This study aims to inform future genetic reanalysis management by evaluating the yield of whole-exome sequencing (WES) reanalysis in standard patient care in the Netherlands. Single-center data of... Show moreThis study aims to inform future genetic reanalysis management by evaluating the yield of whole-exome sequencing (WES) reanalysis in standard patient care in the Netherlands. Single-center data of 159 patients with a neurodevelopmental disorder (NDD), in which WES analysis and reanalysis were performed between January 1, 2014, and December 31, 2021, was retrospectively collected. Patients were included if they were under the age of 18 years at initial analysis and if this initial analysis did not result in a diagnosis. Demographic, phenotypic, and genotypic characteristics of patients were collected and analyzed. The primary outcomes of our study were (i) diagnostic yield at reanalysis, (ii) reasons for detecting a new possibly causal variant at reanalysis, (iii) unsolicited findings, and (iv) factors associated with positive result of reanalysis. In addition, we conducted a questionnaire study amongst the 7 genetic department in the Netherlands creating an overview of used techniques, yield, and organization of WES reanalysis. The single-center data show that in most cases, WES reanalysis was initiated by the clinical geneticist (65%) or treating physician (30%). The mean time between initial WES analysis and reanalysis was 3.7 years. A new (likely) pathogenic variant or VUS with a clear link to the phenotype was found in 20 initially negative cases, resulting in a diagnostic yield of 12.6%. In 75% of these patients, the diagnosis had clinical consequences, as for example, a screening plan for associated signs and symptoms could be devised. Most (32%) of the (likely) causal variants identified at WES reanalysis were discovered due to a newly described gene-disease association. In addition to the 12.6% diagnostic yield based on new diagnoses, reclassification of a variant of uncertain significance found at initial analysis led to a definite diagnosis in three patients. Diagnostic yield was higher in patients with dysmorphic features compared to patients without clear dysmorphic features (yield 27% vs. 6%; p = 0.001).Conclusions: Our results show that WES reanalysis in patients with NDD in standard patient care leads to a substantial increase in genetic diagnoses. In the majority of newly diagnosed patients, the diagnosis had clinical consequences. Knowledge about the clinical impact of WES reanalysis, clinical characteristics associated with higher yield, and the yield per year after a negative WES in larger clinical cohorts is warranted to inform guidelines for genetic reanalysis. These guidelines will be of great value for pediatricians, pediatric rehabilitation specialists, and pediatric neurologists in daily care of patients with NDD. Show less
Pouls, K.P.M.; Cuypers, M.; Mastebroek, M.; Wieland, J.; Koks-Leensen, M.C.J.; Leusink, G.L.; Assendelft, W.J.J. 2023
BackgroundAdults with mild intellectual disability (MID) experience more mental health disorders than the general population. However, mental healthcare may be insufficiently tailored to match... Show moreBackgroundAdults with mild intellectual disability (MID) experience more mental health disorders than the general population. However, mental healthcare may be insufficiently tailored to match their needs. Detailed information is lacking regarding care provided to people with MID in mental health services. AimsTo compare mental health disorders and care provided to patients with and without MID in Dutch mental health services, including patients with missing MID status in the service files. MethodIn this population-based database study, we used a Statistics Netherlands mental health service database, containing health insurance claims of patients who utilised advanced mental health services in 2015-2017. Patients with MID were identified by linking this database with Statistic Netherlands' social services and long-term care databases. ResultsWe identified 7596 patients with MID, of whom 60.6% had no intellectual disability registration in the service files. Compared with patients without intellectual disability (n = 329 864), they had different profiles of mental health disorders. They received fewer diagnostic (odds ratio 0.71, 95% CI 0.67-0.75) and treatment activities (odds ratio 0.56, 95% CI 0.53-0.59), and required more interprofessional consultations outside of the service (odds ratio 2.06, 95% CI 1.97-2.16), crisis interventions (odds ratio 2.00, 95% CI 1.90-2.10) and mental health-related hospital admissions (odds ratio 1.72, 95% CI 1.63-1.82). ConclusionsPatients with MID in mental health services have different profiles of mental health disorders and care than patients without intellectual disability. In particular, fewer diagnostics and treatments are provided, especially in those with MID with no intellectual disability registration, putting patients with MID at risk of undertreatment and poorer mental health outcomes. Show less
