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Inside out
Behavioral phenotyping in genetic syndromes
Mulder, P.A.
Publication date
2020
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Mulder, P. A. (2020). Inside out: Behavioral phenotyping in genetic syndromes.
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Summary
and
General
discussion
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The objective of this dissertation was to study development and behavior of individuals with rare genetic syndromes stratified by genetic cause. To examine manifestation of behavior in the context of developmental level and environment and to look into sensory processing difficulties.
This chapter first discusses the most important results per chapter (Summary). Subsequently, the five specific areas of interest, the complex interplay between genetics, behavior and environment in genetic syndromes, future research and the clinical significance for patients and families are discussed (Discussion).
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SUMMARY
INTRODUCTION (Chapter 1)
Developments in genetic research have led to an increase in correlating genetic syndromes (genotypes) with developmental and behavioral characteristics (behavioral phenotypes). However, research shows that development and behavior are not solely the result of genetic background, but the result of a continuous complex dynamic between genes, behavior and environment.
The increasing possibilities to find a genetic diagnosis enables the opportunity to identify and specify behavioral phenotypes in genetic syndromes. This new knowledge might provide clinically relevant information to adapt environment, treatment and support towards individual needs.
This thesis studied the behavioral phenotypes of Cornelia de Lange syndrome, Malan syndrome and Marshall-Smith syndrome. We performed a clinical study on development and behavior in the context of developmental level and environment. Literature reviews and patient studies were used. Specific areas of interest were cognition, Autism Spectrum Disorder, sensory processing, adaptive behavior and self-injurious behavior. Results were stratified by genetic cause.
SELF-INJURIOUS BEHAVIOR IN GENETIC SYNDROMES (Chapter 2)
Self-injurious behavior (SIB) is frequently observed in individuals with intellectual disability (ID) of unknown etiology and in genetic syndromes. SIB is associated with behavioral factors such as severity of ID, Autism Spectrum Disorder and stereotypic behavior and environmental conditions (such as social demand). SIB can be reinforced by internal or external stimuli due to an operant learning mechanism. Associations with somatic factors have hardly been studied. In this review we systematically reviewed phenomenology of SIB in twelve genetic syndromes: Angelman Syndrome, Cornelia de Lange Syndrome, Cri du Chat Syndrome, Down Syndrome, Fragile X Syndrome, Lesch-Nyhan Syndrome, Lowe Syndrome, Prader-Willi Syndrome, Rett Syndrome, Smith-Magenis Syndrome, Tuberous Sclerosis Syndrome, and Williams-Beuren Syndrome. 169 eligible studies, published between 1960 and 2014, were included. Studies reported up to 30 various definitions of SIB. In order to discuss SIB involving the same main elements, we proposed the following definition: “SIB is non-accidental behavior
resulting in demonstrable, self-inflicted physical injury, without intent of suicide or sexual arousal. Typically SIB is repetitive and persistent”.
Results showed that SIB is noticeably higher in several genetic syndromes than in the general population with an ID. Age of onset and topography differed widely across syndromes. Studied syndromes are all caused by a mutation in a different gene, possibly allowing detection of several pathways that may lead to
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SIB. To understand etiology of SIB and identify possible intervention strategies, the importance of accurate and detailed description of neurobiological, physical and behavioral characteristics following a uniform definition and standardized methodology is emphasized.
STUDYING BEHAVIOR IN CDLS: A SYSTEMATIC REVIEW (Chapter 3)
To better understand behavior in Cornelia de Lange syndrome (CdLS), it is important to accurately describe and carefully evaluate behavior. We studied literature on behavioral research in CdLS from 1946 to 2015 with special attention to cognition, Autism Spectrum Disorder (ASD) and self-injurious behavior (SIB). We included 43 eligible papers and described the used methodology and results. Quality was assessed by Cochrane criteria adapted for the purpose of this study.
