A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases.

Newborn screening (NBS) dramatically improves outcomes in severe childhood disorders by treatment before symptom onset. In many genetic diseases, however, outcomes remain poor because NBS has lagged behind drug development. Rapid whole-genome sequencing (rWGS) is attractive for comprehensive NBS because it concomitantly examines almost all genetic diseases and is gaining acceptance for genetic disease diagnosis in ill newborns. We describe prototypic methods for scalable, parentally consented, feedback-informed NBS and diagnosis of genetic diseases by rWGS and virtual, acute management guidance (NBS-rWGS). Using established criteria and the Delphi method, we reviewed 457 genetic diseases for NBS-rWGS, retaining 388 (85%) with effective treatments. Simulated NBS-rWGS in 454,707 UK Biobank subjects with 29,865 pathogenic or likely pathogenic variants associated with 388 disorders had a true negative rate (specificity) of 99.7% following root cause analysis. In 2,208 critically ill children with suspected genetic disorders and 2,168 of their parents, simulated NBS-rWGS for 388 disorders identified 104 (87%) of 119 diagnoses previously made by rWGS and 15 findings not previously reported (NBS-rWGS negative predictive value 99.6%, true positive rate [sensitivity] 88.8%). Retrospective NBS-rWGS diagnosed 15 children with disorders that had been undetected by conventional NBS. In 43 of the 104 children, had NBS-rWGS-based interventions been started on day of life 5, the Delphi consensus was that symptoms could have been avoided completely in seven critically ill children, mostly in 21, and partially in 13. We invite groups worldwide to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness.

Improving access to exome sequencing in a medically underserved population through the Texome Project.

PURPOSE: Genomic medicine can end diagnostic odysseys for patients with complex phenotypes; however, limitations in insurance coverage and other systemic barriers preclude individuals from accessing comprehensive genetics evaluation and testing. METHODS: The Texome Project is a 4-year study that reduces barriers to genomic testing for individuals from underserved and underrepresented populations. Participants with undiagnosed, rare diseases who have financial barriers to obtaining exome sequencing (ES) clinically are enrolled in the Texome Project. RESULTS: We highlight the Texome Project process and describe the outcomes of the first 60 ES results for study participants. Participants received a genetic evaluation, ES, and return of results at no cost. We summarize the psychosocial or medical implications of these genetic diagnoses. Thus far, ES provided molecular diagnoses for 18 out of 60 (30%) of Texome participants. Plus, in 11 out of 60 (18%) participants, a partial or probable diagnosis was identified. Overall, 5 participants had a change in medical management. CONCLUSION: To date, the Texome Project has recruited a racially, ethnically, and socioeconomically diverse cohort. The diagnostic rate and medical impact in this cohort support the need for expanded access to genetic testing and services. The Texome Project will continue reducing barriers to genomic care throughout the future study years.

Diagnostic odyssey in amyotrophic lateral sclerosis: diagnostic criteria and reality.

BACKGROUND: Diagnosing a rare disease, such as amyotrophic lateral sclerosis, is a major challenge for physicians and patients. Despite detailed diagnostic criteria, this process often does not proceed as it should, exacerbating the problems of patients. In the following study, we show how the process, which in medical sciences has been called the "diagnostic odyssey", proceeds and how it affects patients. MATERIALS AND METHODS: Participants were recruited via a neurology clinic. Twenty-four patients with the diagnosed disease were interviewed using in-depth interviews and an author questionnaire: 9 females and 15 males ages ranging from 30-39 to 60-69. RESULTS: The median time from 1st symptoms to diagnosis was almost 12 months and mean almost 20 months (min. 3, max 106). Only 5 patients waited less than 6 months for being diagnosed. Over 80% of patients received an alternative diagnosis on the first attempt. CONCLUSION: ALS is a fast-paced fatal disease, which requires immediate action to slow down the course of the disease and improve patients' quality of life. However, in many cases, the disease is diagnosed too late. It also happens that a wrong diagnosis causes inaccurate treatment, which accelerates the development of ALS. For this reason, it is necessary to expand the clinical and communication competences of medical personnel already at the stage of medical studies. In addition, the diagnostic criteria should highlight the common problem with diagnosing ALS.

