Carolina Digital Repository (University of North Carolina at Chapel Hill), 2015
Drs Vorstman, Breetvelt and Bassett had full access to all of the data in the study and take resp... more Drs Vorstman, Breetvelt and Bassett had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Vorstman and Breetvelt contributed equally to the study.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Journal of Intellectual Disability Research, Feb 21, 2022
BackgroundThe world has suffered immeasurably during the COVID‐19 pandemic. Increased distress an... more BackgroundThe world has suffered immeasurably during the COVID‐19 pandemic. Increased distress and mental and medical health concerns are collateral consequences to the disease itself. The Genes to Mental Health (G2MH) Network consortium sought to understand how individuals affected by the rare copy number variations of 22q11.2 deletion and duplication syndrome, associated with neurodevelopmental/neuropsychiatric conditions, were coping. The article focuses on worry and disruptions in medical care caused by the pandemic.MethodsThe University of Pennsylvania COVID‐19 Stressor List and care disruption questions were circulated by 22 advocacy groups in English and 11 other languages.ResultsA total of 512 people from 23 countries completed the survey; most were caregivers of affected individuals. Worry about family members acquiring COVID‐19 had the highest average endorsed worry, whilst currently having COVID‐19 had the lowest rated worry. Total COVID‐19 worries were higher in individuals completing the survey towards the end of the study (later pandemic wave); 36% (n = 186) of the sample reported a significant effect on health due to care interruption during the pandemic; 44% of individuals (n = 111) receiving care for their genetic syndrome in a hospital setting reported delaying appointments due to COVID‐19 fears; 12% (n = 59) of the sample reported disruptions to treatments; and of those reporting no current disruptions, 59% (n = 269) worried about future disruptions if the pandemic continued. Higher levels of care disruptions were related to higher COVID‐19 worries (Ps < 0.005). Minimal differences by respondent type or copy number variation type emerged.ConclusionsWidespread medical care disruptions and pandemic‐related worries were reported by individuals with 22q11.2 syndrome and their family members. Reported worries were broadly consistent with research results from prior reports in the general population. The long‐term effects of COVID‐19 worries, interruptions to care and hospital avoidance require further study.
Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40–50% of... more Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40–50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotrunc...
BackgroundCongenital heart disease (CHD) affecting the conotruncal region of the heart, occur in ... more BackgroundCongenital heart disease (CHD) affecting the conotruncal region of the heart, occur in half of patients with 22q11.2 deletion syndrome. This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, mapped to the 22q11.2 region, encoding a T-box transcription factor, is one of the main genes for the etiology of the syndrome. We suggest that genetic modifiers of CHD in patients with 22q11.2 deletion syndrome may be in the TBX1 gene network.MethodsTo identify genetic modifiers of 22q11.2 deletion syndrome, we analyzed whole genome sequence of subjects with 22q11.2DS, of which 456 were cases with conotruncal heart defects and 537 were controls with normal cardiac structures. We retained the most damaging rare coding variants and examined 19 functional gene sets for association that were weighted upon expression of genes in cardiac progenitor cells in mouse embryos identified by RNA-sequen...
Journal of Applied Research in Intellectual Disabilities
BackgroundIndividuals with Phelan–McDermid syndrome (PMS) are characterised by phenotypical trait... more BackgroundIndividuals with Phelan–McDermid syndrome (PMS) are characterised by phenotypical traits that can be experienced as challenging by their environment. This study assessed parenting stress and Family Quality of Life (FQOL) in parents of individuals with PMS and identified potential contributing variables.MethodMothers (n = 14) and fathers (n = 13) of individuals with PMS (n = 14; 6 females, 8 males; age 2–37, M = 20, SD = 11.92) completed questionnaires on parenting stress, FQOL, adaptive behaviour and background characteristics.ResultsMothers and fathers experienced high, similar and related levels of parenting stress and FQOL satisfaction. Parenting stress and FQOL satisfaction were inversely related. High and low ratings were retrieved for subscales measuring feelings of parental role restriction and emotional well‐being, respectively. The adaptive skills of the individuals with PMS were related to fathers’ parenting stress and FQOL satisfaction.ConclusionsClinical practi...
