Penetrant Variants Research Articles

Informing patients about their mutation tests: CDKN2A c.256G>A in melanoma as an example

BackgroundWhen germline mutations are suspected as causal in cancer, patient DNA may be sequenced to detect variants in relevant genes. If a particular mutation has not been reported in reliable family studies, genetic counselors are facing a dilemma of appropriately informing patients. Many sequencing facilities provide an interpretation of the findings based on the available sequence databases or on prediction tools that are curated from bioinformatics and mechanistic datasets. The counseling dilemma is exacerbated if the pedigree data are not informative but the in silico predictions suggest pathogenicity.MethodsWe present here a real world example of the c.256G > A CDKN2A variant, which was detected in one melanoma patient where two siblings were diagnosed with melanoma in situ. We investigated a detailed family history of the affected siblings in order to survey probability of the cancer risks within the context to this mutation.ResultsThis c.256G > A CDKN2A variant was detected in one of the brothers and in the melanoma-free mother while the other brother in the family tested negative. The variant had been previously described in one patient from a melanoma family. In the family under investigation, the mother’s 16 first-and second-degree relatives had survived past the median onset age for melanoma and none presented melanoma. We tested the variant using multiple bioinformatic tools that all predicted deleteriousness of the variant. The genetic counseling report to the melanoma patient stated that the CDKN2A variant was ‘likely pathogenic’ and the disease was defined as ‘likely hereditary melanoma’.ConclusionsThe pedigree data showed at the most a low penetrance variant, which, if taken into consideration, might have altered the provided diagnosis. When dealing with ‘practically’ unknown variants the counselors would be advised to incorporate a detailed family history rather than basing predictions on functionality provided by sequencing facilities.

Precision medicine for pancreatic diseases.

We describe and contrast the strengths of precision medicine with Western medicine, and complex trait genetics with Mendelian genetics. Classic genetics focuses on highly penetrant pathogenic variants in a single gene believed to cause or confer a high risk for well-defined phenotypes. However, a minority of disorders have a single gene cause. Further, even individuals with identical Mendelian disease-associated genotypes may exhibit substantial phenotypic variability indicative of genetic and environmental modifiers. Still, most diseases are considered complex traits (or complex diseases). New insights into the genetic underpinnings of complex traits provide opportunities for advances in diagnosis and management. Precision medicine provides the framework for integrating complex trait knowledge into clinical care through a sophisticated analysis pipeline. Multidimensional modeling of acquired diseases includes multiple genetic risks scattered over many genes and gene regulators that must be interpreted on the basis of functional evidence (e.g., genomics, transcriptomics) with structured models and expert systems; strengthened with machine learning and artificial intelligence. The choice of genotyping approaches (shotgun sequencing, single nucleotide polymorphism chips, targeted panels) is discussed. The result of a good precision medicine tool is clinical-decision support and guidance to tackle complex disorders such as pancreatitis, diabetes, and pancreatic cancer oncogenesis.

The impact of RB1 genotype on incidence of second tumours in heritable retinoblastoma

BackgroundPatients with heritable retinoblastoma are at risk for bilateral retinoblastoma and second primary malignancies (SPMs). The incidence of SPM is significantly raised after radiotherapy. We analysed the impact of the class of constitutional RB1 variant on the incidence of SPM in survivors with and without previous radiotherapy. MethodsFrom 1940 to 2008, 655 national patients were treated for heritable retinoblastoma at the German referral centre. Data on SPM, therapy and constitutional RB1 variant were available for 317 patients (48.3%). Heterozygous RB1 variants were classified into variants with regular and incomplete penetrance for retinoblastoma. ResultsSPM occurred in 51 of 317 survivors of heritable retinoblastoma. The incidence rate (IR) of SPM per 1000 person years was 8.4 (95% confidence interval (CI): 6.3–11.1) in individuals heterozygous for an oncogenic RB1 variant and 2.1 (95% CI: 0.0–11.4) with RB1 mosaicism. The incidence of SPM was higher in patients with regular penetrance compared with incomplete penetrance RB1 variants (IR 10.3 [95% CI: 7.5–13.8] vs. IR 3.2 [95% CI: 1.0–7.5]; p < 0.05). In the subgroup without previous radiotherapy SPM were only observed in patients with regular penetrance variants (IR 6.3 [95% CI: 3.0–11.5]). Carriers of incomplete penetrance variants developed similar tumour entities as those with regular penetrance. ConclusionsPatients heterozygous for regular penetrance RB1 variants had a higher risk to develop SPM than patients with incomplete penetrance variants. Increased knowledge on genotype-phenotype relation regarding SPM may influence screening recommendations for SPM in survivors of heritable retinoblastoma.

