Genotype-phenotype correlation in the spectrum of frontotemporal dementia-parkinsonian syndromes and advanced diagnostic approaches.

The term frontotemporal dementia (FTD) refers to a group of progressive neurodegenerative disorders characterized mainly by atrophy of the frontal and anterior temporal lobes. Based on clinical presentation, three main clinical syndromes have traditionally been described: behavioral variant frontotemporal dementia (bvFTD), non-fluent/agrammatic primary progressive aphasia (nfPPA), and semantic variant PPA (svPPA). However, over the last 20 years, it has been recognized that cognitive phenotypes often overlap with motor phenotypes, either motor neuron diseases or parkinsonian signs and/or syndromes like progressive supranuclear palsy (PSP) and cortico-basal syndrome (CBS). Furthermore, FTD-related genes are characterized by genetic pleiotropy and can cause, even in the same family, pure motor phenotypes, findings that underlie the clinical continuum of the spectrum, which has pure cognitive and pure motor phenotypes as the extremes. The genotype-phenotype correlation of the spectrum, FTD-motor neuron disease, has been well defined and extensively investigated, while the continuum, FTD-parkinsonism, lacks a comprehensive review. In this narrative review, we describe the current knowledge about the genotype-phenotype correlation of the spectrum, FTD-parkinsonism, focusing on the phenotypes that are less frequent than bvFTD, namely nfPPA, svPPA, PSP, CBS, and cognitive-motor overlapping phenotypes (i.e. PPA + PSP). From a pathological point of view, they are characterized mainly by the presence of phosphorylated-tau inclusions, either 4 R or 3 R. The genetic correlate of the spectrum can be heterogeneous, although some variants seem to lead preferentially to specific clinical syndromes. Furthermore, we critically review the contribution of genome-wide association studies (GWAS) and next-generation sequencing (NGS) in disentangling the complex heritability of the FTD-parkinsonism spectrum and in defining the genotype-phenotype correlation of the entire clinical scenario, owing to the ability of these techniques to test multiple genes, and so to allow detailed investigations of the overlapping phenotypes. Finally, we conclude with the importance of a detailed genetic characterization and we offer to patients and families the chance to be included in future randomized clinical trials focused on autosomal dominant forms of FTLD.

Emerging technology: a definition for laboratory medicine.

The term "emerging technology" (ET) is used extensively, and there are numerous definitions offered, but to our knowledge, none specifically encompass the field of laboratory medicine. An ET definition that incorporates the overarching IFCC aim of "Advancing excellence in laboratory medicine to support healthcare worldwide" would clarify discussions. We discuss key aspects of the term "emerging technology(ies)" as it applies to laboratory medicine with a view to laying the foundations for a practical definition for the profession and propose the definition of an ET as "An analytical method or device that by virtue of its stage of development, translation into broad routine clinical practice, or geographical adoption and implementation has the potential to add value to clinical diagnostics".

Toolkit for emerging technologies in laboratory medicine.

An emerging technology (ET) for laboratory medicine can be defined as an analytical method (including biomarkers) or device (software, applications, and algorithms) that by its stage of development, translation into broad routine clinical practice, or geographical adoption and implementation has the potential to add value to clinical diagnostics. Considering the laboratory medicine-specific definition, this document examines eight key tools, encompassing clinical, analytical, operational, and financial aspects, used throughout the life cycle of ET implementation. The tools provide a systematic approach starting with identifying the unmet need or identifying opportunities for improvement (Tool 1), forecasting (Tool 2), technology readiness assessment (Tool 3), health technology assessment (Tool 4), organizational impact map (Tool 5), change management (Tool 6), total pathway to method evaluation checklist (Tool 7), and green procurement (Tool 8). Whilst there are differences in clinical priorities between different settings, the use of this set of tools will help support the overall quality and sustainability of the emerging technology implementation.

Impaired turnover of hyperfused mitochondria in severe axonal neuropathy due to a novel DRP1 mutation.

