor survival rates after treatment with conventional therapies. To improve outcomes, we retrospectively investigated whether the application of a more comprehensive genetic test of tumor biopsies samples from LABM patients could provide the basis for treatment with more effective tyrosine kinase inhibitors (TKIs) regimens.MethodsFine needle biopsies were taken from the primary tumor (PT) and a secondary bone metastasis (BM) of 17 LABM patients before treatment. Simple genetic profiles for selecting therapies were initially obtained using an ARMS-PCR test for EGFR and ALK fusion mutations. More detailed genetic profiles of somatic exon SNVs and CNVs in 457 cancer-related genes were retrospectively derived using capture single molecule amplification and resequencing technology (capSMART).ResultsARMS-PCR identified 14 EGFR positive, 3 EGFR negative and 1 ALK fusion positive patient. A therapy regimen incorporating TKIs Gefitinib and Crizotinib was offered to the EGFR and ALK fusion positive patients, respectively. With the exception of two patients, molecular profiling of matching PT and BM biopsies identified a highly shared somatic variant fingerprint, although the BMs exhibited additional genomic instability. In six of 13 EGFR positive patients and in all three EGFR negative patients, examination of the genetic profiles identified additional clinically significant mutations that are known or experimental drug targets for treatment of lung cancer.ConclusionOur findings firstly suggest that treatment regimens based on comprehensive genetic assessment of newly diagnosed LABM patients should target both the PT and secondary BMs, including rogue clones with potential to form new BMs. Second, the additional information gained should allow clinicians to design and implement more personalized treatment regimens and potentially improve outcomes for LABM patients.

The Multifaced Perspectives of Genetic Testing in Pediatric Cardiomyopathies and Channelopathies.

Pediatric inherited cardiomyopathies (CMPs) and channelopathies (CNPs) remain important causes of death in this population, therefore, there is a need for prompt diagnosis and tailored treatment. Conventional evaluation fails to establish the diagnosis of pediatric CMPs and CNPs in a significant proportion, prompting further, more complex testing to make a diagnosis that could influence the implementation of lifesaving strategies. Genetic testing in CMPs and CNPs may help unveil the underlying cause, but needs to be carried out with caution given the lack of uniform recommendations in guidelines about the precise time to start the genetic evaluation or the type of targeted testing or whole-genome sequencing. A very diverse etiology and the scarce number of randomized studies of pediatric CMPs and CNPs make genetic testing of these maladies far more particular than their adult counterpart. The genetic diagnosis is even more puzzling if the psychological impact point of view is taken into account. This review aims to put together different perspectives, state-of-the art recommendations—synthetizing the major indications from European and American guidelines—and psychosocial outlooks to construct a comprehensive genetic assessment of pediatric CMPs and CNPs.

Genetic Risk Factors for Cardiovascular Disease in Adult Lymphoma Patients

Purpose The development of cardiovascular disease (CVD) is a relatively rare but a clinically important adverse event in the treatment of lymphoma, particularly in individuals receiving anthracyclines. There are few studies assessing the role of germline genetic susceptibility as a predictor of CVD in this setting. We evaluated the association of 24 single nucleotide polymorphisms (SNPs) from candidate genes involved in anthracycline-induced cardiotoxicity, CVD, and venous thromboembolism with new-onset CVD in a prospective cohort of lymphoma patients treated in the modern era. Methods All patients were from the Mayo component of the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE. Enrollment from 2002-2015 was offered to patients with newly diagnosed lymphoma who were age ≥18 years. Clinical, pathology and treatment data were abstracted using a standard protocol, and participants provided a peripheral blood sample, from which DNA was extracted. All patients were prospectively contacted every 6 months for the first 3 years from diagnosis and then annually thereafter to assess disease status, re-treatment and development of new morbidities, including CVD. Reported CVD events included congestive heart failure (CHF), coronary heart disease (CHD), arrhythmia, valvular heart disease (VHD), and other CVD. These events were identified during follow-up and validated against medical records. Genotyping was conducted using a custom Illumina iSelect platform with rigorous quality controls. For each SNP, Cox regression was used to estimate Hazard Ratios (HRs) and 95% confidence intervals (CI) with time to first CVD, using death without CVD as a competing risk. HRs were also obtained for time to CHF, using death without CVD as a competing risk. We also modeled these events for all patients and for patients receiving frontline anthracyclines. Each SNP was modeled as having a log-additive (per minor allele) effect in the regression model. An ordinal test was used to assess the trend, with a nominal P&lt;0.05 considered statistically significant. Results There were a total of 3,063 newly diagnosed lymphoma patients (excluding chronic lymphocytic leukemia) with no history of CVD at time of lymphoma diagnosis, of which 1280 had genotype data available for analysis. The median age at diagnosis was 59 years (range, 18-95) and 56% were male. The most common subtypes were follicular (26.3%), diffuse large B-cell (23.2%), Hodgkin (11.3%), marginal zone (11.2%), mantle cell (6.3%) and T-cell (5.4%) lymphoma. Anthracycline-based chemotherapy as initial therapy was used in 52% of individuals. At a median follow-up of 6.9 years (range, 0.1-17.1), 363 (30.7%) patients died, and 173 (13.5%) had new-onset CVD after lymphoma diagnosis. There were 234 incident CVD events in the 173 patients: 49 CHD, 50 CHF, 27 VHD, 103 arrhythmias, and 5 other CVD. Results are shown in the Table. When assessing all CVD, F5 (rs4524) (HR=1.28, 95% CI=1.03-1.58) and F11 (rs4253399) (HR=1.30, 95% CI=1.06-1.61) were associated with CVD at P&lt;0.05; both associations attenuated slightly when restricted to anthracycline-treated patients (F5 HR=1.18, 95% CI=0.89-1.57; F11 HR=1.23, 95% CI=0.92-1.65). F11 was more strongly associated with CHF (HR=1.55, 95% CI=1.03-2.34) and CHF in anthracycline-treated patients (HR=1.64, 95% CI=0.98-2.76). NCF4 (rs1883112) was marginally associated with lower risk of CVD overall (HR=0.81, 95% CI=0.66-1.00), and this association strengthened when restricted to anthracycline-treated patients (HR=0.67, 95% CI=0.49-0.91) and showed similar trends in HRs for CHF (HR=0.77, 95% CI=0.51-1.16) and CHF in anthracycline-treated patients (HR=0.72, 95% CI=0.41-1.28), although neither estimate was statistically significant at P&lt;0.05. Finally, while XDH (rs2236168) was not associated with all CVD (HR=1.00, 95% CI=0.81-1.23), it was associated with CHF (HR=0.66, 95% CI=0.47-0.93) overall, but attenuated in anthracycline-treated patients (HR=0.81, 95% CI=0.55-1.18). Conclusions In this exploratory study of candidate SNPs from the literature, we found limited evidence for a role of germline genetic variability in predicting risk of CVD or CHF in a cohort of lymphoma patients, especially after accounting for multiple testing. To fully address this hypothesis, future studies will need larger sample sizes and more comprehensive genetic assessment. Disclosures Maurer: Celgene: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Nowakowski:NanoString: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Celgene: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees. Cerhan:Celgene: Research Funding; NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.