Exploring Diagnostic and Therapeutic Odyssey in Pulmonary Arterial Hypertension: Insights from In-Depth Semi-Structured Interviews.

INTRODUCTION: Establishing a diagnosis is paramount in medical practice as it shapes patients' experiences and guides treatment. Patients grappling with rare diseases face a triple challenge: prolonged diagnostic journeys, limited responses to existing therapies, and the absence of effective monitoring tools. Genetic diagnosis often provides crucial diagnostic and prognostic information, opening up possibilities for genotype-targeted treatments and facilitating counselling and relative testing. The NIHR BioResource - Rare Diseases (NBR) Study and the Cohort Study in Idiopathic and Hereditary Pulmonary Arterial Hypertension (PAH Cohort study) aimed to enhance diagnosis and treatment for PAH, successfully identifying the genetic cause in 25% of idiopathic cases. However, the diagnostic and therapeutic odyssey in patients with PAH remains largely unexplored. METHODS: Stakeholders from the NBR and PAH Cohort studies were recruited using purposive sampling. In-depth interviews and focus groups were recorded, transcribed, anonymised, and analysed thematically using MAXQDA software. RESULTS: The study involved 53 interviews and focus groups with 63 participants, revealing key themes across five stages of the diagnostic odyssey: initial health concerns and interactions with general practitioners, experiences of misdiagnosis, relief upon receiving the correct diagnosis, and mixed emotions regarding genetic results and the challenges of living with the disease. Following the diagnosis, participants embarked on a therapeutic journey, facing various challenges, including the disease's impact on professional and social lives, the learning curve associated with understanding the disease, shifts in communication dynamics with healthcare providers, therapeutic hurdles, and insurance-related issues. Building on these insights, we identified areas of unmet needs, such as improved collaboration with primary care providers and local hospitals, the provision of psychological support and counselling, and the necessity for ongoing patient education in the ever-evolving realms of research and therapy. CONCLUSIONS: The study highlights the significant challenges encountered throughout the diagnostic and therapeutic journey in PAH. To enhance patient outcomes, it is crucial to raise awareness of the disease, establish clear diagnostic pathways, and seamlessly integrate genetic diagnostics into clinical practice. Streamlining the diagnostic process can be achieved by utilising existing clinical infrastructure to support research and fostering better communication within the NHS. Moreover, there is an urgent need for more effective therapies alongside less burdensome drug delivery methods.

Detection of a novel gross deletion in the UNC13D gene ends the diagnostic odyssey for a family with familial hemophagocytic lymphohistiocytosis 3.

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is an immunological disorder characterized by overactivation of macrophages and T lymphocytes. This autosomal recessive condition has been characterized into multiple types depending on the genetic etiology. FHL type 3 is associated with bi-allelic pathogenic variants in the UNC13D gene. CASE PRESENTATION: We present a 12-year diagnostic odyssey for a family with FHL that signifies the advances of FHL genetic testing in a clinical genetic diagnostic laboratory setting. We describe the first case of a large UNC13D gross deletion in trans to a nonsense variant in a family with FHL3, which may have been mediated by Alu elements within introns 12 and 25 of the UNC13D gene. CONCLUSIONS: This case highlights the importance of re-evaluating past genetic testing for a patient and family as test technology evolves in order to end a diagnostic odyssey.

'You're just a Guinea pig': Exploring the barriers and impacts of living with long COVID-19: A view from the undiagnosed.

