Search

Mutations in the N-terminal WD40 domain of coatomer protein complex subunit a (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In [COPA.sup.R1142X] and [COPA.sup.R1058C] fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-[kappa]B signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinflammatory signaling., Introduction The COPA gene encodes coatomer protein complex subunit [alpha] (COPA) (1). COPA was described in 1991 as a coat subunit of Golgi derived non-clathrin-coated vesicles, later termed 'coatomer' (2, [...]

Aims: We identified the first Belgian SCN5A founder mutation, c.4813 + 3_4813 + 6dupGGGT. To describe the clinical spectrum and disease severity associated with this mutation, clinical data of 101 SCN5A founder mutation carriers and 46 non-mutation carrying family members from 25 Belgian families were collected.Methods and Results: The SCN5A founder mutation was confirmed by haplotype analysis. The clinical history and electrocardiographic parameters of the mutation carriers and their family members were gathered and compared. A cardiac electrical abnormality was observed in the majority (82%) of the mutation carriers. Cardiac conduction defects, defined as PR or QRS prolongation on electrocardiogram (ECG), were most frequent, occurring in 65% of the mutation carriers. Brugada syndrome (BrS) was the second most prevalent phenotype identified in 52%, followed by atrial dysrythmia in 11%. Overall, 33% of tested mutation carriers had a normal sodium channel blocker test. Negative tests were more common in family members distantly related to the proband. Overall, 23% of the mutation carriers were symptomatic, with 8% displaying major adverse events. As many as 13% of the patients tested with a sodium blocker developed ventricular arrhythmia. One family member who did not carry the founder mutation was diagnosed with BrS.Conclusion: The high prevalence of symptoms and sensitivity to sodium channel blockers in our founder population highlights the adverse effect of the founder mutation on cardiac conduction. The large phenotypical heterogeneity, variable penetrance, and even non-segregation suggest that other genetic (and environmental) factors modify the disease expression, severity, and outcome in these families. [ABSTRACT FROM AUTHOR]

STING-associated vasculopathy with onset in infancy (SAVI) is an autosomal dominant disorder due to gain-of-function mutations in STING1 , also known as TMEM173 , encoding for STING. It was reported as a vasculopathy of infancy. However, since its description a wider spectrum of associated manifestations and disease-onset has been observed. We report a kindred with a heterozygous STING mutation (p.V155M) in which the 19-year-old proband suffered from isolated adult-onset ANCA-associated vasculitis. His father suffered from childhood-onset pulmonary fibrosis and renal failure attributed to ANCA-associated vasculitis, and died at the age of 30 years due to respiratory failure. In addition, an overview of the phenotypic spectrum of SAVI is provided highlighting (a) a high phenotypic variability with in some cases isolated manifestations, (b) the potential of adult-onset disease, and (c) a novel manifestation with ANCA-associated vasculitis. [ABSTRACT FROM AUTHOR]

Introduction: Loss-of-function (LoF) mutations in the SCN5A gene cause multiple phenotypes including Brugada Syndrome (BrS) and a diffuse cardiac conduction defect. Markers of increased risk for sudden cardiac death (SCD) in LoF SCN5A mutation carriers are ill defined. We hypothesized that late potentials and fragmented QRS would be more prevalent in SCN5A mutation carriers compared to SCN5A-negative BrS patients and evaluated risk markers for SCD in SCN5A mutation carriers.Methods: We included all SCN5A loss-of-function mutation carriers and SCN5A-negative BrS patients from our center. A combined arrhythmic endpoint was defined as appropriate ICD shock or SCD.Results: Late potentials were more prevalent in 79 SCN5A mutation carriers compared to 39 SCN5A-negative BrS patients (66% versus 44%, p = .021), while there was no difference in the prevalence of fragmented QRS. PR interval prolongation was the only parameter that predicted the presence of a SCN5A mutation in BrS (OR 1.08; p < .001). Four SCN5A mutation carriers, of whom three did not have a diagnostic type 1 ECG either spontaneously or after provocation with a sodium channel blocker, reached the combined arrhythmic endpoint during a follow-up of 44 ± 52 months resulting in an annual incidence rate of 1.37%.Conclusion: LP were more frequently observed in SCN5A mutation carriers, while fQRS was not. In SCN5A mutation carriers, the annual incidence rate of SCD was non-negligible, even in the absence of a spontaneous or induced type 1 ECG. Therefore, proper follow-up of SCN5A mutation carriers without Brugada syndrome phenotype is warranted. [ABSTRACT FROM AUTHOR]