Mitochondria undergo continuous cycles of fusion and fission in response to physiopathological stimuli. The key player in mitochondrial fission is dynamin-related protein 1 (DRP1), a cytosolic protein encoded by dynamin 1-like (DNM1L) gene, which relocalizes to the outer mitochondrial membrane, where it assembles, oligomerizes and drives mitochondrial division upon guanosine-5'-triphosphate (GTP) hydrolysis. Few DRP1 mutations have been described so far, with patients showing complex and variable phenotype ranging from early death to encephalopathy and/or optic atrophy. The disease is the consequence of defective mitochondrial fission due to faulty DRP1 function. However, the underlying molecular mechanisms and the functional consequences at mitochondrial and cellular level remain elusive. Here we report on a 5-year-old girl presenting psychomotor developmental delay, global hypotonia and severe ataxia due to axonal sensory neuropathy harboring a novel de novo heterozygous missense mutation in the GTPase domain of DRP1 (NM_012062.3:c.436G>A, NP_036192.2: p.D146N variant in DNM1L). Patient's fibroblasts show hyperfused/balloon-like giant mitochondria, highlighting the importance of D146 residue for DRP1 function. This dramatic mitochondrial rearrangement phenocopies what observed overexpressing DRP1-K38A, a well-known experimental dominant negative version of DRP1. In addition, we demonstrated that p.D146N mutation has great impact on peroxisomal shape and function. The p.D146N mutation compromises the GTPase activity without perturbing DRP1 recruitment or assembly, causing decreased mitochondrial and peroxisomal turnover. In conclusion, our findings highlight the importance of sensory neuropathy in the clinical spectrum of DRP1 variants and, for the first time, the impact of DRP1 mutations on mitochondrial turnover and peroxisomal functionality.

Fluoroindate Glass Co-Doped with Yb3+/Ho3+ as a 2.85 µm Luminescent Source for MID-IR Sensing.

This work reports on the fabrication and analysis of near-infrared and mid-infrared luminescence spectra and their decays in fluoroindate glasses co-doped with Yb3+/Ho3+. The attention has been paid to the analysis of the Yb3+→ Ho3+ energy transfer processed ions in fluoroindate glasses pumped by 976 nm laser diode. The most effective sensitization for 2 µm luminescence has been obtained in glass co-doped with 0.8YbF3/1.6HoF3. Further study in the mid-infrared spectral range (2.85 µm) showed that the maximum emission intensity has been obtained in fluoroindate glass co-doped with 0.1YbF3/1.4HoF3. The obtained efficiency of Yb3+→ Ho3+ energy transfer was calculated to be up to 61% (0.8YbF3/1.6HoF3), which confirms the possibility of obtaining an efficient glass or glass fiber infrared source for a MID-infrared (MID-IR) sensing application.

Luminescent Ink Based on Upconversion of NaYF4:Er,Yb@MA Nanoparticles: Environmental Friendly Synthesis and Structural and Spectroscopic Assessment.

NaYF4:Er,Yb upconversion luminescent nanoparticles (UCNPs) were prepared by hydrothermal methods at 180 °C for 24 h. The X-ray diffraction (XRD) and TEM (transmission electron microscopy) images show that the resulting 60 nm UCNPs possess a hexagonal structure. In this work, maleic anhydride (MA) was grafted on the surface of UCNPs to induce hydrophilic properties. The photoluminescence spectra (PL) show upconversion emissions centered around 545 nm and 660 nm under excitation at 980 nm. The luminescent inks, including UCNPs@MA, polyvinyl alcohol (PVA), deionized water (DI), and ethylene glycol (EG), exhibit suitable properties for screen printing, such as high stability, emission intensity, and tunable dynamic viscosity. The printed patterns with a height of 5 mm and a width of 1.5 mm were clearly observed under the irradiation of a 980 nm laser. Our strategy provides a new route for the controlled synthesis of hydrophilic UCNPs, and shows that the UCNPs@MAs have great potential in applications of anti-counterfeiting packing.