Challenges in the diagnosis and discovery of rare genetic disorders using contemporary sequencing technologies.

Next generation sequencing (NGS) has revolutionised rare disease diagnostics. Concomitant with advancing technologies has been a rise in the number of new gene disorders discovered and diagnoses made for patients and their families. However, despite the trend towards whole exome and whole genome sequencing, diagnostic rates remain suboptimal. On average, only ~30% of patients receive a molecular diagnosis. National sequencing projects launched in the last 5 years are integrating clinical diagnostic testing with research avenues to widen the spectrum of known genetic disorders. Consequently, efforts to diagnose genetic disorders in a clinical setting are now often shared with efforts to prioritise candidate variants for the detection of new disease genes. Herein we discuss some of the biggest obstacles precluding molecular diagnosis and discovery of new gene disorders. We consider bioinformatic and analytical challenges faced when interpreting next generation sequencing data and showcase some of the newest tools available to mitigate these issues. We consider how incomplete penetrance, non-coding variation and structural variants are likely to impact diagnostic rates, and we further discuss methods for uplifting novel gene discovery by adopting a gene-to-patient-based approach.

Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation.

Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS). Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates. Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain. We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.

Analysis of p.Tyr307Asn variant in the LRP10 gene in Parkinson’s disease in southern Spain

Lipoprotein receptor-related protein 10 (LRP10) has been proposed as a novel causative gene for autosomal dominant Parkinson’s disease (PD), and the c.919T>A (p.Tyr307Asn) variant has been identified as possibly involved in the development of familial PD and PD with dementia. We screened for the p.Tyr307Asn variant in a southern Spain population of 679 PD patients, of who 129 were familial cases, and 1217 unrelated healthy controls. A total of 3 carriers of the LRP10 p.Tyr307Asn variant were identified: 1 PD patient and 2 healthy controls. Together with the absence of a family history of PD, this finding might suggest a low penetrance variant as well as a limited role for p.Tyr307Asn in PD in our cohort. Nevertheless, a family history of Alzheimer’s disease in the LRP10 p.Tyr307Asn carriers provides evidence for a possible association with dementia.

The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG)

The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG)

Dementia and its genes

Dementia is a collective term for a range of conditions that lead to a progressive deterioration in cognitive function. Together they are a major cause of disability, and it is estimated that 10 000 000 new cases are diagnosed every year, worldwide. Studies suggest that 1-in-20 individuals develop symptoms below the age of 65 years. Although non-genetic causes must be considered, a young age of onset or a strong family history could be due to the presence of a particularly strong genetic factor; a highly penetrant pathogenic variant. This article aims to provide GPs with an introduction to inherited forms of adult-onset dementia, their presenting features and clues to look out for in the family history.

The evolution of gene-guided management of inherited arrhythmia syndromes: Peering beyond monogenic paradigms towards comprehensive genomic risk scores.

Inherited arrhythmia syndromes have traditionally been viewed as monogenic forms of disease whose pathophysiology is driven by a single highly penetrant rare genetic variant. Although an accurate depiction of a proportion of genetic variants, the variable penetrance frequently noted in genotype positive families and the presence of sporadic genotype negative cases have long highlighted a more nuanced truth being operative. Coupled with our more recent recognition that many rare variants implicated in inherited arrhythmia syndromes possess unexpectedly high allele frequencies within the general population, these observations have contributed to the realization that a spectrum of pathogenicity exists among clinically relevant genetic variants. Notably, variable mutation pathogenicity and corresponding variable degrees of penetrance emphasize a limitation of contemporary guidelines, which attempt to dichotomize genetic variants as pathogenic or benign. Recognition of the existence of low and intermediate penetrant variants insufficient to be causative for disease in isolation has served to emphasize the importance of additional genetic, clinical, and environmental factors in the pathogenesis of rare inherited arrhythmia syndromes. Despite being rare, it has also become increasingly evident that common genetic variants play critical roles in both heritable channelopathies and cardiomyopathies and in aggregate may even be the primary drivers in certain instances, such as genotype negative Brugada syndrome. Our growing realization that the genetic substrates of inherited arrhythmia syndromes have intricacies that extend beyond traditionally perceived monogenic paradigms has highlighted a potential value of leveraging more comprehensive genomic risk scores for predicting disease development and arrhythmic risk.