Methodology and quality were very heterogeneous. Seven studies used direct in-person assessments to evaluate cognition. Most participants in the studies were reported to have a profound to severe intellectual disability. Nineteen papers evaluated prevalence of ASD of which two papers assessed participants via direct observations. Prevalence rates of ASD varied between 27-82%. Social behavior in individuals with an ID showed overlap with ASD characteristics. No studies described social behavior in context of developmental level, hampering differentiation of behavior characteristics as part of the ID or (co-morbid) ASD. SIB was reported in 15 papers, six studies described genetic information of the studied population. Heterogeneity of study populations and methodology hampered comparability of results. To better understand behavior, a standard set of instruments is proposed to evaluate cognition, adaptive functioning, ASD, sensory processing, SIB, physical and sensory limitations, level of support and living environment. We concluded that it is of utmost importance to combine standardized direct in-person assessments with questionnaires and interviews. This way interpreting and understanding behavior in the context of the developmental level and daily environment of individuals with ID and genetic syndromes can be improved.
CdLS: A SYNDROME WITH DIFFERING GENOTYPE-PHENOTYPE CORRELATIONS (Chapter 4)
CdLS is caused by changes in different genes, all encoding proteins of the cohesion complex. Most frequent causes are changes in NIPBL and SMC1A. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compared results to those in 67 individuals with NIPBL variants.
Results showed individuals with SMC1A variants resembling a Rett syndrome phenotype, identified through exome sequencing. Individuals with SMC1A variants that resemble CdLS, showed less marked classic CdLS characteristics compared to individuals with NIPBL variants (better growth, less marked facial features,
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no major limb abnormalities and higher cognitive and adaptive functioning). Self-injurious behavior was more present in NIPBL variants compared to SMC1A variants, however gastro-esophageal reflux disease and constipation were equally common in the NIPBL and SMC1A groups. The absence of SIB in SMC1A variants and epileptic encephalopathy, supports the hypothesis that SIB may be caused by another gene function of NIPBL, i.e. the moonlighting hypothesis.
We concluded that SMC1A variants can result in different phenotypes: one that overlaps with mild manifestations of CdLS and another that overlaps with Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggested that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.
DEVELOPMENT AND BEHAVIOR IN CdLS: VARIABILITY WITHIN ONE SYNDROME (Chapter 5)
We performed an international, interdisciplinary study on development and behavior in 51 individuals with SMC1A variants. Results of questionnaire studies are compared to those in individuals with Down Syndrome (N=139) and with Autism Spectrum Disorder (ASD; N=247). Results on cognition and self-injurious behavior (SIB) are compared to individuals with CdLS caused by NIPBL variants (N=67). For Dutch participants with SMC1A variants (N=9) we performed direct in-person assessments of cognition and ASD, added an interview on adaptive behavior and a questionnaire on sensory processing.
We found that participants with SMC1A variants showed higher cognitive functioning and less self-injurious behavior than participants with NIPBL variants. Participants with SMC1A variants resembling a phenotype that is more similar to Rett syndrome, had a more profound ID and no SIB compared to participants with SMC1A variants resembling CdLS characteristics. In the Dutch SMC1A population, eight out of nine participants scored above the cut-off for ASD based on questionnaires. Evaluation through direct in-person assessments and observations showed that only two out of nine participants showed symptoms of autism when behavior was weighed in the context of developmental level and environment. Sensory information processing (the way we perceive and process stimuli) was clearly atypical. We emphasized the importance of adjustments to the environment and assessment battery in a way that is suitable to the participant. This study demonstrated the importance of careful behavioral research in the context of a person's level of development and their daily environment. We strongly advocated direct in-person assessments by behavioral scientists with experience in (severe) ID, and stratifying study samples by genetic cause. Fine-grained assessments and detailed, interdisciplinary approaches yield important information for tailored care, which may eventually contribute to improvement of quality of life.
