UNASSIGNED: Preimplantation genetic testing (PGT) is a reproductive technology that selects embryos without (familial) genetic variants. PGT has been applied in inherited cardiac disease and is included in the latest American Heart Association/American College of Cardiology guidelines. However, guidelines selecting eligible couples who will have the strongest risk reduction most from PGT are lacking. We developed an objective decision model to select eligibility for PGT and compared its results with those from a multidisciplinary team.
UNASSIGNED: All couples with an inherited cardiac disease referred to the national PGT center were included. A multidisciplinary team approved or rejected the indication based on clinical and genetic information. We developed a decision model based on published risk prediction models and literature, to evaluate the severity of the cardiac phenotype and the penetrance of the familial variant in referred patients. The outcomes of the model and the multidisciplinary team were compared in a blinded fashion.
UNASSIGNED: Eighty-three couples were referred for PGT (1997-2022), comprising 19 different genes for 8 different inherited cardiac diseases (cardiomyopathies and arrhythmias). Using our model and proposed cutoff values, a definitive decision was reached for 76 (92%) couples, aligning with 95% of the multidisciplinary team decisions. In a prospective cohort of 11 couples, we showed the clinical applicability of the model to select couples most eligible for PGT.
UNASSIGNED: The number of PGT requests for inherited cardiac diseases increases rapidly, without the availability of specific guidelines. We propose a 2-step decision model that helps select couples with the highest risk reduction for cardiac disease in their offspring after PGT.

Although current long-read sequencing technologies have a long-read length that facilitates assembly for genome reconstruction, they have high sequence errors. While various assemblers with different perspectives have been developed, no systematic evaluation of assemblers with long reads for diploid genomes with varying heterozygosity has been performed. Here, we evaluated a series of processes, including the estimation of genome characteristics such as genome size and heterozygosity, de novo assembly, polishing, and removal of allelic contigs, using six genomes with various heterozygosity levels. We evaluated five long-read-only assemblers (Canu, Flye, miniasm, NextDenovo and Redbean) and five hybrid assemblers that combine short and long reads (HASLR, MaSuRCA, Platanus-allee, SPAdes and WENGAN) and proposed a concrete guideline for the construction of haplotype representation according to the degree of heterozygosity, followed by polishing and purging haplotigs, using stable and high-performance assemblers: Redbean, Flye and MaSuRCA.

Nemaline myopathy (NM) is a heterogeneous genetic neuromuscular disorder characterized by rod bodies in muscle fibers resulting in multiple complications due to muscle weakness. NM patients and their families could benefit from genetic analysis for early diagnosis, carrier and prenatal testing; however, clinical classification of variants is subject to change as further information becomes available. Reclassification can significantly alter the clinical management of patients and their families. We used the newly published data and ACMG/AMP guidelines to reassess NM-associated variants previously reported by clinical laboratories (ClinVar). Our analyses on rare variants that were not canonical loss-of-function (LOF) resulted in the downgrading of ~29% (28/97) of variants from pathogenic or likely-pathogenic (P/LP) to variants of uncertain significance (VUS). In addition, we analyzed the splicing effect of variants identified in NM patients by clinical laboratories or research, using an accurate in silico prediction tool that applies a deep-learning network. We identified 55 rare variants that may impact splicing (cryptic splicing). We also analyzed six new NM families and identified eight variants in NEB and ACTA1, including three novel variants: homozygous pathogenic c.164A > G (p.Tyr55Cys), and homozygous likely pathogenic c.980T > C (p.Met327Thr) in ACTA1, and heterozygous VUS c.18694-3T > G in NEB. This study demonstrates the importance of reclassifying variants to facilitate more definitive \"calls\" on causality or no causality in clinical genetic testing of patients with NM. Reclassification of ~150 variants is now available for improved clinical management, risk counseling and screening of NM patients.