The COVID-19 pandemic had a disproportionate impact on ethnically minoritised and other marginalised communities, yet little is known about the impacts of long COVID-19 (LC) on this group. Living with LC takes its toll both physically, emotionally and financially and even more so when a diagnosis is hard to come by. By using qualitative interviews centring the view of undiagnosed and marginalised communities already classed as 'underserved' in the medical literature, we show the range of barriers and impacts faced by these groups in the UK, and the strategies of resilience they use. Whether trapped on a 'diagnostic odyssey' at the level of primary care, struggling to maintain employment and businesses, or managing family commitments, we argue many minoritised communities are caught in a liminal space of misrecognition, invalidation and ambiguity. We show how these impacts are generated by tensions and challenges in the process and categorisation of diagnosis, and how this effects the daily lives of many individuals already on the receiving end of health inequity. We also offer some examples and suggestions for best practices.

A Rare Coincidence of Three Inherited Diseases in a Family with Cardiomyopathy and Multiple Extracardiac Abnormalities.

A genetic diagnosis of primary cardiomyopathies can be a long-unmet need in patients with complex phenotypes. We investigated a three-generation family with cardiomyopathy and various extracardiac abnormalities that had long sought a precise diagnosis. The 41-year-old proband had hypertrophic cardiomyopathy (HCM), left ventricular noncompaction, myocardial fibrosis, arrhythmias, and a short stature. His sister showed HCM, myocardial hypertrabeculation and fibrosis, sensorineural deafness, and congenital genitourinary malformations. Their father had left ventricular hypertrophy (LVH). The proband's eldest daughter demonstrated developmental delay and seizures. We performed a clinical examination and whole-exome sequencing for all available family members. All patients with HCM/LVH shared a c.4411-2A>C variant in ALPK3, a recently known HCM-causative gene. Functional studies confirmed that this variant alters ALPK3 canonical splicing. Due to extracardiac symptoms in the female patients, we continued the search and found two additional single-gene disorders. The proband's sister had a p.Trp329Gly missense in GATA3, linked to hypoparathyroidism, sensorineural deafness, and renal dysplasia; his daughter had a p.Ser251del in WDR45, associated with beta-propeller protein-associated neurodegeneration. This unique case of three monogenic disorders in one family shows how a comprehensive approach with thorough phenotyping and extensive genetic testing of all symptomatic individuals provides precise diagnoses and appropriate follow-up, embodying the concept of personalized medicine. We also present the first example of a splicing functional study for ALPK3 and describe the genotype-phenotype correlations in cardiomyopathy.

New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases.

Accurate diagnosis is the cornerstone of medicine; it is essential for informed care and promoting patient and family well-being. However, families with a rare genetic disease (RGD) often spend more than five years on a diagnostic odyssey of specialist visits and invasive testing that is lengthy, costly, and often futile, as 50% of patients do not receive a molecular diagnosis. The current diagnostic paradigm is not well designed for RGDs, especially for patients who remain undiagnosed after the initial set of investigations, and thus requires an expansion of approaches in the clinic. Leveraging opportunities to participate in research programs that utilize new technologies to understand RGDs is an important path forward for patients seeking a diagnosis. Given recent advancements in such technologies and international initiatives, the prospect of identifying a molecular diagnosis for all patients with RGDs has never been so attainable, but achieving this goal will require global cooperation at an unprecedented scale.

Referral odyssey plot to visualize causes of surgical delay in mesial temporal lobe epilepsy with hippocampal sclerosis.

