Algorithm for detection and screening of familial hypercholesterolemia in Lithuanian population.

BACKGROUND: Familial hypercholesterolemia (FH) is one of the most common autosomal dominant diseases. FH causes a lifelong increase in low-density lipoprotein cholesterol (LDL-C) levels, which in turn leads to atherosclerotic cardiovascular disease. The incidence of FH is widely underestimated and undertreated, despite the availability and effectiveness of lipid-lowering therapy. Patients with FH have an increased cardiovascular risk; therefore, early diagnosis and treatment are vital. To address the burden of FH, several countries have implemented national FH screening programmes. The currently used method for FH detection in Lithuania is mainly based on opportunistic testing with subsequent cascade screening of index cases' first-degree relatives. METHODS: A total of 428 patients were included in this study. Patients with suspected FH are referred to a lipidology center for thorough evaluation. Patients who met the criteria for probable or definite FH according to the Dutch Lipid Clinic Network (DLCN) scoring system and/or had LDL-C > = 6.5 mmol/l were subjected to genetic testing. Laboratory and instrumental tests, vascular marker data of early atherosclerosis, and consultations by other specialists, such as radiologists and ophthalmologists, were also recorded. RESULTS: A total of 127/428 (30%) patients were genetically tested. FH-related mutations were found in 38.6% (n = 49/127) of the patients. Coronary artery disease (CAD) was diagnosed in 13% (n = 57/428) of the included patients, whereas premature CAD was found in 47/428 (11%) patients. CAD was diagnosed in 19% (n = 9/49) of patients with FH-related mutations, and this diagnosis was premature for all of them. CONCLUSIONS: Most patients in this study were classified as probable or possible FH without difference of age and sex. The median age of FH diagnosis was 47 years with significantly older females than males, which refers to the strong interface of this study with the LitHir programme. CAD and premature CAD were more common among patients with probable and definite FH, as well as those with an FH-causing mutation. The algorithm described in this study is the first attempt in Lithuania to implement a specific tool which allows to maximise FH detection rates, establish an accurate diagnosis of FH, excluding secondary causes of dyslipidaemia, and to select patients for cascade screening initiation more precisely.

Results of a Pilot External Quality Assessment Scheme for Genetic Testing of Newborns with Spinal Muscular Atrophy.

BACKGROUND: This study aims to evaluate the ability of laboratories to perform spinal muscular atrophy (SMA) genetic testing in newborns based on dried blood spot (DBS) samples, and to provide reference data and advance preparation for establishing the pilot external quality assessment (EQA) scheme for SMA genetic testing of newborns in China. METHODS: The pilot EQA scheme contents and evaluation principles of this project were designed by National Center for Clinical Laboratories (NCCL), National Health Commission. Two surveys were carried out in 2022, and 5 batches of blood spots were submitted to the participating laboratory each time. All participating laboratories conducted testing upon receiving samples, and test results were submitted to NCCL within the specified date. RESULTS: The return rates were 75.0% (21/28) and 95.2% (20/21) in the first and second surveys, respectively. The total return rate of the two examinations was 83.7% (41/49). Nineteen laboratories (19/21, 90.5%) had a full score passing on the first survey, while in the second survey twenty laboratories (20/20, 100%) scored full. CONCLUSIONS: This pilot EQA survey provides a preliminary understanding of the capability of SMA genetic testing for newborns across laboratories in China. A few laboratories had technical or operational problems in testing. It is, therefore, of importance to strengthen laboratory management and to improve testing capacity for the establishment of a national EQA scheme for newborn SMA genetic testing.

Australian public perspectives on genomic newborn screening: which conditions should be included?

BACKGROUND: Implementing genomic sequencing into newborn screening programs allows for significant expansion in the number and scope of conditions detected. We sought to explore public preferences and perspectives on which conditions to include in genomic newborn screening (gNBS). METHODS: We recruited English-speaking members of the Australian public over 18 years of age, using social media, and invited them to participate in online focus groups. RESULTS: Seventy-five members of the public aged 23-72 participated in one of fifteen focus groups. Participants agreed that if prioritisation of conditions was necessary, childhood-onset conditions were more important to include than later-onset conditions. Despite the purpose of the focus groups being to elicit public preferences, participants wanted to defer to others, such as health professionals or those with a lived experience of each condition, to make decisions about which conditions to include. Many participants saw benefit in including conditions with no available treatment. Participants agreed that gNBS should be fully publicly funded. CONCLUSION: How many and which conditions are included in a gNBS program will be a complex decision requiring detailed assessment of benefits and costs alongside public and professional engagement. Our study provides support for implementing gNBS for treatable childhood-onset conditions.