A putative silencer variant in a spontaneous canine model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is the leading cause of blindness with nearly two million people affected worldwide. Many genes have been implicated in RP, yet in 30–80% of the RP patients the genetic cause remains unknown. A similar phenotype, progressive retinal atrophy (PRA), affects many dog breeds including the Miniature Schnauzer. We performed clinical, genetic and functional experiments to identify the genetic cause of PRA in the breed. The age of onset and pattern of disease progression suggested that at least two forms of PRA, types 1 and 2 respectively, affect the breed, which was confirmed by genome-wide association study that implicated two distinct genomic loci in chromosomes 15 and X, respectively. Whole-genome sequencing revealed a fully segregating recessive regulatory variant in type 1 PRA. The associated variant has a very recent origin based on haplotype analysis and lies within a regulatory site with the predicted binding site of HAND1::TCF3 transcription factor complex. Luciferase assays suggested that mutated regulatory sequence increases expression. Case-control retinal expression comparison of six best HAND1::TCF3 target genes were analyzed with quantitative reverse-transcriptase PCR assay and indicated overexpression of EDN2 and COL9A2 in the affected retina. Defects in both EDN2 and COL9A2 have been previously associated with retinal degeneration. In summary, our study describes two genetically different forms of PRA and identifies a fully penetrant variant in type 1 form with a possible regulatory effect. This would be among the first reports of a regulatory variant in retinal degeneration in any species, and establishes a new spontaneous dog model to improve our understanding of retinal biology and gene regulation while the affected breed will benefit from a reliable genetic testing.

Is hormonal therapy after risk-reducing salpingo-oophorectomy associated with an increased risk of malignancy in pathogenic variant carriers?

ObjectivesThis study aimed to assess the association between hormone replacement therapy and the incidence of subsequent malignancies in patients who underwent risk-reducing salpingo-oophorectomy and had mutations predisposing them to Müllerian cancers. MethodsThis Institutional Review Board-approved retrospective study was performed at five academic institutions. Women were included if they were age 18–51 years, had one or more confirmed germline highly penetrant pathogenic variants, and underwent risk-reducing salpingo-oophorectomy. Patients with a prior malignancy were excluded. Clinicodemographic data were collected by chart review. Patients with no documented contact for one year prior to study termination were called to confirm duration of hormone use and occurrence of secondary outcomes. Hormone replacement therapy included any combination of estrogen or progesterone. ResultsData were analyzed for 159 women, of which 82 received hormone replacement therapy and 77 did not. In both groups an average of 6 years since risk reduction had passed. The patients treated with hormone replacement therapy did not have a higher risk of subsequent malignancy than those not treated with hormone replacement therapy (6 out of 82 vs. 7 out of 77, P = .68). Patients who received hormone replacement therapy were younger than those who did not receive hormone replacement therapy (39.0 vs. 43.9 years, P < .01) and were more likely to have undergone other risk reductive procedures including mastectomy and/or hysterectomy, though this difference was not statistically significant (69.5% vs. 55.8%, P = .07). ConclusionsIn this multi-institution retrospective study of data from patients with high-risk variant carriers who underwent risk-reducing salpingo-oophorectomy, there was no statistically significant difference in the incidence of malignancy between women who did and did not receive hormone replacement therapy.

Germline alterations in patients with testicular cancer.