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DELINEATION OF MALAN SYNDROME: ‘SOTOS SYNDROME TYPE 2’ OR A SEPARATE ENTITY? (Chapter 6)
Malan syndrome and Marshall-Smith syndrome are both caused by changes in NFIX. Malan syndrome is also referred to as ‘Sotos syndrome type 2’ due to the overlap in phenotypical characteristics. However, in order to adjust care to syndrome-specific needs, it is important to carefully evaluate characteristics and further delineate phenotypes. This study described the phenotype of Malan syndrome and compared results with Marshall-Smith syndrome, Sotos syndrome and Weaver syndrome. Objective of this paper was to further refine the phenotype and describe the clinical relevance of precise and careful phenotyping.
Data was collected on 45 patients with molecularly confirmed diagnosis of Malan syndrome. Results showed overlap in characteristics between Malan syndrome and Sotos syndrome, however also clear differences were found. Facial features of Malan syndrome were distinct to Sotos syndrome or Weaver syndrome. Cardinal facial characteristics included a long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. ID was commonly present and anxiety frequently mentioned. It was concluded that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. We postulated Malan syndrome as a separate entity and questioned the accuracy of naming this phenotype as "Sotos syndrome type 2". Distinguishing Malan syndrome from Sotos syndrome or Weaver syndrome is only possible on the basis of clinical assessment. Future research should provide clarity as to whether a specific behavioral phenotype is present.
BEHAVIORAL PHENOTYPES OF MARSHALL-SMITH SYNDROME AND MALAN SYNDROME (Chapter 7)
Following the previous study (Chapter 6), we investigated development and behavior in Marshall-Smith syndrome (N=8) and Malan syndrome (N=7). Both syndromes are characterized by ID, sensory impairments and challenging behavior, however questions regarding the behavioral phenotype remain. We described and compared development and behavior between and within both syndromes and stratified results to genetic information. Long-term follow-up assessment of cognition and adaptive behavior was possible in three individuals with Marshall-Smith syndrome.
Participants with Marshall-Smith syndrome had a more severe ID, less adaptive behavior, more impaired speech and less reciprocal interaction compared to individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behavior in Marshall-Smith syndrome showed different individual learning curves over time. Comparison of results presented clear variability in behavioral phenotypes
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between and within both syndromes, although both syndromes are caused by changes in NFIX. This supported the hypothesis that different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments were common in both syndromes, hamper development and social participation and increase the risk for challenging behavior. Adaptations to environment, support and treatment were suggested, to create a better person-environment fit and improve quality of life.
INTERDISCIPLINARY GUIDELINE FOR CARE IN INDIVIDUALS WITH CdLS (Chapter 8)
In this chapter, information and questions from parents and patient associations about care for individuals with CdLS are joint with the evidence and practice based knowledge built up in the last decades. Previous studies showed that heterogeneity in molecular and clinical manifestations of CdLS leads to great diversity in the required care. A group of international experts who are member of the Scientific Advisory Counsel of the World Federation of CdLS Support Groups recognized variability in practices regarding diagnostic procedures and care of individuals with CdLS. To address this issue, an International CdLS Consensus Group was established, which performed an extensive literature review, evaluated literature and data critically, drafted documents on each of the major topics, and held a face-to-face meeting together with patient group representatives. Here we documented the resultant consensus on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS, and a protocol for molecular investigations. The most important health problems and the most appropriate care was described separately for children and adults. Considerable attention was paid to development and behavior. Severity of intellectual disability, self-injurious behavior, sensory information processing and social functioning and autism spectrum disorder were extensively described. The guideline contributes to the multidisciplinary organization of care, which is of eminent importance for individuals with a genetic syndrome such as CdLS.
GENERAL DISCUSSION
Behavioral phenotyping in genetic syndromes
During this research project we highlighted five specific domains within the behavioural phenotype of Cornelia de Lange syndrome (CdLS), Marshall-Smith and Malan syndrome, namely: cognition, Autism Spectrum Disorder, sensory processing, adaptive behavior and self-injurious behavior. In our systematic review on behavior in CdLS, we discussed the importance of the use of a dedicated test-battery and evaluation of behavior in the context of developmental level and environment. In this paragraph, overarching findings will be discussed following the five areas of interest.