Clinical features and genetic analysis of 15 Chinese children with dent disease.

OBJECTIVE:  The clinical characteristics, genetic mutation spectrum, treatment strategies and prognoses of 15 children with Dent disease were retrospectively analyzed to improve pediatricians' awareness of and attention to this disease. METHODS:  We analyzed the clinical and laboratory data of 15 Chinese children with Dent disease who were diagnosed and treated at our hospital between January 2017 and May 2023 and evaluated the expression of the CLCN5 and OCRL1 genes. RESULTS:  All 15 patients were male and complained of proteinuria, and the incidence of low-molecular-weight proteinuria (LMWP) was 100.0% in both Dent disease 1 (DD1) and Dent disease 2 (DD2) patients. The incidence of hypercalciuria was 58.3% (7/12) and 66.7% (2/3) in DD1 and DD2 patients, respectively. Nephrocalcinosis and nephrolithiasis were found in 16.7% (2/12) and 8.3% (1/12) of DD1 patients, respectively. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in 1 patient, minimal change lesion in 5 patients, and small focal acute tubular injury in 1 patient. A total of 11 mutations in the CLCN5 gene were detected, including 3 missense mutations (25.0%, c.1756C > T, c.1166T > G, and c.1618G > A), 5 frameshift mutations (41.7%, c.407delT, c.1702_c.1703insC, c.137delC, c.665_666delGGinsC, and c.2200delG), and 3 nonsense mutations (25.0%, c.776G > A, c.1609C > T, and c.1152G > A). There was no significant difference in age or clinical phenotype among patients with different mutation types (p > 0.05). All three mutations in the OCRL1 gene were missense mutations (c.1477C > T, c.952C > T, and c.198A > G). CONCLUSION:  Pediatric Dent disease is often misdiagnosed. Protein electrophoresis and genetic testing can help to provide an early and correct diagnosis.

Development, validation and application of single molecule molecular inversion probe based novel integrated genetic screening method for 29 common lysosomal storage disorders in India.

BACKGROUND: Current clinical diagnosis pathway for lysosomal storage disorders (LSDs) involves sequential biochemical enzymatic tests followed by DNA sequencing, which is iterative, has low diagnostic yield and is costly due to overlapping clinical presentations. Here, we describe a novel low-cost and high-throughput sequencing assay using single-molecule molecular inversion probes (smMIPs) to screen for causative single nucleotide variants (SNVs) and copy number variants (CNVs) in genes associated with 29 common LSDs in India. RESULTS: 903 smMIPs were designed to target exon and exon-intron boundaries of targeted genes (n = 23; 53.7 kb of the human genome) and were equimolarly pooled to create a sequencing library. After extensive validation in a cohort of 50 patients, we screened 300 patients with either biochemical diagnosis (n = 187) or clinical suspicion (n = 113) of LSDs. A diagnostic yield of 83.4% was observed in patients with prior biochemical diagnosis of LSD. Furthermore, diagnostic yield of 73.9% (n = 54/73) was observed in patients with high clinical suspicion of LSD in contrast with 2.4% (n = 1/40) in patients with low clinical suspicion of LSD. In addition to detecting SNVs, the assay could detect single and multi-exon copy number variants with high confidence. Critically, Niemann-Pick disease type C and neuronal ceroid lipofuscinosis-6 diseases for which biochemical testing is unavailable, could be diagnosed using our assay. Lastly, we observed a non-inferior performance of the assay in DNA extracted from dried blood spots in comparison with whole blood. CONCLUSION: We developed a flexible and scalable assay to reliably detect genetic causes of 29 common LSDs in India. The assay consolidates the detection of multiple variant types in multiple sample types while having improved diagnostic yield at same or lower cost compared to current clinical paradigm.

Implementation of a primary-tertiary shared care model to improve the detection of familial hypercholesterolaemia (FH): a mixed methods pre-post implementation study protocol.