The "odyssey plot" was used to visualize referral delays in epilepsy surgery. Participants were 36 patients (19 males; 13-67 years, median 27 years) with mesial temporal lobe epilepsy with hippocampal sclerosis (HS) who underwent resection surgery. The "referral odyssey plot" included five clinical episodes: seizure onset (T1), first visits to a non-epileptologist (T2) and to an epileptologist (T3), first admission to our epilepsy monitoring unit (EMU) (T4), and resection surgery (T5). For each patient, we identified the first seizure type: the physician who first diagnosed focal aware seizure (FAS), focal impaired awareness seizure (FIAS), focal to bilateral tonic-clonic seizure (FBTCS), and radiologically suspected HS. Within the overall delay (T1-T5, median 18 years; interquartile range [IQR] 14), non-epileptologist's delay (T2-T3, 11.5 years; IQR 12.25) was far (p < 0.0001) longer than patient's (T1-T2, 0 year; IQR 2.25), epileptologist's (T3-T4, 1 year; IQR 4), or after-EMU delay (T4-T5, 1 year; IQR 1). FAS onset cases had significantly longer T1-T2 (N = 5, median 7 years; IQR 6) than FIAS (N = 22, 0 year; IQR 1, p < 0.005) or FBTCS onset cases (N = 9, 0 year; IQR 0, p < 0.001). FAS was correctly diagnosed first by non-epileptologists in 17.9%, by out-patient epileptologists in 35.7%, and at the EMU in 46.4%. FIAS was correctly diagnosed first by non-epileptologists in 94.4% and by out-patient epileptologists in 5.6%. Non-epileptologists diagnosed FBTCS in all cases. HS was diagnosed by non-epileptologists in 13.9%, by out-patient epileptologists in 47.2%, and at the EMU in 38.9%. Early referral to epileptologists is most critical for early surgery. Early utilization of the EMU is highly recommended because FAS is often overlooked by outpatient epileptologists. The odyssey plot will be useful to improve the healthcare system for other types of epilepsy.

Informing a value care model: lessons from an integrated adult neurogenomics clinic.

BACKGROUND: Advances in genomics provide improved opportunities for diagnosis of complex neurogenetic disorders, yet the optimal approach to translate these benefits to the outpatient clinic is unclear. AIMS: We retrospectively reviewed referral indications and outcomes of an integrated multidisciplinary team (MDT) clinic pathway for adults with suspected neurogenetic disorders. The associated cost implications were estimated. METHODS: Consecutive patients who attended the neurogenomics clinic from January 2017 to April 2020 were included. The clinic comprised neurologists, clinical geneticists and genetic counsellors, who assessed each patient concurrently. RESULTS: Ninety-nine new patients were referred spanning 45 different clinical diagnoses. Following MDT clinical assessment, 23% (23/99) of referral diagnoses were revised prior to molecular testing. Eighty-one patients (82%) underwent genetic testing, including 43 exome-based panels, 15 whole-genome sequencing, 14 single gene tests, 27 repeat-primed polymerase chain reaction testing and two chromosomal microarrays. Overall, 33/99 patients (33%) received a diagnosis, either a molecular diagnosis (n = 24, of which 22 were diagnostic and two were predictive) or a clinical diagnosis (n = 9). Of the clinical diagnosis cohort, five patients received a diagnosis without molecular testing and four patients whose negative testing (one diagnostic and three predictive) allowed exclusion of genetic differentials and, hence, confirmation of clinical diagnoses. The diagnostic rate following MDT and diagnostic testing was 30% (28/94), excluding the five predictive testing cases. MDT assessment aligned with eventual molecular diagnoses in 96% of cases. The estimated average costs were AU$1386 per patient undergoing MDT assessment and AU$4159 per diagnosis achieved. CONCLUSIONS: We present an integrated multidisciplinary neurogenomics clinic pathway providing a diagnostic yield of 33% (30% excluding predictive testing cases), with costing implications. The relatively high diagnostic yield may be attributed to multidisciplinary input integrating accurate phenotyping of complex disorders and interpretation of genomic findings.

Alirocumab after acute coronary syndrome in patients with a history of heart failure.