Delanne, J.; Lecat, M.; Blackburn, P.R.; Klee, E.W.; Stumpel, C.T.R.M.; Stegmann, S.; ... ; Thauvin-Robinet, C. 2022
Background: Since the first description of a BRWD3-associated nonsydromic intellectual disability (ID) disorder in 2007, 21 additional families have been reported in the literature.Methods: Using... Show moreBackground: Since the first description of a BRWD3-associated nonsydromic intellectual disability (ID) disorder in 2007, 21 additional families have been reported in the literature.Methods: Using exome sequencing (ES) and international data sharing, we identified 14 additional unrelated individuals with pathogenic BRWD3 variants (12 males and 2 females, including one with skewed X -inactiva-tion). We reviewed the 31 previously published cases in the literature with clinical data available, and describe the collective phenotypes of 43 males and 2 females, with 33 different BRWD3 variants.Results: The most common features in males (excluding one patient with a mosaic variant) included ID (39/39 males), speech delay (24/25 males), postnatal macrocephaly (28/35 males) with prominent forehead (18/25 males) and large ears (14/26 males), and obesity (12/27 males). Both females presented with macrocephaly, speech delay, and epilepsy, while epilepsy was only observed in 4/41 males. Among the 28 variants with available segregation reported, 19 were inherited from unaffected mothers and 9 were de novo.Conclusion: This study demonstrates that the BRWD3-related phenotypes are largely non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach, however, allows for the more effi-cient diagnosis of the BRWD3-related nonsyndromic ID. The refined clinical features presented here may provide additional diagnostic assistance for reverse phenotyping efforts. Show less
Het doel van de dissertatie van David Gast is: het onderzoeken in hoeverre voedingssupplementen (vitaminen, mineralen en omega-3 vetzuren) in de praktijk gebruikt kunnen worden als interventie voor... Show moreHet doel van de dissertatie van David Gast is: het onderzoeken in hoeverre voedingssupplementen (vitaminen, mineralen en omega-3 vetzuren) in de praktijk gebruikt kunnen worden als interventie voor het verminderen van agressief gedrag bij mensen met een verstandelijke beperking (Chapter 1). Daartoe zijn verschillende studies verricht, te beginnen met een onderzoek naar de kwaliteit van voedingspatroon(Chapter 2). De tweede studie is een focusgroep onderzoek, waarin wordt onderzocht in hoeverre professionals en cliënten in de gehandicaptenzorg een interventie met voedingssupplementen accepteren als interventie voor moeilijk verstaanbaar gedrag (Chapter 3). De derde en vierde studies zijn RCT’s waarin het effect van voedingssupplementen wordt onderzocht op agressief gedrag bij respectievelijk gedetineerden (Chapter 4), en mensen met een verstandelijke beperking (Chapter 5). Het laatste onderzoek (Chapter 6) is een meta-analyse van de door ons gevonden studies naar het effect van een interventie met multivitaminen- mineralen op agressief gedrag. Om toekomstig onderzoek met voedingssupplementen in een kwetsbare populatie te faciliteren hebben we de door ons geleerde lessen geordend en van kanttekeningen voorzien (Chapter 7). Tot slot volgt een samenvatting en algemene discussie over de inhoud van de dissertatie (Chapter 8). Show less
Kloth, K.; Lozic, B.; Tagoe, J.; Hoffer, M.J.V.; Ven, A. van der; Thiele, H.; ... ; Lessel, D. 2021
ANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type... Show moreANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum. Show less
Background We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern. Results Methylome analysis from peripheral blood samples of six... Show moreBackground We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern. Results Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This "episignature" was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying this model to a cohort of undiagnosed probands allowed us to reach diagnosis in one subject. Conclusions We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis. Show less
Moffat, J.J.; Jung, E.M.; Ka, M.; Smith, A.L.; Jeon, B.T.; Santen, G.W.E.; Kim, W.Y. 2019
BACKGROUND: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP... Show moreBACKGROUND: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking.METHODS: We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires.RESULTS: We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected.CONCLUSIONS: This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype. Show less