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal dominant inherited disorder of lipid metabolism and a preventable cause of premature cardiovascular disease. Current detection rates for this highly treatable condition are low. Early detection and management of FH can significantly reduce cardiac morbidity and mortality. This study aims to implement a primary-tertiary shared care model to improve detection rates for FH. The primary objective is to evaluate the implementation of a shared care model and support package for genetic testing of FH. This protocol describes the design and methods used to evaluate the implementation of the shared care model and support package to improve the detection of FH. METHODS AND ANALYSIS: This mixed methods pre-post implementation study design will be used to evaluate increased detection rates for FH in the tertiary and primary care setting. The primary-tertiary shared care model will be implemented at NSW Health Pathology and Sydney Local Health District in NSW, Australia, over a 12-month period. Implementation of the shared care model will be evaluated using a modification of the implementation outcome taxonomy and will focus on the acceptability, evidence of delivery, appropriateness, feasibility, fidelity, implementation cost and timely initiation of the intervention. Quantitative pre-post and qualitative semistructured interview data will be collected. It is anticipated that data relating to at least 62 index patients will be collected over this period and a similar number obtained for the historical group for the quantitative data. We anticipate conducting approximately 20 interviews for the qualitative data. ETHICS AND DISSEMINATION: Ethical approval has been granted by the ethics review committee (Royal Prince Alfred Hospital Zone) of the Sydney Local Health District (Protocol ID: X23-0239). Findings will be disseminated through peer-reviewed publications, conference presentations and an end-of-study research report to stakeholders.

Germline Predisposition in Hematologic Malignancies: Testing, Management, and Implications.

Although numerous barriers for clinical germline cancer predisposition testing exist, the increasing recognition of deleterious germline DNA variants contributing to myeloid malignancy risk is yielding steady improvements in referrals for testing and testing availability. Many germline predisposition alleles are common in populations, and the increasing number of recognized disorders makes inherited myeloid malignancy risk an entity worthy of consideration for all patients regardless of age at diagnosis. Germline testing is facilitated by obtaining DNA from cultured skin fibroblasts or hair bulbs, and cascade testing is easily performed via buccal swab, saliva, or blood. Increasingly as diagnostic criteria and clinical management guidelines include germline myeloid malignancy predisposition, insurance companies recognize the value of testing and provide coverage. Once an individual is recognized to have a deleterious germline variant that confers risk for myeloid malignancies, a personalized cancer surveillance plan can be developed that incorporates screening for other cancer risk outside of the hematopoietic system and/or other organ pathology. The future may also include monitoring the development of clonal hematopoiesis, which is common for many of these cancer risk disorders and/or inclusion of strategies to delay or prevent progression to overt myeloid malignancy. As research continues to identify new myeloid predisposition disorders, we may soon recommend testing for these conditions for all patients diagnosed with a myeloid predisposition condition.

Exome sequencing reveals genetic heterogeneity and clinically actionable findings in children with cerebral palsy.

Cerebral palsy (CP) is the most common motor disability in children. To ascertain the role of major genetic variants in the etiology of CP, we conducted exome sequencing on a large-scale cohort with clinical manifestations of CP. The study cohort comprised 505 girls and 1,073 boys. Utilizing the current gold standard in genetic diagnostics, 387 of these 1,578 children (24.5%) received genetic diagnoses. We identified 412 pathogenic and likely pathogenic (P/LP) variants across 219 genes associated with neurodevelopmental disorders, and 59 P/LP copy number variants. The genetic diagnostic rate of children with CP labeled at birth with perinatal asphyxia was higher than the rate in children without asphyxia (P = 0.0033). Also, 33 children with CP manifestations (8.5%, 33 of 387) had findings that were clinically actionable. These results highlight the need for early genetic testing in children with CP, especially those with risk factors like perinatal asphyxia, to enable evidence-based medical decision-making.

Current Status of Molecular Diagnosis of Hereditary Hemolytic Anemia in Korea.

Hereditary hemolytic anemia (HHA) is considered a group of rare hematological diseases in Korea, primarily because of its unique ethnic characteristics and diagnostic challenges. Recently, the prevalence of HHA has increased in Korea, reflecting the increasing number of international marriages and increased awareness of the disease. In particular, the diagnosis of red blood cell (RBC) enzymopathy experienced a resurgence, given the advances in diagnostic techniques. In 2007, the RBC Disorder Working Party of the Korean Society of Hematology developed the Korean Standard Operating Procedure for the Diagnosis of Hereditary Hemolytic Anemia, which has been continuously updated since then. The latest Korean clinical practice guidelines for diagnosing HHA recommends performing next-generation sequencing as a preliminary step before analyzing RBC membrane proteins and enzymes. Recent breakthroughs in molecular genetic testing methods, particularly next-generation sequencing, are proving critical in identifying and providing insight into cases of HHA with previously unknown diagnoses. These innovative molecular genetic testing methods have now become important tools for the management and care planning of patients with HHA. This review aims to provide a comprehensive overview of recent advances in molecular genetic testing for the diagnosis of HHA, with particular emphasis on the Korean context.