AIMS: Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis, we evaluated outcomes in ODYSSEY OUTCOMES in patients with vs. without a history of HF randomized to the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo. METHODS AND RESULTS: Among 18 924 patients with recent acute coronary syndrome (ACS) receiving intensive or maximum-tolerated statin treatment, the primary outcome of major adverse cardiovascular events (MACE) was compared in patients with or without a history of HF. The pre-specified secondary outcome of hospitalization for HF was also analysed. Overall, 2815 (14.9%) patients had a history of HF. Alirocumab reduced low-density lipoprotein cholesterol and lipoprotein(a) similarly in patients with or without HF. Overall, alirocumab reduced MACE compared with placebo [hazard ratio (HR): 0.85; 95% confidence interval (CI): 0.78-0.93; P = 0.0001]. This effect was observed among patients without a history of HF (HR: 0.78; 95% CI: 0.70-0.86; P < 0.0001), but not in those with a history of HF (HR: 1.17; 95% CI: 0.97-1.40; P = 0.10) (Pinteraction = 0.0001). Alirocumab did not reduce hospitalization for HF, overall or in patients with or without prior HF. CONCLUSION: Alirocumab reduced MACE in patients without a history of HF but not in patients with a history of HF. Alirocumab did not reduce hospitalizations for HF in either group. Patients with a history of HF are a high-risk group that does not appear to benefit from PCSK9 inhibition after ACS.

The Burden of COVID-19 on Caregivers of Children with Suspected Genetic Conditions: A Therapeutic Odyssey.

AIMS: Children with disabilities and rare or undiagnosed conditions and their families have faced numerous hardships of living during the COVID-19 pandemic. For those with undiagnosed conditions, the diagnostic odyssey can be long, expensive, and marked by uncertainty. We, therefore, sought to understand whether and how COVID-19 impacted the trajectory of children's care. METHODS: We conducted semi-structured qualitative interviews with 25 caregivers who, prior to the pandemic, were on a diagnostic odyssey for their children. RESULTS: Most caregivers did not report any interruptions to their child's diagnostic odyssey. The greatest impact was access to therapy services, including the suspension or loss of their child's in-person therapeutic care and difficulties with virtual therapies. This therapy gap caused caregivers to fear that their children were not making progress. CONCLUSION: Although much has been written about the challenges of diagnostic odysseys for children and their families, this study illustrates the importance of expanding the focus of these studies to include therapeutic odysseys. Because therapeutic odysseys continue regardless of whether diagnoses are made, future research should investigate how to support caregivers through children's therapies within and outside of the COVID-19 context.

Diagnostic experiences of Duchenne families and their preferences for newborn screening: A mixed-methods study.

Duchenne muscular dystrophy is the most common form of muscular dystrophy diagnosed in childhood but is not routinely screened for prenatally or at birth in the United States. We sought to characterize the diagnostic experiences of families and describe their preferences for newborn screening (NBS). We conducted a registry-based survey of families with Duchenne and Becker muscular dystrophy that included open- and closed-ended questions regarding the journey to a diagnosis, preferences for when to learn of a diagnosis, and how knowledge of a diagnosis would impact life decisions. Open-ended responses were analyzed thematically, and closed-ended responses were analyzed descriptively. Sixty-five families completed the survey. The average ages of first concern and diagnosis were 2 and 4 years, respectively. One-third of families (30%) indicated that they would prefer to receive a diagnosis in the newborn period irrespective of treatment options available, and nearly all of the remaining families (93%) indicated that they would want to learn about a diagnosis if there were treatments that worked well during the newborn period. All families (100%) indicated that a diagnosis in the newborn period would impact life decisions. We identified three overarching themes, which described the stages of the diagnostic journey, including having concerns about the child, seeking answers, and receiving the diagnosis. NBS can facilitate improved health outcomes through early access to care, and inform families on major health and nonhealth decisions. The preferences and experiences of families and other stakeholders should be considered when determining the potential value and benefit of expanding NBS programs.

Patients with Ehlers-Danlos syndrome on the diagnostic odyssey: Rethinking complexity and difficulty as a hero's journey.