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Cognition
Assessment procedures of the Bayley-III and Wechsler Intelligence Scales were adapted to individual needs. For example by offering extra time or reducing environmental stimuli (e.g. closing curtains), which enabled a more genuine measurement of cognitive abilities. We noticed heightened levels of arousal at start of the assessments in almost all participants. Reducing used speech by researchers, step-by-step showing what was asked and non-verbal (visually supported) communication put the participants at ease. All participants seem to benefit from a structured environment which provides clear augmentative and alternative communication to support understanding and enhance daily functioning.
In individuals with CdLS, as well as in individuals with Marshall-Smith syndrome and Malan syndrome, a clear difference in performance between verbal and visual tasks was found. Tasks combining verbal and visual input were more difficult in contrast to tasks which included only visual input. It is hypothesized that individuals with CdLS, Marshall-Smith syndrome and Malan syndrome have difficulties with perceptual learning, impairing the ability to make sense of what
they see, hear, feel, taste and smell.[1] Language difficulties reported in all studied
syndrome groups[2-4] might partly be explained by the difficulties in perceptual
learning.[5] Strengthening of perceptual abilities by the use of augmentative and
alternative communication and adaptations of environment towards individual sensory needs (discussed later this section) might enable better attention and motivation for assessment.
Autism Spectrum Disorder
Assessment of ASD in individuals with CdLS with SMC1A variants (Chapter 5) was performed by combining the Social Communication Questionnaire (SCQ), the Autism Diagnostic Observation Scale-2 (ADOS-2) and direct observations. Based on the SCQ, 8/9 participants scored above the clinical cut-off for ASD-spectrum. However evaluation of the ADOS-2 shows only three individuals scoring within ‘moderate to high level of symptoms related to autism‘. After clinical consideration of behavior in the context of level of development, only two individuals met diagnostic criteria for ASD according the Diagnostic and Statistical
Manual for Mental Disorders (5th ed.; DSM-5).[8] In these individuals, social and
communication skills were more impaired than expected based on developmental age. These results show the importance of vigilant behavioral observations, combining questionnaires with direct in-person assessments and interpretation of behavior in the context of developmental level and daily environment.
Sensory processing
The Sensory Profile[9] is used to describe clinically relevant data on sensory
processing issues in daily life, explain behavioral responses and to give directions for adjustments in environment, treatment and support. In this study, all three
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syndrome groups show difficulties with sensory processing, as assessed with
the Short Sensory Profile.[10] Well-developed sensory processing enables us to
adequately respond to environmental stimuli.[11]
During the direct in-person assessments we observed many sensory processing difficulties (e.g. auditory sensitivity, movement sensitivity and visual sensitivity), hampering participation in assessment and reducing task-performances.
[12] Adaptations in environment (e.g. sitting with the back to a window, close
curtains, offering a toy to activate themselves through tactile stimulation) enabled participants to better focus on the assessment. It is known that sensory processing difficulties hamper social interaction and participation in daily activities. Environmental changes might prevent sensory over- or
under-stimulation and enhance social participation and daily functioning.[13]
Adaptive behavior
Assessment of adaptive behavior shows an overall level of adaptive functioning corresponding the cognitive level of functioning in all three syndrome groups. The domains Communication and Socialization are the most affected in all three syndrome groups. Within the Communication domain, receptive communication is less affected than expressive communication. Direct-in person evaluation of level of development showed the clinical importance of tailored communication.