Becker muscular dystrophy (BMD) is one of the most frequent among neuromuscular diseases, affecting approximately 1 in 18,000 male births. It is linked to a genetic mutation on the X chromosome. In contrast to Duchenne muscular dystrophy, for which improved care and management have changed the prognosis and life expectancy of patients, few guidelines have been published for management of BMD. Many clinicians are inexperienced in managing the complications of this disease. In France, a committee of experts from a wide range of disciplines met in 2019 to establish recommendations, with the goal of improving care of patients with BMD. Here, we present the tools to provide diagnosis of BMD as quickly as possible and for differential diagnoses. Then, we describe the multidisciplinary approach essential for optimum management of BMD. We give recommendations for the initial assessment and follow-up of the neurological, respiratory, cardiac, and orthopedic consequences of males who present with BMD. Finally, we describe the optimal therapeutic management of these complications. We also provide guidance on cardiac management for female carriers.

UNASSIGNED: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management.
UNASSIGNED: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2.
UNASSIGNED: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence.
UNASSIGNED: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined.
UNASSIGNED: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.

As atherosclerosis begins in childhood, early diagnosis and treatment of familial hypercholesterolemia (FH) is considered necessary. The basic diagnosis of pediatric FH (under 15 years of age) is based on hyper-low-density lipoprotein (LDL) cholesterolemia and a family history of FH; however, in this guideline, to reduce overlooked cases, \"probable FH\" was established. Once diagnosed with FH or probable FH, efforts should be made to promptly provide lifestyle guidance, including diet. It is also important to conduct an intrafamilial survey, to identify family members with the same condition. If the level of LDL-C remains above 180 mg/dL, drug therapy should be considered at the age of 10. The first-line drug should be statin. Evaluation of atherosclerosis should be started using non-invasive techniques, such as ultrasound. The management target level is an LDL-C level of less than 140 mg/dL. If a homozygous FH is suspected, consult a specialist and determine the response to pharmacotherapy with evaluating atherosclerosis. If the response is inadequate, initiate lipoprotein apheresis as soon as possible.

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Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.

This nationwide study assessed the impact of Lynch syndrome-related risk management guidelines on clinicians\' recommendations of risk management strategies to carriers of pathogenic variants in mismatch repair genes and the extent to which carriers took up strategies in concordance with guidelines.
Clinic files of 464 carriers (with and without colorectal cancer) were audited for carriers who received their genetic testing results in July 2008-July 2009 (i.e. before guideline release), July 2010-July 2011 and July 2012-July 2013 (both after guideline release) at 12 familial cancer clinics (FCCs) to ascertain the extent to which carriers were informed about risk management in accordance with guidelines. All carriers captured by the audit were invited to participate in interviews; 215 were interviewed to assess adherence to recommended risk management guidelines.
The rates of documentation in clinic files increased significantly from pre- to post-guideline for only two out of eight risk management strategies. The strategies with the highest compliance of carriers post-guidelines were: uptake of one or two-yearly colonoscopy (87%), followed by hysterectomy to prevent endometrial cancer (68%), aspirin as risk-reducing medication (67%) and risk-reducing salpingo-oophorectomy (63%). Interrater reliability check for all guidelines showed excellent agreement (k statistics = 0.89).
These results indicate that there is scope to further increase provision of advice at FCCs to ensure that all carriers receive recommendations about evidence-based risk management. A multi-pronged behaviour change and implementation science approach tailored to specific barriers is likely to be needed to achieve optimal clinician behaviours and outcomes for carriers.

Spinal muscular atrophy (SMA) is one of the most common fatal autosomal recessive genetic disorders among infants. It is caused by mutations of motor neuron survival gene 1 (SMN1). The incidence of SMA among newborns is approximately 1/10 000 - 1/6000, and the carrier rate is 1/72 - 1/47 with an ethnic variance. Based on the time of onset and clinical phenotype, SMA can be divided into types I - IV. Approximately 95% of SMA patients have carried homozygous deletions of exon 7 of the (SMN1)] gene. For its significant phenotypic difference, abundant changes of (SMN1)] gene copy number, presence of pseudogene interference and high carrier rate, early diagnosis, genetic consultation, treatment and prevention of SMA can be difficult. This guideline summarizes the relevant research, guideline and consensus issued at home and abroad, clinical manifestations and pathogenesis of SMA patients, and experience in its diagnosis and genetic counseling, with an aim to promote a standardized diagnosis and treatment and reduce the births of children affected with the disease.