The ability to tell a story involves a number of language and cognitive skills. In order to tell ... more The ability to tell a story involves a number of language and cognitive skills. In order to tell a good story a child needs to understand cause-effect relationships, outline events and use precise vocabulary to convey ideas to aid a listener in comprehending the tale (Boudreau, 2008). Children with some genetic syndromes seem to have difficulties acquiring these skills, which has impact on their everyday social communication. Cross-syndrome and cross-linguistic research on this topic is rare. Methods: A cross syndrome comparison of the narrative skills of Dutch speaking school-aged children with 22q11.2 deletion syndrome (22q11.2 DS) and children with Williams Syndrome is presented. These children are compared with (a) mental age matched control groups of children with an intellectual disability (ID) with unknown etiology, (b) children with ID with unknown etiology and comorbid autism spectrum disorder and (c) typically developing children. In addition, a cross linguistic Dutch-English comparison is summarized highlighting story (re)telling characteristics in children with 22q11.2 DS. A fine-grained story analysis based upon samples of the Bus Story Test (Renfrew, 1997) and the Expression, Reception and Recall of Narrative Instrument (Bishop, 2004) was carried out. Results: The results indicate cross-syndrome and within-syndrome variability in narrative skills. Cross-linguistic profiles are discussed and the impact on everyday communication is highlighted. Conclusion: Evaluating pragmatic and more specifically narrative language skills across syndromes can contribute to the understanding of the communicative behavioral phenotype. Detailed language assessments may improve intervention targeting communication, and lead to specific parental advices for these groups of children.
Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cog... more Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQ-scores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p < 0.01). Our findings suggest that using variant-specific normative IQ data significantly reduces required sample size in a research context, and may facilitate a more clinically informative interpretation of IQ data. This approach allows identification of individuals that deviate from their expected, variant-specific, trajectory. This group may be at increased risk for comorbid conditions, such as schizophrenia in the case of 22q11DS.
Carolina Digital Repository (University of North Carolina at Chapel Hill), 2015
Drs Vorstman, Breetvelt and Bassett had full access to all of the data in the study and take resp... more Drs Vorstman, Breetvelt and Bassett had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Vorstman and Breetvelt contributed equally to the study.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Journal of Intellectual Disability Research, Feb 21, 2022
BackgroundThe world has suffered immeasurably during the COVID‐19 pandemic. Increased distress an... more BackgroundThe world has suffered immeasurably during the COVID‐19 pandemic. Increased distress and mental and medical health concerns are collateral consequences to the disease itself. The Genes to Mental Health (G2MH) Network consortium sought to understand how individuals affected by the rare copy number variations of 22q11.2 deletion and duplication syndrome, associated with neurodevelopmental/neuropsychiatric conditions, were coping. The article focuses on worry and disruptions in medical care caused by the pandemic.MethodsThe University of Pennsylvania COVID‐19 Stressor List and care disruption questions were circulated by 22 advocacy groups in English and 11 other languages.ResultsA total of 512 people from 23 countries completed the survey; most were caregivers of affected individuals. Worry about family members acquiring COVID‐19 had the highest average endorsed worry, whilst currently having COVID‐19 had the lowest rated worry. Total COVID‐19 worries were higher in individuals completing the survey towards the end of the study (later pandemic wave); 36% (n = 186) of the sample reported a significant effect on health due to care interruption during the pandemic; 44% of individuals (n = 111) receiving care for their genetic syndrome in a hospital setting reported delaying appointments due to COVID‐19 fears; 12% (n = 59) of the sample reported disruptions to treatments; and of those reporting no current disruptions, 59% (n = 269) worried about future disruptions if the pandemic continued. Higher levels of care disruptions were related to higher COVID‐19 worries (Ps &lt; 0.005). Minimal differences by respondent type or copy number variation type emerged.ConclusionsWidespread medical care disruptions and pandemic‐related worries were reported by individuals with 22q11.2 syndrome and their family members. Reported worries were broadly consistent with research results from prior reports in the general population. The long‐term effects of COVID‐19 worries, interruptions to care and hospital avoidance require further study.
Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40–50% of... more Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40–50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotrunc...
BackgroundCongenital heart disease (CHD) affecting the conotruncal region of the heart, occur in ... more BackgroundCongenital heart disease (CHD) affecting the conotruncal region of the heart, occur in half of patients with 22q11.2 deletion syndrome. This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, mapped to the 22q11.2 region, encoding a T-box transcription factor, is one of the main genes for the etiology of the syndrome. We suggest that genetic modifiers of CHD in patients with 22q11.2 deletion syndrome may be in the TBX1 gene network.MethodsTo identify genetic modifiers of 22q11.2 deletion syndrome, we analyzed whole genome sequence of subjects with 22q11.2DS, of which 456 were cases with conotruncal heart defects and 537 were controls with normal cardiac structures. We retained the most damaging rare coding variants and examined 19 functional gene sets for association that were weighted upon expression of genes in cardiac progenitor cells in mouse embryos identified by RNA-sequen...
Journal of Applied Research in Intellectual Disabilities
BackgroundIndividuals with Phelan–McDermid syndrome (PMS) are characterised by phenotypical trait... more BackgroundIndividuals with Phelan–McDermid syndrome (PMS) are characterised by phenotypical traits that can be experienced as challenging by their environment. This study assessed parenting stress and Family Quality of Life (FQOL) in parents of individuals with PMS and identified potential contributing variables.MethodMothers (n = 14) and fathers (n = 13) of individuals with PMS (n = 14; 6 females, 8 males; age 2–37, M = 20, SD = 11.92) completed questionnaires on parenting stress, FQOL, adaptive behaviour and background characteristics.ResultsMothers and fathers experienced high, similar and related levels of parenting stress and FQOL satisfaction. Parenting stress and FQOL satisfaction were inversely related. High and low ratings were retrieved for subscales measuring feelings of parental role restriction and emotional well‐being, respectively. The adaptive skills of the individuals with PMS were related to fathers’ parenting stress and FQOL satisfaction.ConclusionsClinical practi...
The ability to tell a story involves a number of language and cognitive skills. In order to tell ... more The ability to tell a story involves a number of language and cognitive skills. In order to tell a good story a child needs to understand cause-effect relationships, outline events and use precise vocabulary to convey ideas to aid a listener in comprehending the tale (Boudreau, 2008). Children with some genetic syndromes seem to have difficulties acquiring these skills, which has impact on their everyday social communication. Cross-syndrome and cross-linguistic research on this topic is rare. Methods: A cross syndrome comparison of the narrative skills of Dutch speaking school-aged children with 22q11.2 deletion syndrome (22q11.2 DS) and children with Williams Syndrome is presented. These children are compared with (a) mental age matched control groups of children with an intellectual disability (ID) with unknown etiology, (b) children with ID with unknown etiology and comorbid autism spectrum disorder and (c) typically developing children. In addition, a cross linguistic Dutch-English comparison is summarized highlighting story (re)telling characteristics in children with 22q11.2 DS. A fine-grained story analysis based upon samples of the Bus Story Test (Renfrew, 1997) and the Expression, Reception and Recall of Narrative Instrument (Bishop, 2004) was carried out. Results: The results indicate cross-syndrome and within-syndrome variability in narrative skills. Cross-linguistic profiles are discussed and the impact on everyday communication is highlighted. Conclusion: Evaluating pragmatic and more specifically narrative language skills across syndromes can contribute to the understanding of the communicative behavioral phenotype. Detailed language assessments may improve intervention targeting communication, and lead to specific parental advices for these groups of children.
Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cog... more Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQ-scores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p < 0.01). Our findings suggest that using variant-specific normative IQ data significantly reduces required sample size in a research context, and may facilitate a more clinically informative interpretation of IQ data. This approach allows identification of individuals that deviate from their expected, variant-specific, trajectory. This group may be at increased risk for comorbid conditions, such as schizophrenia in the case of 22q11DS.
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