Assessment of level of sense-making in communication[14] in all three syndrome
groups might be helpful, for example with the ComFor-2.[15] Personalized
augmentative and alternative communication strategies might support perceptual
learning, increase social participation and reduce challenging behavior.[16]
Within the domain Socialization, the subdomain community is most impaired in all three syndrome groups. It reflects the difficulty of participation in daily (social) activities. Continuous investment in social interaction and social play is important in order to stimulate overall development in individuals with genetic syndromes. Play and social interaction are of great importance for the
cognitive, social and emotional development.[17],[18] During the direct in-person
assessments we noticed the significance of aligning our approach to the individual developmental profile, to strengthen social interaction, motivation and task performance.
Self-injurious behavior
Self-injurious behavior (SIB) is common in individuals with ID, however higher
prevalence is seen in some specific genetic syndromes.[19] Following our results
on SIB in CdLS, showing differences in prevalence of SIB within one genetic syndrome, there is a clear need for a careful interdisciplinary evaluation. Biological (genetic, neurologic and somatic), personal (developmental and behavioral) and environmental characteristics may contribute to the onset of SIB. The
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communication difficulties as reported in CdLS, Marshall-Smith syndrome and Malan syndrome, can hamper early recognition of underlying medical problems causing pain or discomfort. Detailed genotyping and phenotyping individuals with genetic syndromes and studying the interactions between all these influencing factors is essential in order to understand the mechanisms underlying SIB. This way we might be able to earlier recognize the underlying factors leading to SIB, possibly enabling more effective treatment and interventions.
The interplay between genetics, behavior and environment
Genetic syndromes are often defined as fixed categorical definitions, with a
prototypical phenotype, frequently determined by severe clinical cases.[20] Our
study shows considerable variability in behavioral phenotypes between and within genetic syndromes. Physical and behavioral examination of individuals with CdLS (in chapter 4 and 5), stratified to genetic cause, presents that physical and neurodevelopmental characteristics follow a continuum. This leads to the point whether using the term CdLS is valuable for daily practice and if it does justice to the observed variability in phenotypes. The term CdLS often refers to the physical and behavioral phenotype of individuals with a NIPBL variant
(considered to be the classic phenotype of CdLS).[21] However, our study feeds the
hypothesis of a possible CdLS spectrum (Chapter 8) including varying physical and behavioral phenotypes and emphasizes the importance of genetic counselling.
Where the differences in behavioral phenotype of CdLS are partly correlated to the identified changes in different genes, the opposite applies when studying Marshall-Smith syndrome and Malan syndrome. These syndromes show clear differences in physical and behavioral characteristics, though both syndromes are caused by changes in the same gene (NFIX). Detailed genotyping and phenotyping genetic syndromes, might advance our understanding of the interaction between genes, behavior and environment (over time) and enhance possibilities for intervention strategies to improve development and daily functioning.
Studying participants in their daily environment revealed important implications. Participants were more at ease in their own environment and some needed the proximity of a familiar person (e.g. parent or carer) to reduce overall level of stress. These adaptations in assessments were beneficial for the interaction with the researcher and the motivation and attention of the participant towards the assessments. Understanding behavior as a result of the complex dynamic between person and environment is difficult, yet remains urgent to adequately adapt care, support and environment towards the individual needs.
Challenging behavior, such as self-injurious behavior, is pre-eminently an example of a problematic situation in which biological, personal and environmental factors might be involved. It urges professionals of different
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disciplines to work together. As a discipline, special needs education strongly focuses on the interaction between person, carer and environment and is therefore (together with pediatricians, physicians for individuals with ID, psychologists, psychiatrists, geneticists etc.) indispensable in the field of care for individuals with genetic syndromes. The outcomes of this thesis underline the clinical significance of involvement of special needs education in studying genetic syndromes. Merging the different paradigms in an interdisciplinary team can lead to complementary theories and hypotheses, whereby diagnosis
and treatment can be refined and improved.[22] It is up to the individual
professional to take responsibility in terms of monitoring the boundaries of their own profession (and thus seek cooperation where needed).