397 Background: There are limited data for the association of testis cancer (TC) with hereditary cancer genes. We report the prevalence of germline mutations among men with TC completing germline genetic testing through a large, commercial laboratory. Methods: We reviewed a de-identified dataset of men from across the USA with history of TC who underwent testing of 1 to 130 genes via massively parallel sequencing with customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number alterations. Pathogenic (P) and likely pathogenic (LP) were confirmed using orthogonal technology in accordance with Invitae standard operating practices. P/LP variants including single nucleotide variants/indels/copy number variants are reported. Fisher’s Exact test was used to analyze categorical variables. Results: The cohort of 250 men was 84% White/Caucasian. The median number of genes tested was 48. P/LP variants were found in 18% (n = 45) of subjects. P/LP variants occurred in several moderate to high penetrance genes, including CHEK2 (n = 10 [4.0%]), BRCA1/2 (n = 6 [2.4%]), ATM (n = 6 [2.4%]) and Lynch syndrome genes (n = 4 [1.6%]). Heterozygous MUTYH (n = 6) and NTHL1 (n = 1) mutations were also found. DNA damage repair (DDR) mutations were found in 14.8% (n = 37) of subjects. Of the 45 carriers, 18 (40%) had no other personal cancer history while 27 (60%) had an additional primary cancer, but there was no significant association between having another primary and risk of carrying a mutation (p = 0.253). CHEK2 was the single most frequently mutated gene, with 2 of the low penetrance I157T mutations identified, but 8 other higher penetrance variants, including 2 1100delC mutations. Conclusions: A high percentage of hereditary cancer gene mutations were found in testicular cancer patients, many which were not associated with a history of another malignancy. Several mutations were in high penetrance DDR genes such as BRCA1/2 and Lynch genes, which may also serve as actionable targets. CHEK2 mutations were common, supporting prior data suggesting an association with testicular cancer. Further multigene panel testing in unselected patients and the study of association with histologic subtype, race, stage and family history is warranted.

Abstract P6-08-33: A remarkably high yield of identified hereditary breast cancer cases in a single oncology center, followed by inversely proportional rate of cascade testing in family relatives

Abstract Background: Individuals carrying pathogenic, cancer-predisposing, variants face an increased lifetime risk for various diagnoses, depending on the gene and maybe, variant. Traditionally, germline genetic testing is ordered for a cancer patient who fulfills certain eligibility criteria; mainly based on early age at diagnosis and family history for cancer. Although the test results provide useful information for the clinical management of the patients themselves, this information is pivotal for the primary disease prevention of their blood relatives. Targeted testing for the causative variant (so-called cascade testing), already identified in an affected individual, provide valuable information, while minimizing testing cost. Asymptomatic carriers who are at elevated risk may be offered risk-reducing measurements or early-stage diagnoses, resulting in improved outcomes or even no cancer diagnosis. Methods: In a single breast oncology clinic, with a turnaround of ~200 new breast cancer patients annually, and throughout years 2014-2019, a total of ninety-five cancer patients fulfilled the NCCN criteria, agreed and consented to genetic testing. Of these, eighty-nine were breast cancer patients, of which two were males, while six were ovarian cancer patients. A comprehensive cancer-gene panel was implemented, which targets a total of 94 genes. Results: Overall, 25.2% (24/95) of the tested patients carried a loss-of-function variant in a breast/ovarian cancer susceptibility gene (BRCA1, BRCA2, PALB2, TP53, ATM, RAD51C and PMS2), while secondary findings were identified in 5.2% (5/95) of the patients. All carriers in the first group were counselled and were informed to notify their blood relatives. Of these, thirty-nine family relatives from fourteen different families (range 1-6 per family), actually pursued cascade testing based on their relatives’ genetic test result, contributing in a rate of 56%. Interestingly, all the aforementioned were first-degree relatives and no second-degree relative came forward. Of these, twenty individuals (51.2%; 20/39) tested positive, five males and fifteen females. Conclusion: Although cascade testing for high penetrant pathogenic variants can provide primary prevention options for asymptomatic carriers, as well as assurance in non-carriers, patients with a positive genetic test result are reluctant to inform their family relatives. The rate of notification is inversely proportional to the degree of relation, with individuals in our study being restricted only to their first degree relatives. Changes in law and health policies will maximize the benefits of targeted testing. Considering the clinical actionability and the potential for preventing tumor diagnoses through cascade testing, raising awareness and educating our patients seems inevitable. Citation Format: Florentia Fostira, Vasiliki Rapti, Paraskevi Apostolou, Angeliki Delimitsou, Myrto Papamentzelopoulou, Drakoulis Yannoukakos, Ioannis Misitzis, Georgios Koumakis, Stamatina Demiri, Irene Konstantopoulou, Dimitrios Tryfonopoulos. A remarkably high yield of identified hereditary breast cancer cases in a single oncology center, followed by inversely proportional rate of cascade testing in family relatives [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-33.

