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Matthew Hurles and colleagues report exome sequencing of 1,891 individuals with syndromic or nonsyndromic congenital heart defects (CHD). They found that nonsyndromic CHD patients were enriched for protein-truncating variants in CHD-associated genes inherited from unaffected parents and identified three new syndromic CHD disorders caused by de novo mutations. Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1% (refs. 1 , 2 ). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%) 3 , suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance 4 , 5 . De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations 6 , 7 . We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings 8 . Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4 , CDK13 and PRKD1 . Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

Increasing numbers of genes are being implicated in Mendelian disorders and incorporated into clinical test panels. However, lack of evidence supporting the gene-disease relationship can hinder interpretation. We explored the utility of testing 51 additional genes for hypertrophic cardiomyopathy (HCM), one of the most commonly tested Mendelian disorders. Using genome sequencing data from 240 sarcomere gene negative HCM cases and 6229 controls, we undertook case-control and individual variant analyses to assess 51 genes that have been proposed for HCM testing. We found no evidence to suggest that rare variants in these genes are prevalent causes of HCM. One variant, in a single case, was categorized as likely to be pathogenic. Over 99% of variants were classified as a variant of uncertain significance (VUS) and 54% of cases had one or more VUS. For almost all genes, the gene-disease relationship could not be validated and lack of evidence precluded variant interpretation. Thus, the incremental diagnostic yield of extending testing was negligible, and would, we propose, be outweighed by problems that arise with a high rate of uninterpretable findings. These findings highlight the need for rigorous, evidence-based selection of genes for clinical test panels.

Background The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) was launched in 2017 and involves, to date, 35 highly specialised multidisciplinary expert centres (from the 30 full Healthcare Provider members) coming from 11 countries and more than 70 patient organizations from 16 countries. The eHealth Working Group (WG) of VASCERN was set up to develop practical, patient-centred solutions and strategies for effective use of eHealth tools to answer the needs of patients with multisystemic vascular rare diseases. The eHealth WG Following the identified patients’ needs and following the guiding principles of collaboration and patient-centredness, the eHealth WG was created with the following aims: to develop a mobile app to help patients find expert centres and patient organizations, and to develop resources (Pills of Knowledge, PoK) for training and education via digital platforms (eLearning). The mobile app includes, to date, functionalities that allow users to find expert centres and patient organizations across Europe in the area of rare multisystemic vascular diseases. Discussed app developments include personalized digital patient passports, educational material, emergency management guidelines and remote consultations. Regarding training and education, a variety of PoK have been developed. The PoK cover several topics, target several user groups, and are delivered in various formats so that they are easy-to-use, easy-to-understand, informative, and viable for delivery and sharing through digital platforms (eLearning) including, e.g., the VASCERN YouTube™ channel. Conclusion Overall, the work carried out by the eHealth WG of VASCERN can be seen as a pilot experience that may serve as a basis to for collaborative development of patient-centred eHealth tools that answer the needs of patients with various rare diseases, not limited to rare multisystemic vascular diseases. By expanding the multidisciplinary approach here described, clinical and research networks can take advantage of eHealth services and use them as strategic assets in achieving the ultimate goal of ensuring equity of access to prevention programs, timely and accurate diagnosis and specialized care for patients with rare diseases throughout Europe.

The ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2 -related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits. Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2 . The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2- related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.

IntroductionRecent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations.MethodsPatients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause.ResultsOur cohort comprised 16 individuals aged 4–16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898–1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain.ConclusionsThese patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.

The 100,000 Genomes Project is a U.K. government project that is sequencing the genomes of patients with cancer or rare or infectious diseases. This pilot study involving 4660 participants with rare diseases provided actionable diagnoses and identified three newly implicated disease genes and offers a road map for the larger implementation of genome sequencing in the setting of a national health service.

De novo mutations in protein-coding genes are a well-established cause of developmental disorders 1 . However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations 1 , 2 . Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders. By integrating healthcare and exome-sequencing data from parent–offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year. Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described. De novo mutations in developmental disorders Matthew Hurles, Jeremy McRae and colleagues from the Deciphering Developmental Disorders Study report exome sequencing of 4,293 families containing individuals with severe, undiagnosed developmental disorders. They find enrichment of damaging de novo mutations in 94 genes, implicating them in developmental disorders. They estimate that 42% of the cohort carry pathogenic de novo mutations in coding sequences resulting in disrupted or altered protein function.

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies 1 – 3 . Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed 4 ) identified multiple new candidate PID-associated genes, including IVNS1ABP . We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans. Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Paediatric cardiomyopathy (PC) has multiple genetic causes and can present in infancy with cardiac failure and sudden death. Within the Bristol Genetics Laboratory analysis of Barth Syndrome (TAZ gene) is triggered by an abnormal cardiolipin ratio, but only 7% of referred cases are mutation positive. Next generation sequencing technology enables large sets of related genes to be analysed simultaneously. As considerable clinical and genetic heterogeneity exists within and between PC families, a one off cost-effective gene panel test helps diagnosis and elucidates complex clinical presentations. An Agilent SureSelect custom enrichment kit was designed to include 71 paediatric cardiomyopathy genes, with data analysis through an in-house bioinformatics pipeline (Broad Institute) and Geneticist Assistant (SoftGenetics). This assay has been validated and introduced into service as a United Kingdom Genetic Testing network (UKGTN) approved test.Validation involved two runs using 17 patients, including 14 with known pathogenic variants with100% concordance. The assay coverage at 30x was close to the predicted 99.7% at design with one exonic gap (CTF1, exon 3). Since introduction into service 37 patients have been tested, including infantile/paediatric cases; patients negative for other genes and patients who have phenotypic incompatibility with their reported pathogenic variant where digenic inheritance is suspected. 32/37 (86%) patients have at least one potentially pathogenic variant.In onefamily with HCM, aMYBPC3 variant c.1505G >A, p.(Arg502Gln) and a previously reportedNEBL pathogenic variant c.180G >C, p.(Lys60Asn) (nebulette protein) were detected in a severely affected male demonstrating that multiple variants can explain phenotypic severity. The utility of testing rare genes is exemplified by: 1) A teenager with LV dilation and FH of sudden death who was heterozygous for a RMB20 (RNA binding protein) variant c.1907G >A, p.(Arg636His), previously reported with severe familial DCM; 2) a patient with congenital heart block, LV dilation and FH was heterozygous for a novel likely pathogenic MYH6 (alpha heavy chain subunit) variant c.3578C >T, p.(Ala1193Val). Furthermore, a novel heterozygous TTN A-band frameshift variant was identified in an infantile DCM patient; recent data suggests TTN frameshift variants have not been reported in infantile cardiomyopathy.Details of the validation of this technology, an audit of this patient cohort illustrated by interesting cases will be presented.