Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature.

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

A Decision Aid to Support Vocational Rehabilitation Professionals Offering Tailored Care to Benefit Recipients with a Long-Term Work Disability: A Feasibility Study.

PURPOSE: This feasibility study focusses on the implementation and use of a decision aid, which supports vocational rehabilitation (VR) professionals in helping clients with a disability pension return to work in practice. The decision aid shows an overview of the clients' return to work barriers and suggests suitable VR interventions based on these barriers. METHODS: The study population consisted of VR professionals working at the Dutch Social Security Institute and their clients receiving a (partial) work disability pension. The feasibility was measured with concepts of the Linnan and Steckler framework and the attitude, social norm and self-efficacy model. Data were collected using questionnaires, checklists and qualitative interviews. RESULTS: Ten professionals participated in this study. Fifty-four clients were asked to fill in the questionnaire of the decision aid and 32 clients received VR care based on the decision aid. In general, VR professionals and clients were satisfied with the decision aid and perceived a few barriers for using the decision aid. CONCLUSIONS: This study showed that it is feasible to implement and use the decision aid. To improve the implementation of this decision aid, it should be implemented in digital systems used by professionals to improve efficiency of working with the decision aid.

Elements of Return-to-Work Interventions for Workers on Long-Term Sick Leave: A Systematic Literature Review.

PURPOSE: The aim of this systematic review is to identify vocational rehabilitation (VR) interventions that are effective to enhance return-to-work (RTW) for people on long-term sick leave (> 90 days) and to identify main elements of these interventions. METHODS: Six electronic databases were searched for peer-reviewed studies published up to February 2022. Each article was screened independently by two different reviewers. Thereafter, one author performed the data-extraction which was checked by another author. The EPHPP quality assessment tool was used to appraise the methodological quality of the studies. RESULTS: 11.837 articles were identified. 21 articles were included in the review, which described 25 interventions. Results showed that ten interventions were more effective than usual care on RTW. Two interventions had mixed results. The effective interventions varied widely in content, but were often more extensive than usual care. Common elements of the effective interventions were: coaching, counseling and motivational interviewing, planning return to work, placing the worker in work or teaching practical skills and advising at the workplace. However, these elements were also common in interventions that were not effective on RTW compared to usual care and can therefore not explain why certain interventions are effective and others are not. CONCLUSION: The effective interventions included in this study were often quite extensive and aimed at multiple phases of the RTW-process of the worker. In the future, researchers need to describe the population and the content of the investigated interventions more elaborate to be able to better compare VR interventions and determine what elements make interventions effective.

Return to work factors and vocational rehabilitation interventions for long-term, partially disabled workers: a modified Delphi study among vocational rehabilitation professionals.

BACKGROUND: Long-term disability has a great impact on both society and workers with disabilities. Little is known about the barriers which prohibit workers with long-term disabilities from returning to work and which interventions are best suited to counteract these barriers. The main purpose of this study was to obtain consensus among professionals on important return to work (RTW) factors and effective vocational rehabilitation (VR) interventions for long-term (> 2 years), partially disabled workers. Our three research questions were: (1) which factors are associated with RTW for long-term disabled workers?; (2) which factors associated with RTW can be targeted by VR interventions?; and (3) which VR interventions are the most effective to target these factors? METHODS: A modified Delphi Study was conducted using a panel of 22 labour experts, caseworkers, and insurance physicians. The study consisted of several rounds of questionnaires and one online meeting. RESULTS: The multidisciplinary panel reached consensus that 58 out of 67 factors were important for RTW and that 35 of these factors could be targeted using VR interventions. In five rounds, the expert panel reached consensus that 11 out of 22 VR interventions were effective for at least one of the eight most important RTW factors. CONCLUSIONS: Consensus was reached among the expert panel that many factors that are important for the RTW of short-term disabled workers are also important for the RTW of long-term partially disabled workers and that a substantial number of these factors could effectively be targeted using VR interventions. The results of this study will be used to develop a decision aid that supports vocational rehabilitation professionals in profiling clients and in choosing suitable VR interventions.