Pathogenic variants account for 4 to 41% of patients with intellectual disability (ID) or developmental delay (DD). In Sub‐Saharan Africa, the prevalence of ID is thought to be higher, but data in Central Africa are limited to some case reports. In addition, clinical descriptions of some syndromes are not available for this population. This study aimed at providing an estimate for the fraction of ID/DD for which an underlying etiological genetic cause may be elucidated and provide insights into their clinical presentation in special institutions in a Central African country. A total of 127 patients (33 females and 94 males, mean age 10.03 ± 4.68 years), were recruited from six institutions across Kinshasa. A clinical diagnosis was achieved in 44 but molecular confirmation was achieved in 21 of the 22 patients with expected genetic defect (95% clinical sensitivity). Identified diseases included Down syndrome (15%), submicroscopic copy number variants (9%), aminoacylase deficiency (0.8%), Partington syndrome in one patient (0.8%) and his similarly affected brother, X‐linked syndromic Mental Retardation type 33 (0.8%), and two conditions without clear underlying molecular genetic etiologies (Oculo‐Auriculo‐Vertebral and Amniotic Bands Sequence). We have shown that genetic etiologies, similar to those reported in Caucasian subjects, are a common etiologic cause of ID in African patients from Africa. We have confirmed the diagnostic utility of clinical characterization prior to genetic testing. Finally, our clinical descriptions provide insights into the presentation of these genetic diseases in African patients. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Placental mesenchymal dysplasia (PMD) occurs in about 1 in 5000 pregnancies. The differential diagnosis between PMD and partial mole is difficult on ultrasound scan, and karyotyping plays a key role in distinguishing PMD from partial mole. Our report is the first to report on the discordancy for PMD in a monochorionic setting. [ABSTRACT FROM AUTHOR]

Congenital or neonatal cardiomyopathies are commonly associated with a poor prognosis and have multiple etiologies. In two siblings, a male and female, we identified an undescribed type of lethal congenital restrictive cardiomyopathy affecting the right ventricle. We hypothesized a novel autosomal recessive condition. To identify the cause, we performed genetic, in vitro and in vivo studies. Genome-wide SNP typing and parametric linkage analysis was done in a recessive model to identify candidate regions. Exome sequencing analysis was done in unaffected and affected siblings. In the linkage regions, we selected candidate genes that harbor two rare variants with predicted functional effects in the patients and for which the unaffected sibling is either heterozygous or homozygous reference. We identified two compound heterozygous variants in KIF20A; a maternal missense variant (c.544C>T: p.R182W) and a paternal frameshift mutation (c.1905delT: p.S635Tfs*15). Functional studies confirmed that the R182W mutation creates an ATPase defective form of KIF20A which is not able to support efficient transport of Aurora B as part of the chromosomal passenger complex. Due to this, Aurora B remains trapped on chromatin in dividing cells and fails to translocate to the spindle midzone during cytokinesis. Translational blocking of KIF20A in a zebrafish model resulted in a cardiomyopathy phenotype. We identified a novel autosomal recessive congenital restrictive cardiomyopathy, caused by a near complete loss-of-function of KIF20A. This finding further illustrates the relationship of cytokinesis and congenital cardiomyopathy. [ABSTRACT FROM AUTHOR]