Late gadolinium enhancement role in arrhythmic risk stratification of patients with LMNA cardiomyopathy: results from a long-term follow-up multicentre study.

AIMS: We aimed at addressing the role of late gadolinium enhancement (LGE) in arrhythmic risk stratification of LMNA-associated cardiomyopathy (CMP). METHODS AND RESULTS: We present data from a multicentre national cohort of patients with LMNA mutations. Of 164 screened cases, we finally enrolled patients with baseline cardiac magnetic resonance (CMR) including LGE sequences [n = 41, age 35 ± 17 years, 51% males, mean left ventricular ejection fraction (LVEF) by echocardiogram 56%]. The primary endpoint of the study was follow-up (FU) occurrence of malignant ventricular arrhythmias [MVA, including sustained ventricular tachycardia (VT), ventricular fibrillation, and appropriate implantable cardioverter-defibrillator (ICD) therapy]. At baseline CMR, 25 subjects (61%) had LGE, with non-ischaemic pattern in all of the cases. Overall, 23 patients (56%) underwent ICD implant. By 10 ± 3 years FU, eight patients (20%) experienced MVA, consisting of appropriate ICD shocks in all of the cases. In particular, the occurrence of MVA in LGE+ vs. LGE- groups was 8/25 vs. 0/16 (P = 0.014). Of note, no significant differences between LGE+ and LGE- patients were found in currently recognized risk factors for sudden cardiac death (male gender, non-missense mutations, baseline LVEF <45% and non-sustained VT), all P-value >0.05. CONCLUSIONS: In LMNA-CMP patients, LGE at baseline CMR is significantly associated with MVA. In particular, as suggested by this preliminary experience, the absence of LGE allowed to rule-out MVA at 10 years mean FU.

Biosafety measures for preventing infection from COVID-19 in clinical laboratories: IFCC Taskforce Recommendations.

Coronavirus disease 2019 (COVID-19) is the third coronavirus outbreak that has emerged in the past 20 years, after severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). One important aspect, highlighted by many global health organizations, is that this novel coronavirus outbreak may be especially hazardous to healthcare personnel, including laboratory professionals. Therefore, the aim of this document, prepared by the COVID-19 taskforce of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), is to provide a set of recommendations, adapted from official documents of international and national health agencies, on biosafety measures for routine clinical chemistry laboratories that operate at biosafety levels 1 (BSL-1; work with agents posing minimal threat to laboratory workers) and 2 (BSL-2; work with agents associated with human disease which pose moderate hazard). We believe that the interim measures proposed in this document for best practice will help minimazing the risk of developing COVID-19 while working in clinical laboratories.

Operational considerations and challenges of biochemistry laboratories during the COVID-19 outbreak: an IFCC global survey.

Objectives: The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 conducted a global survey to understand how biochemistry laboratories manage the operational challenges during the coronavirus disease 2019 (COVID-19) pandemic. Materials and methods: An electronic survey was distributed globally to record the operational considerations to mitigate biosafety risks in the laboratory. Additionally, the laboratories were asked to indicate the operational challenges they faced. Results: A total of 1210 valid submissions were included in this analysis. Most of the survey participants worked in hospital laboratories. Around 15% of laboratories restricted certain tests on patients with clinically suspected or confirmed COVID-19 over biosafety concerns. Just over 10% of the laboratories had to restrict their test menu or services due to resource constraints. Approximately a third of laboratories performed temperature monitoring, while two thirds of laboratories increased the frequency of disinfection. Just less than 50% of the laboratories split their teams. The greatest reported challenge faced by laboratories during the COVID-19 pandemic is securing sufficient supplies of personal protective equipment (PPE), analytical equipment, including those used at the point of care, as well as reagents, consumables and other laboratory materials. This was followed by having inadequate staff, managing their morale, anxiety and deployment. Conclusions: The restriction of tests and services may have undesirable clinical consequences as clinicians are deprived of important information to deliver appropriate care to their patients. Staff rostering and biosafety concerns require longer-term solutions as they are crucial for the continued operation of the laboratory during what may well be a prolonged pandemic.