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns.

PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

Guidelines in CHARGE syndrome and the missing link: Cranial imaging.

"CHARGE syndrome" is a complex syndrome with high and extremely variable comorbidity. As a result, clinicians may struggle to provide accurate and comprehensive care, and this has led to the publication of several clinical surveillance guidelines and recommendations for CHARGE syndrome, based on both single case observations and cohort studies. Here we perform a structured literature review to examine all the existing advice. Our findings provide additional support for the validity of the recently published Trider checklist. We also identified a gap in literature when reviewing all guidelines and recommendations, and we propose a guideline for neuroradiological evaluation of patients with CHARGE syndrome. This is of importance, as patients with CHARGE are at risk for peri-anesthetic complications, making recurrent imaging procedures under anesthesia a particular risk in clinical practice. However, comprehensive cranial imaging is also of tremendous value for timely diagnosis, proper treatment of symptoms and for further research into CHARGE syndrome. We hope the guideline for neuroradiological evaluation will help clinicians provide efficient and comprehensive care for individuals with CHARGE syndrome.

Autosomal dominant frontometaphyseal dysplasia: Delineation of the clinical phenotype.

Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGFß-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.

Tailored vocational rehabilitation for people with a work disability pension in The Netherlands; an in-depth data analysis of the content and outcomes of vocational rehabilitation trajectories of the Social Security Institute.

PURPOSE: People with a work disability pension receive vocational rehabilitation (VR) services from the Dutch Social Security Institute (SSI) in order to facilitate return-to-work (RTW). The SSI offers tailored VR existing of two trajectories (aimed at getting fit for work or aimed at returning to work). The purpose of this study is to describe the current practice of VR. This includes a description of client characteristics, RTW barriers and the intensity, duration, content and the outcomes of the offered trajectories. MATERIALS AND METHODS: We analyzed data from 197 clients that were randomly selected from clients who attended a VR trajectory between 1 January t 2017 and 31 December 2018. Data were obtained from the SSI registration databases and client files. RESULTS: Both VR trajectories at the SSI have a different aim, but in practice the content of the VR interventions often overlaps. Around half of both trajectories reached their goal. Reasons for unsuccessful trajectories were that the client did not find work or barriers were more complex than initially assessed. CONCLUSIONS: The SSI delivers tailored VR to the specific needs of the client, however substantiations for why a certain VR intervention is offered are limited. Guidelines are needed to support professionals.

This study shows the usual practice of vocational rehabilitation by the Dutch Social Security Institute for all clients with a work disability pension who attended between January 2017 and January 2019.The rationale why a certain vocational rehabilitation intervention is offered by vocational rehabilitation professionals is often unclear or missing.This missing rationale may lead to unwanted practice variation, which is a barrier for evidence-based vocational rehabilitation.Tools and guidelines are needed to support professional decision making and evidence-based vocational rehabilitation and improve return to work.

The phenotypic spectrum and genotype-phenotype correlations in 106 patients with variants in major autism gene CHD8.