Introduction Fetal akinesia deformation sequence (FADS) or arthrogryposis multiplex congenita (AMC) is characterized by clinical ambiguity and genetic heterogeneity, hampering genetic diagnosis via traditional sequencing methods. Next generation sequencing (NGS) of all known disease-causing genes offers an elegant solution to identify the genetic etiology of AMC/FADS in a diagnostic setting. Methods An in-house developed disease-associated gene panel was conducted in two unrelated fetuses with FADS. First, a de novo analysis was performed on the entire disease-associated gene panel. If no pathogenic mutation was identified, analysis of variants retained in a specific subpanel with arthrogryposis/fetal akinesia-causing genes was performed. Results In the first family, FADS relates to a homozygous c.484G > A (p.Glu162Lys) mutation in the gene RAPSN . The second case concerns a sporadic patient with brain anomalies and arthrogryposis due to a de novo hemizygous c.498C > T splice-site mutation in the pyruvate dehydrogenase-alpha 1 ( PDHA1 ) gene. Discussion NGS facilitated genetic diagnosis, and hence genetic counseling, for both families with AMC/FADS. Biallelic RAPSN mutations typically result in congenital myasthenia syndrome, or occasionally in FADS. This is the first report attributing the RAPSN mutation c.484G > A, identified in a homozygous state in patient 1, to FADS. The second patient represents the first case of AMC due to a PDHA1 mutation, advocating that pyruvate dehydrogenase deficiency should be considered in the differential diagnosis of fetal akinesia. This study illustrates the relevance of a disease-associated-gene panel as a diagnostic tool in pregnancies complicated by this genetically heterogeneous condition. [ABSTRACT FROM AUTHOR]

Background: Long QT syndrome (LQTS) is characterized by reduced penetrance and variable QT prolongation over time, resulting in an estimate of 25% carriers of a pathogenic mutation with a normal corrected QT (QTc) interval on the resting electrocardiogram (ECG).Objective: The purpose of this study was to test the hypothesis that an individualized corrected QT interval derived from 24-hour Holter data more accurately predicts carriage of a pathogenic LQTS mutation than did QT derived from a standard 12-lead ECG and corrected using the Bazett formula (QTc interval).Methods: Carriers of a pathogenic LQTS mutation and their genotype-negative family members who had both resting ECG and Holter recordings available were included. Automated and manual measurements of QTc were performed. QTi was derived from 24-hour Holter recordings and defined as the QT value at the intersection of an RR interval of 1000 ms, with the linear regression line fitted through QT-RR data points of each individual patient.Results: In total, 69 patients with LQTS (23 long QT type 1, 39 long QT type 2, and 7 long QT type 3) and 55 controls were selected. Demographic characteristics were comparable. A comparison of the receiver operating characteristic curves indicates that the test added diagnostic value compared to manual measurement (P = .02) or automated measurement (P = .005). The diagnostic accuracy of manually measured QTc using conventional cutoff criteria was 72%, while it was 92% using a sex-independent QTi cutoff of 445 ms. This was caused by a 39% increase in sensitivity without compromising the specificity.Conclusion: QTi derived from Holter recordings is superior to conventional QTc measured from a standard 12-lead ECG in predicting the mutation carrier state in families with LQTS. [ABSTRACT FROM AUTHOR]

Background Two siblings from consanguineous parents of Turkish descent presented with isolated dilated cardiomyopathy, leading to early death in infancy. The diagnosis of mitogenic cardiomyopathy was made histologically. Methods and results Linkage analysis combined with exome sequencing identified a homozygous deleterious mutation in the ALMS1 gene as the cause of this phenotype. Conclusions Alström syndrome is characterized by a typically transient dilating cardiomyopathy in infancy, suggesting that mitogenic cardiomyopathy represents the extreme phenotype, resulting in demise before the other clinical symptoms become evident. This observation further illustrates the role of ALMS1 and cell cycle regulation. [ABSTRACT FROM AUTHOR]

The validation and verification of laboratory methods and procedures before their use in clinical testing is essential for providing a safe and useful service to clinicians and patients. This paper outlines the principles of validation and verification in the context of clinical human molecular genetic testing. We describe implementation processes, types of tests and their key validation components, and suggest some relevant statistical approaches that can be used by individual laboratories to ensure that tests are conducted to defined standards. [ABSTRACT FROM AUTHOR]

