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Background Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. Conclusion This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.

Background: Image-guided interventional procedures around the shoulder are commonly performed in clinical practice, although evidence regarding their effectiveness is scarce. We report the results of a Delphi method review of evidence on literature published on image-guided interventional procedures around the shoulder with a list of clinical indications. Methods: Forty-five experts in image-guided musculoskeletal procedures from the ESSR participated in a consensus study using the Delphic method. Peer-reviewed papers regarding interventional procedures around the shoulder up to September 2018 were scored according to the Oxford Centre for Evidence-based Medicine levels of evidence. Statements on clinical indications were constructed. Consensus was considered as strong if more than 95% of experts agreed and as broad if more than 80% agreed. Results: A total of 20 statements were drafted, and 5 reached the highest level of evidence. There were 10 statements about tendon procedures, 6 about intra-articular procedures, and 4 about intrabursal injections. Strong consensus was obtained in 16 of them (80%), while 4 received broad consensus (20%). Conclusions: Literature evidence on image-guided interventional procedures around the shoulder is limited. A strong consensus has been reached for 80% of statements. The ESSR recommends further research to potentially influence treatment options, patient outcomes, and social impact. Key Points: • Expert consensus produced a list of 20 evidence-based statements on clinical indications of image-guided interventional procedures around the shoulder. • The highest level of evidence was reached for five statements. • Strong consensus was obtained for 16 statements (80%), while 4 received broad consensus (20%). © 2019, European Society of Radiology.

Background: Although image-guided interventional procedures of the elbow and wrist are routinely performed, there is poor evidence in the literature concerning such treatments. Our aim was to perform a Delphi-based consensus on published evidence on image-guided interventional procedures around the elbow and wrist and provide clinical indications on this topic. Methods: A board of 45 experts in image-guided interventional musculoskeletal procedures from the European Society of Musculoskeletal Radiology were involved in this Delphi-based consensus study. All panelists reviewed and scored published papers on image-guided interventional procedures around the elbow and wrist updated to September 2018 according to the Oxford Centre for Evidence-based Medicine levels of evidence. Consensus on statements drafted by the panelists about clinical indications was considered as “strong” when more than 95% of panelists agreed and as “broad” if more than 80% agreed. Results: Eighteen statements were drafted, 12 about tendon procedures and 6 about intra-articular procedures. Only statement #15 reached the highest level of evidence (ultrasound-guided steroid wrist injections result in greater pain reduction and greater likelihood of attaining clinically important improvement). Seventeen statements received strong consensus (94%), while one received broad consensus (6%). Conclusions: There is still poor evidence in published papers on image-guided interventional procedures around the elbow and wrist. A strong consensus has been achieved in 17/18 (94%) statements provided by the panel on clinical indications. Large prospective randomized trials are needed to better define the role of these procedures in clinical practice. Key Points: • The panel provided 18 evidence-based statements on clinical indications of image-guided interventional procedures around the elbow and wrist. • Only statement #15 reached the highest level of evidence: ultrasound-guided steroid wrist injections result in greater pain reduction and greater likelihood of attaining clinically important improvement. • Seventeen statements received strong consensus (94%), while broad consensus was obtained by 1 statement (6%). © 2019, European Society of Radiology.

Background: Image-guided interventional procedures of the nerves are commonly performed by physicians from different medical specialties, although there is a lack of clinical indications for these types of procedures. This Delphi-based consensus provided a list of indications on image-guided interventional procedures for nerves of the upper limb based on updated published evidence. Methods: An expert panel of 45 members of the Ultrasound and Interventional Subcommittees of the ESSR participated in this Delphi-based consensus study. After revision of the published papers on image-guided interventional procedures for nerves of the upper limb updated to September 2018, the experts drafted a list of statements according to the Oxford Centre for evidence-based medicine levels of evidence. Consensus on statements regarding clinical indications was considered as strong when more than 95% of experts agreed, and broad if more than 80% agreed. Results: Ten statements were drafted on procedures for nerves of the upper limb. Only two statements reached the highest level of evidence (ultrasound guidance is a safe and effective method for brachial plexus block; ultrasound-guided non-surgical approaches are safe and effective methods to treat carpal tunnel syndrome in the short term, but there is sparse evidence on the mid- and long-term effectiveness of these interventions). Strong consensus was obtained on 6/10 statements (60%), while 4/10 statements reached broad consensus (40%). Conclusions: This Delphi-based consensus study reported poor evidence on image-guided interventional procedures for nerves of the upper limb. Sixty percent of statements on clinical indications provided by the expert board reached a strong consensus. Key Points: • An expert panel of the ESSR provided 10 evidence-based statements on clinical indications for image-guided interventional procedures for nerves of the upper limb • Two statements reached the highest level of evidence • Strong consensus was obtained on 6/10 statements (60%), while 4/10 statements reached broad consensus (40%) © 2019, European Society of Radiology.

Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.