Future research
Long-term follow-up studies
So far, longitudinal studies on development and behavior of individuals with genetic syndromes as CdLS, Marshall-Smith syndrome and Malan syndrome are limited. Long-term follow-up studies collecting data on the developmental and behavioral trajectories of individuals with genetic syndromes might add new knowledge on the behavioral phenotype. Subsequently, this long-term information enables the possibility to better inform patients and their families regarding their questions on daily functioning, future perspective and intervention strategies. Future studies should consider longitudinal studies in order to add significant information to the general phenotype of genetic syndromes. It might enable the possibility to reveal important age-dependent patterns, determine impact on daily functioning and identify essential factors to (preventive) strengthen care and support over time.
Phenotyping in real-world context
For a more thorough understanding of behavior in genetic syndromes, research might benefit from including a more micro-level based methodology which enables evaluation of interaction with the real-world context. Our study shows the influence of (familiar) environment on performance in direct in-person
assessments. Barker[23] described that behavior can only be understood in
relation to the context in which it occurs, suggesting research should (also) take
place outside the laboratory.[24] Studying psychiatric symptoms in the context
of daily-life is increasingly seen as a powerful complementary method to more
regular research methods within mental health care.[25] Experience sampling
methodology[26] is an example of a technique to assess behavior in the context of
daily life instead of assessment through retrospective description of behavior.
[24] Adopting a method like experience sampling methodology may add valuable
data in understanding the behavioral phenotype in genetic syndromes and may provide essential information towards personalized care.
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This may argue for the use of interactive behavioral phenotype as a concept to explain and emphasize the continuous interaction between genes, behavior
and environment.[27] It addresses the observed diversity in behavioral
phenotypes over time and the need for regular evaluation of behavior in the context of daily environment.
Emotional development
Age-dependent cognitive and emotional problems in genetic syndromes are
recently reported in several studies.[27] So far, little attention has been payed
to emotional development in studying genetic syndromes. Our study did not include emotional development as a specific area of interest. However, during the direct in-person assessment we adjusted our approach to the social and emotional needs of the individual, for example by allowing the presence of a familiar other if needed.
A healthy development of personality is depending on a safe and fruitful basis by
the presence of conditions suitable to the individual needs.[28] Martha Nussbaum
considers emotional development as one of the ten essential capabilities for
human dignity and well-being, as described in the capability approach.[29]
Emotional development reflects not being inhibited by overwhelming fears and feelings of insecurity and the availability of human relationships essential
to support emotional development.[29] Nussbaum’s perspective on emotional
development holds for individuals with ID too. There is an inextricable link
between emotion, behavior and environment.[27],[28] Following this viewpoint,
adjusting the environment and care towards the zone of proximate (emotional)
development is essential.[30] It might support and stimulate adaptive functioning,
but moreover it might enhance experiencing well-being in daily life. The
capability approach of Nussbaum[29] might be valuable and complementary to
inform and adapt care, support and environment.
Clinical significance for families
In chapter 1 we introduced Floor. She and her family have gone through a long search to optimize the interaction between Floor and her environment. Individuals with genetic syndromes and their families all face different challenges during life.
Our study contributes to the understanding of the (individual) behavioral phenotype of genetic syndromes at micro- and macro level. At micro level, the variability in development and behavior between individuals with the same genetic syndrome emphasizes the importance of an individual-centered approach. It supports the healthcare professional to answer the questions that parents and carers ask regarding daily functioning of their loved one.
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At macro level, detailed phenotyping contributes to a more precise description of behavior in genetic syndromes. The added information enables clinicians to (even) better inform patients and families about the behavioral phenotypes and developmental trajectories over time. The results also underline the necessity for collaboration with different disciplines. Centralization and formation of interdisciplinary services might be more effective in managing somatic and behavioral problems.
This thesis underpins the importance of regular evaluation of behavior in the context of developmental level and environment. Defining the individual abilities and needs at a certain point in time is essential, but also needs regular follow-up to meet possible changing needs. For parents and carers it is of great value to learn about the developmental profile of their child and the continuous interaction with it’s environment. It allows parents and carers to (even better) adapt their expectations to the abilities and needs of their loved one and to create the conditions to increase participation in daily life.