Public Attitudes, Interests, and Concerns Regarding Polygenic Embryo Screening.

Importance: Polygenic embryo screening (PES) is a novel technology that estimates the likelihood of developing future conditions (eg, diabetes or depression) and traits (eg, height or cognitive ability) in human embryos, with the goal of selecting which embryos to use. Given its commercial availability and concerns raised by researchers, clinicians, bioethicists, and professional organizations, it is essential to inform key stakeholders and relevant policymakers about the public's perspectives on this technology. Objective: To survey US adults to examine general attitudes, interests, and concerns regarding PES use. Design, Setting, and Participants: For this survey study, data were collected from 1 stratified sample and 1 nonprobability sample (samples 1 and 2, respectively) between March and July 2023. The surveys measured approval, interest, and concerns regarding various applications of PES. In the second sample, presentation of a list of potential concerns was randomized (presented at survey onset vs survey end). The survey was designed using Qualtrics and distributed to participants through Prolific, an online sampling firm. Sample 1 was nationally representative with respect to gender, age, and race and ethnicity; sample 2 was recruited without specific demographic criteria. Analyses were conducted between March 2023 and February 2024. Main Outcomes and Measures: Participants reported their approval, interest, and concerns regarding various applications of PES and outcomes screened (eg, traits and conditions). Statistical analysis was conducted using independent samples t tests and repeated-measures analyses of variance. Results: Of the 1435 respondents in sample 1, demographic data were available for 1427 (mean [SD] age, 45.8 [16.0] years; 724 women [50.7%]). Among these 1427 sample 1 respondents, 1027 (72.0%) expressed approval for PES and 1169 (81.9%) expressed some interest in using PES if already undergoing in vitro fertilization (IVF). Approval among these respondents for using PES for embryo selection was notably high for physical health conditions (1109 [77.7%]) and psychiatric health conditions (1028 [72.0%]). In contrast, there was minority approval for embryo selection based on PES for behavioral traits (514 [36.0%]) and physical traits (432 [30.3%]). Nevertheless, concerns about PES leading to false expectations and promoting eugenic practices were pronounced, with 787 of 1422 (55.3%) and 780 of 1423 (54.8%) respondents finding them very to extremely concerning, respectively. Sample 2 included 192 respondents (mean [SD] age 37.7 [12.2] years; 110 men [57.3%]). These respondents were presented concerns at survey onset (n = 95) vs survey end (n = 97), which was associated with less approval (28-percentage point decrease) and more uncertainty (24 percentage-point increase) but with only slightly higher disapproval (4 percentage-point increase). Conclusions and Relevance: These findings suggest that it is critical for health care professionals and medical societies to consider and understand the perspectives of diverse stakeholders (eg, patients undergoing IVF, clinicians, and the general public), given the absence of regulation and the recent commercial availability of PES.

Feasibility and cost-effectiveness of genetic counselling for all patients with newly diagnosed ovarian cancer: a single-centre retrospective study.

BACKGROUND AND AIMS OF THE STUDY: Due to its importance for treatment and potential prevention in family members, germline testing for BRCA1/2 in patients with newly diagnosed ovarian cancer is decisive and considered a standard of care. Maintenance therapy with poly(ADP-ribose) polymerase (PARP) inhibitors substantially improves progression-free survival in patients with BRCA mutations and homologous recombination-deficient tumours by inducing synthetic lethality. In Switzerland, they are licensed only for these patients. Therefore, it is crucial to test patients early while they are receiving adjuvant chemotherapy. This study aimed to determine whether genetic counselling followed by homologous recombination deficiency testing is feasible for initialising maintenance therapy within eight weeks and cost-effective in daily practice in Switzerland compared to somatic tumour analysis of all patients at diagnosis. METHODS: This single-centre retrospective study included 44 patients with newly diagnosed high-grade serous ovarian cancer of a Federation of Gynaecology and Obstetrics (FIGO) stage of IIIA-IVB diagnosed between 12/2020 and 12/2022. It collected the outcomes of genetic counselling, germline testing, and somatic Geneva test for homologous recombination deficiency. Delays in initiating maintenance therapy, total testing costs per patient, and progression-free survival were examined to assess feasibility and cost-effectiveness in clinical practice. RESULTS: Thirty-seven of 44 patients (84%) with newly diagnosed ovarian cancer received counselling, of which 34 (77%) were tested for germline BRCA and other homologous recombination repair gene mutations. Five (15%) BRCA and three (9%) other homologous recombination deficiency mutations were identified. Eleven of the remaining 26 patients (42%) had tumours with somatic homologous recombination deficiency. The mean time to the initiation of maintenance therapy of 5.2 weeks was not longer than in studies for market authorisation (SOLO1, PAOLA, and PRIMA). The mean testing costs per patient were 3880 Swiss Franks (CHF), compared to 5624 CHF if all patients were tested at diagnosis with the myChoice CDx test (p <0.0001). CONCLUSION: Using genetic counselling to consent patients with newly diagnosed ovarian cancer for germline testing fulfils the international gold standard. Subsequent somatic homologous recombination deficiency analysis complements testing and identifies more patients who will benefit from PARP inhibitor maintenance therapy. Contrary to previous health cost model studies, the procedure does not increase testing costs in the Swiss population and does not delay maintenance therapy. Therefore, all patients should be offered a primary germline analysis. The challenge for the future will be to ensure sufficient resources for prompt genetic counselling and germline testing.