Patients with hypermobile Ehlers-Danlos syndrome, an hereditary disorder of the connective tissue, often face a long and difficult diagnostic odyssey in pursuit of a name for their condition. Clinicians may dismiss subjective symptoms of chronic pain, thus prolonging patients' odysseys and worsening their care and satisfaction and creating antagonisms in the patient-provider relationship. A greater understanding of patient experiences is necessary in order to decrease burdens of this relationship and to improve care. To that end, we conducted 22 in-depth, semistructured interviews with individuals who had undergone this diagnostic odyssey. We focused on the impact that the odyssey had on their lives, both inside and outside the clinic. Through narrative analysis, we found a sort of "hero's journey" in the description of their cases, highlighting issues of uncertainty and integration as well as honoring their struggles. Interviewees had encountered difficulties in working with clinicians, in multiplying symptoms, and in negative psychosocial consequences. Attention to patients' lived experience may help to build empathy and understanding for the difficult and complex clinical situation presented by Ehlers-Danlos syndrome. Using the hero's journey as a lens onto this experience allows for a more patient-centered approach to this understanding and has potential value for comprehension of other complex diseases and invisible illnesses.

(Un)standardized testing: the diagnostic odyssey of children with rare genetic disorders in Alberta, Canada.

PURPOSE: We provide a description of the diagnostic odyssey for a cohort of children seeking diagnosis of a rare genetic disorder in terms of the time from initial consultation to most recent visit or receipt of diagnosis, the number of tests per patient, and the types of tests received. METHODS: Retrospective chart review of 299 children seen at the Alberta Children's Hospital (ACH) Genetics Clinic (GC) for whom the result of at least one single-gene test, gene panel, or chromosome microarray analysis (CMA) was recorded. RESULTS: Of 299 patients, 90 (30%) received a diagnosis in the period of the review. Patients had an average of 5.4 tests each; 236 (79%) patients received CMA; 172 (58%) patients received single-gene tests and 34 (11%) received gene panels; 167 (56%) underwent imaging/electrical activity studies. The mean observation period was 898 days (95% confidence interval [CI] 791, 1004). Among patients with visits recorded prior to visiting ACH GC, 43% of the total observation time occurred prior to the GC. CONCLUSION: As genomic technologies expand, the nature of the diagnostic odyssey will change. This study has outlined the current standard of care in the ACH GC, providing a baseline against which future changes can be assessed.

Impact of integrated translational research on clinical exome sequencing.

PURPOSE: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. METHODS: From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. RESULTS: The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. CONCLUSION: Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

"Doctors can read about it, they can know about it, but they've never lived with it": How parents use social media throughout the diagnostic odyssey.

Parents of children with undiagnosed conditions struggle to obtain information about how to treat and support their children. It can be particularly challenging to find communities and other parents who share their experiences and can provide emotional and informational support. This study sought to characterize how parents use social media, both throughout the diagnostic odyssey and post-diagnosis, to meet their informational, social, and emotional support needs. We conducted qualitative semi-structured interviews with 14 parents from the Stanford site of the Undiagnosed Diseases Network (UDN), including five whose children had received a diagnosis through study participation. Interview recordings were analyzed using inductive, team-based coding and thematic analysis based in grounded theory using Dedoose qualitative analysis software. Through this process, we identified four key themes related to social media use. First, parents struggled to find the "right" community, often seeking out groups of similar patients based on symptoms or similar conditions. Second, though they found much valuable information through social media about caring for their child, they also struggled to interpret the relevance of the information to their own child's condition. Third, the social support and access to other patients' and families' lived experiences were described as both highly valued and emotionally challenging, particularly in the case of poor outcomes for similar families. Finally, parents expressed the need to balance concerns about their child's privacy with the value of transparency and data sharing for diagnosis. Our results suggest that the needs and experiences of undiagnosed patients and families differ from those with diagnosed diseases and highlight the need for support in best utilizing social media resources at different stages of the diagnostic odyssey.

The odyssey of complex neurogenetic disorders: From undetermined to positive.

The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a "diagnostic odyssey." An increase in the variability of genetic disorders and the corresponding gene-disease associations suggest the need to periodically re-evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73-3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology.

Effect of alirocumab on individuals with type 2 diabetes, high triglycerides, and low high-density lipoprotein cholesterol.