Strengths and limitations
This thesis contains several strengths and limitations. A major strength of our study is the fact that the used methodology is not syndrome-specific and can be useful for other genetic syndromes. It enhances comparability of behavioral phenotypes between syndromes and therefore the possibility to identify syndrome-specific characteristics to tailor and improve care and support.
A second strength is including assessment of sensory processing as a specific area of interest when studying behavior in CdLS, Malan syndrome and Marshall-Smith syndrome. Sensory processing has hardly been studied in genetic syndromes, despite common prevalence of sensory processing difficulties in the general population of individuals with ID. We used the Sensory Profile to describe clinically relevant data on sensory processing issues in daily life, explain behavioral responses and emphasize the need for adaptations in environment, treatment and support (Chapter 5 and 7).
A third strength is modifying standard test procedures towards cognitive, physical, behavioral and sensory needs. By adjusting standard procedures of assessment of development and behavior in individuals with profound (intellectual) (and) multiple disabilities, we enabled a more genuine measurement of individual abilities and provided valuable information to inform care and support.
A fourth strength is providing individual reports with outcomes on the performed assessments for patients and families during our studies. These reports might be useful to inform their involved professionals and modify care and support where needed based on current information. Subsequently, patients and their
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families might profit directly from participating in scientific (behavior) studies and keep motivated to participate in future research.
A first limitation of this study is the possibility of recruitment bias. Participants in our study were invited through contact with patient federations and clinicians in academic hospitals. This may lead to a skewed representation of individuals with more severe difficulties, as they are often more likely to be linked to expertise centers and patient federations. However, this also might show the need these individuals have for more advanced knowledge to inform support and care.
A second limitation might be the small study populations, although they are relatively large given the rarity of studied syndromes. The fact that genetic counselling is more accurate and accessible than before, enables future studies to include larger sample sizes of individuals with the same genetic variants, leading to a more homogeneous (and representative) population sample.
A third limitation was the lack of appropriate instruments to directly assess cognition and autism spectrum disorders (ASD) in individuals with severe intellectual disability and of varying ages. Regarding cognition, we considered the Bayley-III and the Wechsler Intelligence Scales as most suitable instruments However, based on an a-priori clinical impression of developmental level and Vineland-2 results. Furthermore, we followed the criterion standard of instruments for assessment (Chapter 3) recommended in our study on used methodology in behavioral studies in CdLS. It strengthens interpretation of developmental and behavioral characteristics and enables the possibility for long-term follow-up measurements.
A fourth limitation is the difficulty of differentiating behavior as part of an Autism Spectrum Disorder (ASD) or as part of (severe) ID, as instruments are often not sufficiently sensitive to discriminate behavior as a result of one these two developmental conditions. We combined data from a questionnaire, direct in-person assessment and observations with results on cognitive development to clinically evaluate any presence of ASD. Evaluation of ASD (Chapter 5) showed a separate diagnosis of comorbid ASD to be justified in only two cases after careful weighing and interpreting behavior in the context of developmental level.
Conclusion
This thesis extends the knowledge on the behavioral phenotype in Cornelia de Lange syndrome, Marshall-Smith syndrome and Malan syndrome. Detailed description and consideration of the behavioral phenotype within one’s own developmental and environmental context, stratified to genetic cause, demonstrates the necessity of a macro- and micro level based approach in care and support in genetic syndromes. The used methodology in this thesis can serve as a model for behavioral phenotyping in other genetic syndromes.
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The described behavioral phenotypes in this thesis demonstrate the interaction between genes, behavior and environment and illustrate the associated individual diversity in development and daily functioning. Longitudinal studies can provide information on long-term developmental trajectories and changes in behavioral phenotypes over time. Such approaches reveal the significance of an interdisciplinary method and provide valuable knowledge to inform care and support to improve quality of life of individuals with genetic syndromes and their families.
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