Preimplantation genetic diagnosis (PGD) is now well established and provided in many European countries. However, regulations, professional standards and accreditation requirements can differ notably. Furthermore, no comprehensive independent data exist either about practice and provision in Europe or about the quality assurance practices and procedures designed to optimize the quality of the results. Consequently, a study was launched to obtain knowledge, currently lacking, of the provision and quality assurance of PGD services and cross-border activities in Europe. An online questionnaire was developed and sent to PGD providers, and expert opinions were obtained through interviews with professionals in specific countries. Information was gathered from 53 centres offering PGD in 17 European countries. There is a diverse array of tests available, with a trend for custom-made services. Although half of the centres have a designated quality manager, just 33% have achieved or are preparing for accreditation or certification. About 66% of the centres responded that they did not participate in external quality assessment, a problem exacerbated by the lack of existing PGD-specific schemes. Approximately 19% of the centres do not keep data on accuracy and 9% do not even follow up until birth. PGD is an expanding activity with an increasing international flow that accounts for approximately one-third of the activity reported. The survey highlights a significant need for improvement in quality assurance in PGD centres. On the positive side, important improvements in the quality management of these services are expected with the European Tissue Directive entering into force.European Journal of Human Genetics (2008) 16, 290–299; doi:10.1038/sj.ejhg.5201976; published online 19 December 2007 [ABSTRACT FROM AUTHOR]

The EuroGentest network aims to improve and harmonize the quality of genetic services in Europe, from test development through to information for patients. The network encompasses Biochemical, Clinical, Cyto- and Molecular Genetics, Genetic Counselling and patient groups. Since January 2005, the EuroGentest Quality Management group has disseminated information on accreditation through five international workshops. A database on the current status of QAu in European genetic testing services will soon be publicly available. On the EuroGentest website, laboratories can find the EQA scheme most appropriate to their needs through discipline specific registers of schemes in Europe. All three laboratory disciplines have expanded their repertoire of EQA including a pilot pan-European cytogenetics scheme, CEQA. Minimum quality guidelines have been published for cytogenetics and some biochemical analytes. Draft guidelines for microarrays will be published later this year. In collaboration with EMQN, best practice meetings will be organised in 2007 for Familial Breast Cancer, Spinocerebellar Ataxias and Maturity Onset Diabetes of the Young to generate consensus guidelines. Finally QCMs for Prader-Willi/Angelman syndromes are being developed and validation of MLPA, diagnostic CF-testing kits and DNA extraction methods are in progress through a core group of accredited laboratories with reports due this year. [ABSTRACT FROM AUTHOR]

Abstract: Apert syndrome (OMIM 101200) is a rare genetic condition characterized by craniosynostosis and syndactyly of hands and feet with clinical variability. Two single nucleotides mutations in the linker region between the immunoglobulin-like domains II and IIIa of the ectodomainin the Fibroblast Growth Factor Receptor 2 gene (FGFR2, OMIM 176943) are responsible of the vast majority of cases: c.755C > G; p.Ser252Trp (65%) and c.758C > G; p.Pro253Arg (34%. Three exceptional cases carry multiple substitutions of adjacent nucleotides in the linker region. Here we present a Congolese male patient and his mother, both affected with Apert syndrome of variable severity, carrying a previously undescribed heterozygous mutation of three consecutive nucleotides (c.756_758delGCCinsCTT) in the IgII–IgIIIa linker region. This is the fourth live-born patient to carry a multiple nucleotide substitution in the linker region and is the second alternative amino acid substitutions of the Pro253. Remarkably, this novel mutation was detected in the first Central African patient ever to be tested molecularly for the Apert syndrome. To discriminate between a hitherto unreported mutation and an ethnic specific polymorphism, we tested 105 Congolese controls, and no variation was detected. [Copyright &y& Elsevier]