The term Borderline Intellectual Functioning (BIF) refers to intellectual functioning between normal intellectual functioning and intellectual disability (ID). It is defined as an intelligence... Show moreThe term Borderline Intellectual Functioning (BIF) refers to intellectual functioning between normal intellectual functioning and intellectual disability (ID). It is defined as an intelligence quotient (IQ) between 1 and 2 standard deviations below the mean on the normal curve of intelligence; an IQ between 70 and 85. It has been shown that compared to people with higher IQs (IQ > 85) and possibly also compared to those with lower IQs (IQ< 70), children and adults with BIF are at increased risk for the development of mental health problems. But, as a group they are understudied. More knowledge about psychopathology in this group is needed. It was the aim of this thesis to learn more about the nature and severity of psychiatric symptoms and psychiatric disorders in secondary mental health care outpatients with BIF. We used anonymised diagnostic information recorded in the official registration system of the electronic patient file, we investigated the utility and psychometric properties of the BSI and we then used ROM data from both patients from regular mental health care and patients with BIF and/or mild ID to look at symptom profiles and prognostic factors of treatment. Show less
The book sets out an analysis of how the law is used as a means to remove decision-making rights from people with mental health issues and people with intellectual disabilities. It explains how... Show moreThe book sets out an analysis of how the law is used as a means to remove decision-making rights from people with mental health issues and people with intellectual disabilities. It explains how international law can be used to repatriate these rights. Show less
Yamamoto, T.; Mencarelli, M.A.; Marco, C. di; Mucciolo, M.; Vascotto, M.; Balestri, P.; ... ; Mari, F. 2014
How often does child maltreatment occur in the Netherlands and which factors increase the risk of child maltreatment? In this thesis we describe the findings of two epidemiological studies aimed at... Show moreHow often does child maltreatment occur in the Netherlands and which factors increase the risk of child maltreatment? In this thesis we describe the findings of two epidemiological studies aimed at answering these questions. First, in the Netherlands__ Prevalence study on Maltreatment of children and youth (NPM-2010) we examined the year prevalence of child maltreatment in the general Dutch population, using sentinel reports, substantiated CPS reports, and high school students__ self-report. Overall prevalence rates were 33.8 per 1,000 children based on combined sentinel and CPS reports and 99.4 per 1,000 based on self-report. Important risk factors for maltreatment were low SES, single parent families, large families, stepfamilies, and immigrant status. Second, we examined the year prevalence of child sexual and physical abuse in residential and foster care. Children without disabilities had an increased risk of sexual abuse in residential care, and an increased risk of physical abuse in both types of care compared to the general population. Children with a mild intellectual disability were at increased risk of sexual abuse in both residential and foster care compared to regular out-of-home care and compared to the general population. Findings presented in this thesis contribute to the prevention of future child maltreatment in different care settings. Show less
Children with autism and intellectual disability form a particularly vulnerable group, as both disorders have a significant impact on the way and level of information processing and communication.... Show moreChildren with autism and intellectual disability form a particularly vulnerable group, as both disorders have a significant impact on the way and level of information processing and communication. However, children with autism and co-occurring intellectual disability are often excluded from research. Therefore, this study focused on problems in functions, forms, and content of communication by comparing children with autism and intellectual disability with children with intellectual disability only and typically developing children. The results showed that low-functioning children with autism, especially nonverbal children, have severe problems in the use of communicative functions (Chapter 3). In children with autism and intellectual disability receptive language is generally more impaired than expressive language. Joint attention and symbolic skills are strongly related to concurrent language skills (Chapter 4). Because of the limited symbol understanding in low-functioning children with autism, level of sense-making has to be taken into account before starting interventions (Chapter 5). Relative strengths in visual perception can be used to offer the best suitable intervention (Chapter 6). The results of our study emphasize that communicative interventions should have improvement and support of language comprehension as a key target, but also should target the motivation to communicate. Show less