Laboratory practices to mitigate biohazard risks during the COVID-19 outbreak: an IFCC global survey.

Objectives: A global survey was conducted by the IFCC Task Force on COVID-19 to better understand how general biochemistry laboratories manage the pre-analytical, analytical and post-analytical processes to mitigate biohazard risks during the coronavirus disease 2019 (COVID-19) pandemic. Methods: An electronic survey was developed to record the general characteristics of the laboratory, as well as the pre-analytical, analytical, post-analytical and operational practices of biochemistry laboratories that are managing clinical samples of patients with COVID-19. Results: A total of 1210 submissions were included in the analysis. The majority of responses came from hospital central/core laboratories that serve hospital patient groups and handle moderate daily sample volumes. There has been a decrease in the use of pneumatic tube transport, increase in hand delivery and increase in number of layers of plastic bags for samples of patients with clinically suspected or confirmed COVID-19. Surgical face masks and gloves are the most commonly used personal protective equipment (PPE). Just >50% of the laboratories did not perform an additional decontamination step on the instrument after analysis of samples from patients with clinically suspected or confirmed COVID-19. A fifth of laboratories disallowed add-on testing on these samples. Less than a quarter of laboratories autoclaved their samples prior to disposal. Conclusions: The survey responses showed wide variation in pre-analytical, analytical and post-analytical practices in terms of PPE adoption and biosafety processes. It is likely that many of the suboptimal biosafety practices are related to practical local factors, such as limited PPE availability and lack of automated instrumentation.

Molecular, serological, and biochemical diagnosis and monitoring of COVID-19: IFCC taskforce evaluation of the latest evidence.

The global coronavirus disease 2019 (COVID-19) has presented major challenges for clinical laboratories, from initial diagnosis to patient monitoring and treatment. Initial response to this pandemic involved the development, production, and distribution of diagnostic molecular assays at an unprecedented rate, leading to minimal validation requirements and concerns regarding their diagnostic accuracy in clinical settings. In addition to molecular testing, serological assays to detect antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are now becoming available from numerous diagnostic manufacturers. In both cases, the lack of peer-reviewed data and regulatory oversight, combined with general misconceptions regarding their appropriate use, have highlighted the importance of laboratory professionals in robustly validating and evaluating these assays for appropriate clinical use. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 has been established to synthesize up-to-date information on the epidemiology, pathogenesis, and laboratory diagnosis and monitoring of COVID-19, as well as to develop practical recommendations on the use of molecular, serological, and biochemical tests in disease diagnosis and management. This review summarizes the latest evidence and status of molecular, serological, and biochemical testing in COVID-19 and highlights some key considerations for clinical laboratories operating to support the global fight against this ongoing pandemic. Confidently this consolidated information provides a useful resource to laboratories and a reminder of the laboratory's critical role as the world battles this unprecedented crisis.

IFCC Interim Guidelines on Molecular Testing of SARS-CoV-2 Infection.

The diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection globally has relied extensively on molecular testing, contributing vitally to case identification, isolation, contact tracing, and rationalization of infection control measures during the coronavirus disease 2019 (COVID-19) pandemic. Clinical laboratories have thus needed to verify newly developed molecular tests and increase testing capacity at an unprecedented rate. As the COVID-19 pandemic continues to pose a global health threat, laboratories continue to encounter challenges in the selection, verification, and interpretation of these tests. This document by the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 provides interim guidance on: (A) clinical indications and target populations, (B) assay selection, (C) assay verification, and (D) test interpretation and limitations for molecular testing of SARS-CoV-2 infection. These evidence-based recommendations will provide practical guidance to clinical laboratories worldwide and highlight the continued importance of laboratory medicine in our collective pandemic response.

IFCC Interim Guidelines on Serological Testing of Antibodies against SARS-CoV-2.