CHD8, a major autism gene, functions in chromatin remodelling and has various roles involving several biological pathways. Therefore, unsurprisingly, previous studies have shown that intellectual developmental disorder with autism and macrocephaly (IDDAM), the syndrome caused by pathogenic variants in CHD8, consists of a broad range of phenotypic abnormalities. We collected and reviewed 106 individuals with IDDAM, including 36 individuals not previously published, thus enabling thorough genotype-phenotype analyses, involving the CHD8 mutation spectrum, characterization of the CHD8 DNA methylation episignature, and the systematic analysis of phenotypes collected in Human Phenotype Ontology (HPO). We identified 29 unique nonsense, 25 frameshift, 24 missense, and 12 splice site variants. Furthermore, two unique inframe deletions, one larger deletion (exons 26-28), and one translocation were observed. Methylation analysis was performed for 13 patients, 11 of which showed the previously established episignature for IDDAM (85%) associated with CHD8 haploinsufficiency, one analysis was inconclusive, and one showing a possible gain-of-function signature instead of the expected haploinsufficiency signature was observed. Consistent with previous studies, phenotypical abnormalities affected multiple organ systems. Many neurological abnormalities, like intellectual disability (68%) and hypotonia (29%) were observed, as well as a wide variety of behavioural abnormalities (88%). Most frequently observed behavioural problems included autism spectrum disorder (76%), short attention span (32%), abnormal social behaviour (31%), sleep disturbance (29%) and impaired social interactions (28%). Furthermore, abnormalities in the digestive (53%), musculoskeletal (79%) and genitourinary systems (18%) were noted. Although no significant difference in severity was observed between males and females, individuals with a missense variant were less severely affected. Our study provides an extensive review of all phenotypic abnormalities in patients with IDDAM and provides clinical recommendations, which will be of significant value to individuals with a pathogenic variant in CHD8, their families, and clinicians as it gives a more refined insight into the clinical and molecular spectrum of IDDAM, which is essential for accurate care and counselling.

Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service.

BACKGROUND: Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous. Accurate molecular genetic diagnosis can improve clinical management, provides appropriate genetic counseling and testing of relatives, and allows potential therapeutic trials. OBJECTIVE: To establish the clinical utility of panel-based whole exome sequencing (WES) in NMDs in a population with children and adults with various neuromuscular symptoms. METHODS: Clinical exome sequencing, followed by diagnostic interpretation of variants in genes associated with NMDs, was performed in a cohort of 396 patients suspected of having a genetic cause with a variable age of onset, neuromuscular phenotype, and inheritance pattern. Many had previously undergone targeted gene testing without results. RESULTS: Disease-causing variants were identified in 75/396 patients (19%), with variants in the three COL6-genes (COL6A1, COL6A2 and COL6A3) as the most common cause of the identified muscle disorder, followed by variants in the RYR1 gene. Together, these four genes account for almost 25% of cases in whom a definite genetic cause was identified. Furthermore, likely pathogenic variants and/or variants of uncertain significance were identified in 95 of the patients (24%), in whom functional and/or segregation analysis should be used to confirm or reject the pathogenicity. In 18% of the cases with a disease-causing variant of which we received additional clinical information, we identified a genetic cause in genes of which the associated phenotypes did not match that of the patients. Hence, the advantage of panel-based WES is its unbiased approach. CONCLUSION: Whole exome sequencing, followed by filtering for NMD genes, offers an unbiased approach for the genetic diagnostics of NMD patients. This approach could be used as a first-tier test in neuromuscular disorders with a high suspicion of a genetic cause. With uncertain results, functional testing and segregation analysis are needed to complete the evidence.

Cerebellar Vermis and Midbrain Hypoplasia Upon Conditional Deletion of Chd7 from the Embryonic Mid-Hindbrain Region.

Reduced fibroblast growth factor (FGF) signaling from the mid-hindbrain or isthmus organizer (IsO) during early embryonic development results in hypoplasia of the midbrain and cerebellar vermis. We previously reported evidence for reduced Fgf8 expression and FGF signaling in the mid-hindbrain region of embryos heterozygous for Chd7, the gene mutated in CHARGE (Coloboma, Heart defects, choanal Atresia, Retarded growth and development, Genitourinary anomalies and Ear defects) syndrome. However, Chd7+/- animals only exhibit mild cerebellar vermis anomalies. As homozygous deletion of Chd7 is embryonic lethal, we conditionally deleted Chd7 from the early embryonic mid-hindbrain region to identify the function of CHD7 in mid-hindbrain development. Using a combination of high resolution structural MRI and histology, we report striking midbrain and cerebellar vermis hypoplasia in the homozygous conditional mutants. We show that cerebellar vermis hypoplasia is associated with reduced embryonic Fgf8 expression and an expanded roof plate in rhombomere 1 (r1). These findings identify an essential role for Chd7 in regulating mid-hindbrain development via Fgf8.

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands.

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.