Clinical and genetic analysis of methylmalonic aciduria in 60 patients from Southern China: a single center retrospective study.

BACKGROUND: Methylmalonic aciduria (MMA) is a group of rare genetic metabolic disorders resulting from defects in methylmalonyl coenzyme A mutase (MCM) or intracellular cobalamin (cbl) metabolism. MMA patients show diverse clinical and genetic features across different subtypes and populations. METHODS: We retrospectively recruited 60 MMA patients from a single center and diagnosed them based on their clinical manifestations and biochemical assays. We then performed genetic analysis to confirm the diagnosis and identify the causal variants. RESULTS: We confirmed the common clinical manifestations of MMA reported previously. We also described four rare MMA cases with unusual symptoms or genetic variants, such as pulmonary hypertension or limb weakness in late-onset patients. We identified 15 MMACHC and 26 MMUT variants in 57 patients, including 6 novel MMUT variants. Two patients had only one MMAA variant each, and one patient had mild MMA due to mitochondrial DNA depletion syndrome caused by a SUCLA2 variant. Among 12 critically ill patients, isolated MMA was associated with higher C3, blood ammonia, and acidosis, while combined MMA was linked to hydrocephalus on skull MRI. MMACHC c.658-660delAAG and MMUT c.1280G > A variants were correlated with more severe phenotypes. CONCLUSIONS: Our study demonstrates the clinical and genotypic heterogeneity of MMA patients and indicates that metabolic screening and genetic analysis are useful tools to identify rare cases.

Genetic Screening of Patients with Sporadic Alzheimer's Disease and Frontotemporal Lobar Degeneration in the Chinese Population.

Background: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) account for the vast majority of neurodegenerative dementias. AD and FTLD have different clinical phenotypes with a genetic overlap between them and other dementias. Objective: This study aimed to identify the genetic spectrum of sporadic AD and FTLD in the Chinese population. Methods: A total of 74 sporadic AD and 29 sporadic FTLD participants were recruited. All participants underwent whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 was additionally performed for participants with negative WES results. Results: Four known pathogenic or likely pathogenic variants, including PSEN1 (p.G206D), MAPT (p.R5H), LRRK2 (p.W1434*), and CFAP43 (p.C934*), were identified in AD participants, and 1 novel pathogenic variant of ANXA11 (p.D40G) and two known likely pathogenic variants of MAPT (p.D177V) and TARDBP (p.I383V) were identified in FTLD participants. Twenty-four variants of uncertain significance as well as rare variants in risk genes for dementia, such as ABCA7, SORL1, TRPM7, NOS3, MPO, and DCTN1, were also found. Interestingly, several variants in participants with semantic variant primary progressive aphasia were detected. However, no participants with C9orf72 gene variants were found in the FTLD cohort. Conclusions: There was a high frequency of genetic variants in Chinese participants with sporadic AD and FTLD and a complex genetic overlap between these two types of dementia and other neurodegenerative diseases.

Relationship Between Genotype Status and Clinical Outcome in Hypertrophic Cardiomyopathy.