Serological testing for the detection of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is emerging as an important component of the clinical management of patients with coronavirus disease 2019 (COVID-19) as well as the epidemiological assessment of SARS-CoV-2 exposure worldwide. In addition to molecular testing for the detection of SARS-CoV-2 infection, clinical laboratories have also needed to increase testing capacity to include serological evaluation of patients with suspected or known COVID-19. While regulatory approved serological immunoassays are now widely available from diagnostic manufacturers globally, there is significant debate regarding the clinical utility of these tests, as well as their clinical and analytical performance requirements prior to application. This document by the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Taskforce on COVID-19 provides interim guidance on: (A) clinical indications and target populations, (B) assay selection, (C) assay evaluation, and (D) test interpretation and limitations for serological testing of antibodies against SARS-CoV-2 infection. These evidence-based recommendations will provide practical guidance to clinical laboratories in the selection, verification, and implementation of serological assays and are of the utmost importance as we expand our pandemic response from initial case tracing and containment to mitigation strategies to minimize resurgence and further morbidity and mortality.

IFCC Interim Guidelines on Biochemical/Hematological Monitoring of COVID-19 Patients.

Routine biochemical and hematological tests have been reported to be useful in the stratification and prognostication of pediatric and adult patients with diagnosed coronavirus disease (COVID-19), correlating with poor outcomes such as the need for mechanical ventilation or intensive care, progression to multisystem organ failure, and/or death. While these tests are already well established in most clinical laboratories, there is still debate regarding their clinical value in the management of COVID-19, particularly in pediatrics, as well as the value of composite clinical risk scores in COVID-19 prognostication. This document by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Task Force on COVID-19 provides interim guidance on: (A) clinical indications for testing, (B) recommendations for test selection and interpretation, (C) considerations in test interpretation, and (D) current limitations of biochemical/hematological monitoring of COVID-19 patients. These evidence-based recommendations will provide practical guidance to clinical laboratories worldwide, underscoring the contribution of biochemical and hematological testing to our collective pandemic response.

Cardiac and Neuromuscular Features of Patients With LMNA-Related Cardiomyopathy.

Background: Mutations in the LMNA (lamin A/C) gene have been associated with neuromuscular and cardiac manifestations, but the clinical implications of these signs are not well understood. Objective: To learn more about the natural history of LMNA-related disease. Design: Observational study. Setting: 13 clinical centers in Italy from 2000 through 2018. Patients: 164 carriers of an LMNA mutation. Measurements: Detailed cardiologic and neurologic evaluation at study enrollment and for a median of 10 years of follow-up. Results: The median age at enrollment was 38 years, and 51% of participants were female. Neuromuscular manifestations preceded cardiac signs by a median of 11 years, but by the end of follow-up, 90% of the patients had electrical heart disease followed by structural heart disease. Overall, 10 patients (6%) died, 14 (9%) received a heart transplant, and 32 (20%) had malignant ventricular arrhythmias. Fifteen patients had gait loss, and 6 had respiratory failure. Atrial fibrillation and second- and third-degree atrioventricular block were observed, respectively, in 56% and 51% of patients with combined cardiac and neuromuscular manifestations and 37% and 33% of those with heart disease only. Limitations: Some of the data were collected retrospectively. Neuromuscular manifestations were more frequent in this analysis than in previous studies. Conclusion: Many patients with an LMNA mutation have neurologic symptoms by their 30s and develop progressive cardiac manifestations during the next decade. A substantial proportion of these patients will have life-threatening neurologic or cardiologic conditions. Primary Funding Source: None.

Evaluation of the Oropharyngeal Airway Space in Class II Malocclusion Treated with Mandibular Activator: A Retrospective Study.