BACKGROUND: Mixed dyslipidemia [elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs), and decreased HDL-C] is common in type 2 diabetes mellitus (T2DM) and is associated with increased cardiovascular risk. Non-HDL-C and apolipoprotein B (ApoB) are the preferred therapeutic targets for mixed dyslipidemia. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that effectively reduces low-density lipoprotein cholesterol (LDL-C), non-HDL-C, ApoB, and lipoprotein(a) (Lp[a]), and is well-tolerated in individuals with T2DM. METHODS: The previously reported open-label ODYSSEY DM-DYSLIPIDEMIA trial data demonstrated the effects of alirocumab on individuals with non-HDL-C ≥ 100 mg/dL and TGs ≥ 150 and < 500 mg/dL receiving stable maximally tolerated statin (n = 413). This post hoc subgroup analysis of the primary trial investigated the effects of alirocumab [75 mg every 2 weeks (Q2W) with possible increase to 150 mg Q2W at Week 12] versus usual care [ezetimibe, fenofibrate, or no additional lipid-lowering therapy (LLT)] on non-HDL-C and other lipids in individuals with T2DM and baseline TGs ≥ 200 mg/dL and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). RESULTS: Alirocumab significantly reduced non-HDL-C [LS mean difference (standard error (SE)), - 35.0% (3.9)], ApoB [LS mean difference (SE), - 34.7% (3.6)], LDL-C [LS mean difference (SE), - 47.3% (5.2)], LDL particle number [LS mean difference (SE), - 40.8% (4.1)], and Lp(a) [LS mean difference (SE), - 29.9% (5.4)] versus usual care from baseline to Week 24 (all P < 0.0001). Results were similar for alirocumab versus usual care. TG reductions were similar between alirocumab and usual care (no significant difference), but greater with fenofibrate versus alirocumab (P = 0.3371). Overall, alirocumab significantly increased HDL-C versus usual care [LS mean difference (SE), 7.9% (3.6); P < 0.05], although differences with alirocumab versus ezetimibe or fenofibrate were non-significant. Most individuals receiving alirocumab achieved ApoB < 80 mg/dL (67.9%) and non-HDL-C < 100 mg/dL (60.9%). Adverse event frequency was similar between alirocumab (67.2%) and usual care (70.7%). Additionally, no clinically relevant effect of alirocumab on change in glycemic parameters or use of antihyperglycemic agents was observed. CONCLUSIONS: Alirocumab is an effective therapeutic option for individuals with T2DM, TGs ≥ 200 mg/dL, and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Atherogenic lipid (ApoB and non-HDL) reductions were greater with alirocumab than ezetimibe, fenofibrate, or no LLT. Consistent with previous studies, alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov, NCT02642159. Registered December 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02642159.

Lipoprotein(a) and PCSK9 inhibition: clinical evidence.

Compelling evidence has emerged from epidemiological and Mendelian randomization analyses relative to the causality of lipoprotein(a) [Lp(a)] in atherosclerotic cardiovascular diseases (ASCVD), being elevated Lp(a) a strong risk factor regardless of the reduction of LDL-C achieved by statins. So far, no specific available agent can lower Lp(a) to the extent required to achieve a cardiovascular (CV) benefit, i.e. approximately 100 mg/dL. The most recent outcomes trial FOURIER with evolocumab showed that a 25 nmol/L (12 mg/dL) reduction in Lp(a) corresponded to a 15% decrement in the relative risk of cardiovascular disease. The ODYSSEY OUTCOMES trial with alirocumab has been the first demonstrating that a reduction in Lp(a) associates with less major adverse cardiovascular events (MACE), i.e. hazard ratio: 0.994 per 1 mg/dL decrement in Lp(a). The Lp(a) lowering effect driven by PCSK9 inhibition was confirmed in carriers of PCSK9 loss-of-function mutations in which Lp(a) and oxPL-apoB levels were decreased compared to non-carriers as was for a slight larger number of apo(a) Kringle IV repeats. Although PCSK9 inhibitors are not able to decrease Lp(a) to the extent required to achieve a CV benefit, their use has led to a higher discontinuation rate in lipoprotein apheresis in patients with progressive ASCVD and high plasma Lp(a).