BACKGROUND: The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the relationship between genotype status and clinical outcome is incompletely resolved. METHODS AND RESULTS: We assessed a large international HCM cohort to define in contemporary terms natural history and clinical consequences of genotype. Consecutive patients (n=1468) with established HCM diagnosis underwent genetic testing. Patients with pathogenic (or likely pathogenic) variants were considered genotype positive (G+; n=312; 21%); those without definite disease-causing mutations (n=651; 44%) or variants of uncertain significance (n=505; 35%) were considered genotype negative (G-). Patients were followed up for a median of 7.8 years (interquartile range, 3.5-13.4 years); HCM end points were examined by cumulative event incidence. Over follow-up, 135 (9%) patients died, 33 from a variety of HCM-related causes. After adjusting for age, all-cause and HCM-related mortality did not differ between G- versus G+ patients (hazard ratio [HR], 0.78 [95% CI, 0.46-1.31]; P=0.37; HR, 0.93 [95% CI, 0.38-2.30]; P=0.87, respectively). Adverse event rates, including heart failure progression to class III/IV, heart transplant, or heart failure death, did not differ (G- versus G+) when adjusted for age (HR, 1.20 [95% CI, 0.63-2.26]; P=0.58), nor was genotype independently associated with sudden death event risk (HR, 1.39 [95% CI, 0.88-2.21]; P=0.16). In multivariable analysis, age was the only independent predictor of all-cause and HCM-related mortality, heart failure progression, and sudden death events. CONCLUSIONS: In this large consecutive cohort of patients with HCM, genotype (G+ or G-) was not a predictor of clinical course, including all-cause and HCM-related mortality and risk for heart failure progression or sudden death. G+ status should not be used to dictate clinical management or predict outcome in HCM.

Germline findings in cancer predisposing genes from a small cohort of chordoma patients.

INTRODUCTION: Chordoma is a rare slow-growing tumor that occurs along the length of the spinal axis and arises from primitive notochordal remnants (Stepanek et al., Am J Med Genet 75:335-336, 1998). Most chordomas are sporadic, but a small percentage of cases are due to hereditary cancer syndromes (HCS) such as tuberous sclerosis 1 and 2 (TSC1/2), or constitutional variants in the gene encoding brachyury T (TBXT) (Pillay et al., Nat Genet 44:1185-1187, 2012; Yang et al., Nat Genet 41:1176-1178, 2009). PURPOSE: The genetic susceptibility of these tumors is not well understood; there are only a small number of studies that have performed germline genetic testing in this population. METHODS: We performed germline genetic in chordoma patients using genomic DNA extracted by blood or saliva. CONCLUSION: We report here a chordoma cohort of 24 families with newly found germline genetic mutations in cancer predisposing genes. We discuss implications for genetic counseling, clinical management, and universal germline genetic testing for cancer patients with solid tumors.

On the Hunt for the Missed Genetic Causes of Multiple Primary Tumors.

Improved cancer screening and treatment programs have led to an increased survivorship of patients with cancer, but consequently also to the rise in number of individuals with multiple primary tumors (MPT). Germline testing is the first approach investigating the cause of MPT, as a positive result provides a diagnosis and proper clinical management to the affected individual and their family. Negative or inconclusive genetic results could suggest non-genetic causes, but are negative genetic results truly negative? Herein, we discuss the potential sources of missed genetic causes and highlight the trove of knowledge MPT can provide. See related article by Borja et al., p. 209.

The importance of variant reinterpretation in inherited cardiovascular diseases: Establishing the optimal timeframe.

Inherited cardiovascular diseases are rare diseases that are difficult to diagnose by non-expert professionals. Genetic analyses play a key role in the diagnosis of these diseases, in which the identification of a pathogenic genetic variant is often a diagnostic criterion. Therefore, genetic variant classification and routine reinterpretation as data become available represent one of the main challenges associated with genetic analyses. Using the genetic variants identified in an inherited cardiovascular diseases unit during a 10-year period, the objectives of this study were: 1) to evaluate the impact of genetic variant reinterpretation, 2) to compare the reclassification rates between different cohorts of cardiac channelopathies and cardiomyopathies, and 3) to establish the most appropriate periodicity for genetic variant reinterpretation. All the evaluated cohorts (full cohort of inherited cardiovascular diseases, cardiomyopathies, cardiac channelopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) showed reclassification rates above 25%, showing even higher reclassification rates when there is definitive evidence of the association between the gene and the disease in the cardiac channelopathies. Evaluation of genetic variant reclassification rates based on the year of the initial classification showed that the most appropriate frequency for the reinterpretation would be 2 years, with the possibility of a more frequent reinterpretation if deemed convenient. To keep genetic variant classifications up to date, genetic counsellors play a critical role in the reinterpretation process, providing clinical evidence that genetic diagnostic laboratories often do not have at their disposal and communicating changes in classification and the potential implications of these reclassifications to patients and relatives.