AIM: The development of a class II malocclusion is usually related to a reduced oropharyngeal airway space. In order to prevent airway obstruction, functional appliances are commonly used for orthodontic therapy. The aim of the article is to verify if these appliances could positively influence oropharyngeal diameters preventing the onset of future respiratory disorders. MATERIALS AND METHODS: A group of 10 patients treated at the Dental Clinic of San Gerardo Hospital in Monza with mandibular activator was selected. Ten similar untreated class II subjects with retrognathic mandible were used as control group. The cephalometric tracings were made on lateral teleradiographs of the skull before and after the active therapy with functional devices for the treated group and before and after growth peak for the control one. Descriptive statistical analysis was calculated for all the cephalometric values in both study cases and control group using Excel worksheet. The data distribution was evaluated with Shapiro-Wilk test and the in-between group discrepancies were evaluated with Mann-Whitney U test. RESULTS: At T1 period, both case and control groups showed a class II pattern. At T2 period, the study group shows an improvement in bones relationship with reduced ANB angles and OVJ measurements. The control group otherwise did not show any important changes in maxillo-mandibular discrepancies. The airway size increased in either group in most cases. No significant differences between the treated and control groups were detected for airway size neither in the upper, middle, nor lower level at the T1-T2 interval. CONCLUSION: The upper airway values did not show any significant discrepancies between the two groups during the observation period. CLINICAL SIGNIFICANCE: Functional devices were effective in solving class II relationships, but there is no evidence of successful breathing disorders prevention by using mandibular activators, probably due to the stability of airway tissues reached in pubertal age in both groups.

ADCY10 frameshift variant leading to severe recessive asthenozoospermia and segregating with absorptive hypercalciuria.

STUDY QUESTION: Can whole exome sequencing (WES) reveal a novel pathogenic variant in asthenozoospermia in a multiplex family including multiple patients? SUMMARY ANSWER: Patients were discovered to be homozygous for a rare 2-bp deletion in the ADCY10 coding region (c.1205_1206del, rs779944215). WHAT IS KNOWN ALREADY: ADCY10 encodes for soluble adenylyl cyclase (sAC), which is the predominant adenylate cyclase in sperm. It is already established that proper sAC activity and a constant supply of cAMP are crucial to sperm motility regulation, and knockout mouse models have been reported as severely asthenozoospermic. ADCY10 is a susceptibility gene for dominant absorptive hypercalciuria (OMIM#143870); however, no ADCY10 variations have been confirmed to cause human asthenozoospermia to date. STUDY DESIGN, SIZE, DURATION: This was a retrospective genetics study of a highly consanguineous pedigree of asthenozoospermia. The subject family was recruited in Iran in 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: The two patients were diagnosed as asthenozoospermic through careful clinical investigations. Both patients, respective parents, and an unaffected brother were subjected to WES. The discovered variant was validated by Sanger sequencing and segregated with the phenotype. To confirm the pathogenicity of the variant, sperm samples from both patients, 10 normozoospermic men and 10 asthenozoospermic patients not representing the variation, were treated with a cAMP analogue dissolved in human tubal fluid medium, followed by computer-assisted sperm analysis and statistical analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The discovered homozygous variant occurs at 10 amino acids upstream of the ADCY10 nucleotide binding site leading to a premature termination (p.His402Argfs*41). Treatment of the patients' sperm samples with a cell-permeable cAMP analogue resulted in a significant increase in sperm motility, indicating the pathogenic role of the variant. Moreover, absorptive hypercalciuria, segregating within the family, was also associated with the same variant following a dominant inheritance. LIMITATIONS, REASONS FOR CAUTION: Though nonsense-mediated decay is highly likely to occur in the mutated transcripts, we were not able to confirm this due to low RNA levels in mature sperm. WIDER IMPLICATIONS OF THE FINDINGS: Our finding enlarges the phenotypic spectrum associated with the ADCY10 gene, previously described as a susceptibility gene for dominant absorptive hypercalciuria. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the Royan Institute, Tehran, Iran, and San Raffaele Hospital, Milan, Italy. The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Expanding the spectrum of genes responsible for hereditary motor neuropathies.