Abstract ES6-3: Breast cancer genetic testing: moving from cancer risk assessment to therapeutic biomarker

Abstract In the last two decades germline genetic testing for breast cancer (BC) susceptibility has evolved from a single-gene analysis to a multigene cancer panel risk assessment tool. In addition, identifying a mutation in the BRCA1/2 genes may nowadays represent an opportunity for cancer targeted therapy. Current challenges in our routine clinical practice and for public health policies are to reconcile the implications derived from the identification of a hereditary cancer susceptibility that may impact beyond the person who is performing the genetic test, with and increasing and faster access to the test. Assessment of cancer risk was the first reason to incorporate germline BC genetic testing. As a consequence, mutation carriers are recommended specific screening and/or risk reduction options. While prophylactic bilateral salpingoophorectomy has shown a decrease in mortality and ovarian cancer-specific mortality, its role as a risk reduction option for breast cancer remains controversial. Radiologic imaging with magnetic resonance and mammogram has demonstrated beneficial in early detection of breast cancer, but risk reducing mastectomy may also be an option. Recent prospective data has shown that cancer risks differ between BRCA1 and BRCA2 mutation carriers, and that this estimation may be influenced by a combination of single-nucleotide polymorphism that constitute the polygenic risk score (PRS). Whether a more precise accuracy in cancer risk estimation in the short term (ie 5-10 years) may help to tailor screening and/or risk reduction options is unknown. As more BC-associated genes have been identified and technology has evolved, single gene testing has evolved to multigene panel testing. Available data suggests that patients can cope with multigene cancer panels although more research is needed to fully understand the psychosocial implications of multigene cancer panels, especially for those who have variants of unknown significance or moderate penetrance variants. Research is also needed to explore and develop communication models that maximize patients’ understanding and empower them to make informed decisions. The impact on reproductive-decision making will also be explored. Finally, a mutation in the BRCA1/2 genes is a predictive biomarker for targeted therapies in breast, ovarian, pancreatic and prostate cancer. Therefore, knowing the genetic status of our BC patients may influence their therapeutic options. The challenges and opportunities derived from new clinical scenarios that accompany these advances will be addressed during the educational session. Citation Format: J Balmaña. Breast cancer genetic testing: moving from cancer risk assessment to therapeutic biomarker [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES6-3.

Variants in LRRC34 reveal distinct mechanisms for predisposition to papillary thyroid carcinoma

BackgroundPapillary thyroid carcinoma (PTC) demonstrates high heritability and a low somatic mutation burden relative to other cancers. Therefore, the genetic risk predisposing to PTC is likely due to a combination...

Focus on Causality in ESC/iPSC-Based Modeling of Psychiatric Disorders.

Genome-wide association studies (GWAS) have identified an increasing number of genetic variants that significantly associate with psychiatric disorders. Despite this wealth of information, our knowledge of which variants causally contribute to disease, how they interact, and even more so of the functions they regulate, is still poor. The availability of embryonic stem cells (ESCs) and the advent of patient-specific induced pluripotent stem cells (iPSCs) has opened new opportunities to investigate genetic risk variants in living disease-relevant cells. Here, we analyze how this progress has contributed to the analysis of causal relationships between genetic risk variants and neuronal phenotypes, especially in schizophrenia (SCZ) and bipolar disorder (BD). Studies on rare, highly penetrant risk variants have originally led the field, until more recently when the development of (epi-) genetic editing techniques spurred studies on cause-effect relationships between common low risk variants and their associated neuronal phenotypes. This reorientation not only offers new insights, but also raises issues on interpretability. Concluding, we consider potential caveats and upcoming developments in the field of ESC/iPSC-based modeling of causality in psychiatric disorders.

Genetic variations in olfactory receptor gene OR2AG2 in a large multigenerational family with asthma

It is estimated from twin studies that heritable factors account for at-least half of asthma-risk, of which genetic variants identified through population studies explain only a small fraction. Multi-generation large families with high asthma prevalence can serve as a model to identify highly penetrant genetic variants in closely related individuals that are missed by population studies. To achieve this, a four-generation Indian family with asthma was identified and recruited for examination and genetic testing. Twenty subjects representing all generations were selected for whole genome genotyping, of which eight were subjected to exome sequencing. Non-synonymous and deleterious variants, segregating with the affected individuals, were identified by exome sequencing. A prioritized deleterious missense common variant in the olfactory receptor gene OR2AG2 that segregated with a risk haplotype in asthma, was validated in an asthma cohort of different ethnicity. Phenotypic tests were conducted to verify expected deficits in terms of reduced ability to sense odors. Pathway-level relevance to asthma biology was tested in model systems and unrelated human lung samples. Our study suggests that OR2AG2 and other olfactory receptors may contribute to asthma pathophysiology. Genetic studies on large families of interest can lead to efficient discovery.