BACKGROUND: Inherited peripheral neuropathies (IPNs) represent a broad group of genetically and clinically heterogeneous disorders, including axonal Charcot-Marie-Tooth type 2 (CMT2) and hereditary motor neuropathy (HMN). Approximately 60%-70% of cases with HMN/CMT2 still remain without a genetic diagnosis. Interestingly, mutations in HMN/CMT2 genes may also be responsible for motor neuron disorders or other neuromuscular diseases, suggesting a broad phenotypic spectrum of clinically and genetically related conditions. Thus, it is of paramount importance to identify novel causative variants in HMN/CMT2 patients to better predict clinical outcome and progression. METHODS: We designed a collaborative study for the identification of variants responsible for HMN/CMT2. We collected 15 HMN/CMT2 families with evidence for autosomal recessive inheritance, who had tested negative for mutations in 94 known IPN genes, who underwent whole-exome sequencing (WES) analyses. Candidate genes identified by WES were sequenced in an additional cohort of 167 familial or sporadic HMN/CMT2 patients using next-generation sequencing (NGS) panel analysis. RESULTS: Bioinformatic analyses led to the identification of novel or very rare variants in genes, which have not been previously associated with HMN/CMT2 (ARHGEF28, KBTBD13, AGRN and GNE); in genes previously associated with HMN/CMT2 but in combination with different clinical phenotypes (VRK1 and PNKP), and in the SIGMAR1 gene, which has been linked to HMN/CMT2 in only a few cases. These findings were further validated by Sanger sequencing, segregation analyses and functional studies. CONCLUSIONS: These results demonstrate the broad spectrum of clinical phenotypes that can be associated with a specific disease gene, as well as the complexity of the pathogenesis of neuromuscular disorders.

Comparable clinical characteristics in Brugada syndrome patients harboring SCN5A or novel SCN10A variants.

AIMS: The Brugada syndrome (BrS) is an inherited disease associated with an increased risk of sudden cardiac death. Often, the genetic cause remains undetected. Perhaps due at least in part because the NaV1.8 protein is expressed more in both the central and peripheral nervous systems than in the heart, the SCN10A gene is not included in diagnostic arrhythmia/sudden death panels in the vast majority of cardiogenetics centres. METHODS AND RESULTS: Clinical characteristics were assessed in patients harboring either SCN5A or novel SCN10A variants. Genetic testing was performed using Next Generation Sequencing on genomic DNA. Clinical characteristics, including the arrhythmogenic substrate, in BrS patients harboring novel SCN10A variants and SCN5A variants are comparable. Clinical characteristics, including gender, age, personal history of cardiac arrest/syncope, spontaneous BrS electrocardiogram pattern, family history of sudden death, and arrhythmic substrate are not significantly different between probands harboring SCN10A or SCN5A variants. CONCLUSION: Future studies are warranted to further characterize the role of these specific SCN10A variants.

Novel JAG1 Deletion Variant in Patient with Atypical Alagille Syndrome.

Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by various degrees of abnormalities in the liver, heart, eyes, vertebrae, kidneys, face, vasculature, skeleton, and pancreas. This case report describes a newborn child exhibiting a congenital neural tube defect and peculiar craniofacial appearance characterized by a prominent forehead, deep-set eyes, bulbous nasal tip, and subtle upper lip. Just a few hours after birth, congenital heart disease was suspected for cyanosis and confirmed by heart evaluation. In particular, echocardiography indicated pulmonary atresia with ventricular septal defect with severe hypoplasia of the pulmonary branches (1.5 mm), large patent ductus arteriosus and several major aortopulmonary collateral arteries. Due to the association of peculiar craniofacial appearance and congenital heart disease, a form of Alagille syndrome was suspected. In addition, on the fifth day after birth, the patient developed jaundice, had acholic stools, and high levels of conjugated bilirubin and gamma-glutamyltransferase (GGT) were detected in the blood. Genetic testing revealed the novel variant c.802del in a single copy of the JAG1 gene. No variants in the NOTCH2 gene were detected. To the best of our knowledge, this is the first clinical description of a congenital neural tube defect in a molecularly confirmed Alagille patient. This work demonstrates a novel pathogenic heterozygous JAG1 mutation is associated with an atypical form of Alagille syndrome, suggesting an increased risk for neural tube defects compared to other Alagille patients.