Genetic Basis of Polycystic Ovary Syndrome (PCOS): Current Perspectives.

Polycystic ovary syndrome (PCOS) is a common infertility disorder affecting a significant proportion of the global population. It is the main cause of anovulatory infertility in women and is the most common endocrinopathy affecting reproductive-aged women, with a prevalence of 8–13% depending on the criteria used and population studied. The disease is multifactorial and complex and, therefore, often difficult to diagnose due to overlapping symptoms. Multiple etiological factors have been implicated in PCOS. Due to the complex pathophysiology involving multiple pathways and proteins, single genetic diagnostic tests cannot be determined. Progress has been achieved in the management and diagnosis of PCOS; however, not much is known about the molecular players and signaling pathways underlying it. Conclusively PCOS is a polygenic and multifactorial syndromic disorder. Many genes have been associated with PCOS, which affect fertility either directly or indirectly. However, studies conducted on PCOS patients from multiple families failed to find a fully penetrant variant(s). The present study was designed to review the current genetic understanding of the disease. In the present review, we have discussed the clinical spectrum, the genetics, and the variants identified as being associated with PCOS. The mechanisms by which variants in the genes confer risk to PCOS and the nature of the physical and genetic interaction between the genetic elements underlying PCOS remain to be determined. Elucidation of genetic players and cellular pathways underlying PCOS will certainly increase our understanding of the pathophysiology of this syndrome. The study also discusses the current status of the treatment modalities for PCOS, which is important to find new ways of treatment.

Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles.

We assessed the results of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along with C9orf72 repeat expansion testing. All returned sequencing results were Sanger-validated. Prior clinical diagnoses included Alzheimer's disease, frontotemporal dementia, and unspecified dementia. The mean age of onset was 54 (41–76). Fifty percent of patients had a strong family history, 37.5% had some, and 12.5% had no known family history. Nine of 32 patients (28%) had a variant defined as pathogenic or likely pathogenic (P/LP) by American College of Medical Genetics and Genomics standards, including variants in APP, C9orf72, CSF1R, and MAPT. Nine patients (including three with P/LP variants) harbored established risk alleles with moderate penetrance (odds ratios of ∼2–5) in ABCA7, AKAP9, GBA, PLD3, SORL1, and TREM2. All six patients harboring these moderate penetrance variants but not P/LP variants also had one or two APOE ε4 alleles. One patient had two APOE ε4 alleles with no other established contributors. In total, 16 patients (50%) harbored one or more genetic variants likely to explain symptoms. We identified variants of uncertain significance (VUSs) in ABI3, ADAM10, ARSA, GRID2IP, MME, NOTCH3, PLCD1, PSEN1, TM2D3, TNK1, TTC3, and VPS13C, also often along with other variants. In summary, genome sequencing for early-onset dementia frequently identified multiple established or possible contributory alleles. These observations add support for an oligogenic model for early-onset dementia.

Considerations for clinical curation, classification, and reporting of low-penetrance and low effect size variants associated with disease risk

PurposeClinically relevant variants exhibit a wide range of penetrance. Medical practice has traditionally focused on highly penetrant variants with large effect sizes and, consequently, classification and clinical reporting frameworks are tailored to that variant type. At the other end of the penetrance spectrum, where variants are often referred to as “risk alleles,” traditional frameworks are no longer appropriate. This has led to inconsistency in how such variants are interpreted and classified. Here, we describe a conceptual framework to begin addressing this gap. MethodsWe used a set of risk alleles to define data elements that can characterize the validity of reported disease associations. We assigned weight to these data elements and established classification categories expressing confidence levels. This framework was then expanded to develop criteria for inclusion of risk alleles on clinical reports. ResultsFoundational data elements include cohort size, quality of phenotyping, statistical significance, and replication of results. Criteria for determining inclusion of risk alleles on clinical reports include presence of clinical management guidelines, effect size, severity of the associated phenotype, and effectiveness of intervention. ConclusionThis framework represents an approach for classifying risk alleles and can serve as a foundation to catalyze community efforts for refinement.