Vandana Shashi

Duke University, Durham, North Carolina, United States

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Publications (61)230.79 Total impact

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    ABSTRACT: Background Research suggests children with genetic disorders exhibit greater coping skills when they are aware of their condition and its heritability. While the experiences parents have at diagnosis may influence their decision to disclose the diagnosis to their children, there is little research into this communication. The aim of the current study was to examine the relationship between the diagnosis experience and the disclosure experience for parents of children with developmental disorders of a known genetic aetiology: parents of children with 22q11.2 deletion syndrome (22q11DS) were compared with a group of parents with children affected with other genetic diagnoses, with a similar age of diagnosis (e.g. fragile X syndrome) and a group where diagnosis generally occurs early (i.e. Down syndrome).Method The sample comprised 559 parents and caregivers of children with genetic developmental disorders, and an online survey was utilised. Items from the questionnaire were combined to create variables for diagnosis experience, parental disclosure experience, child's disclosure experience, and parental coping and self-efficacy.ResultsAcross all groups parents reported that the diagnosis experience was negative and often accompanied by a lack of support and appropriate information. Sixty-eight per cent of those in the 22q11DS and 58.3% in the Similar Conditions groups had disclosed the diagnosis to their child, whereas only 32.7% of the Down syndrome group had. Eighty-six per cent of the Down syndrome group felt they had sufficient information to talk to their child compared with 44.1% of the Similar Conditions group and 32.6% of the 22q11DS group. Parents reported disclosing the diagnosis to their child because they did not want to create secrets; and that they considered the child's age when disclosing. In the 22q11DS and Similar Conditions groups, a poor diagnosis experience was significantly associated with negative parental disclosure experiences. In the Similar Conditions group, a poor diagnosis experience was also significantly associated with a more negative child disclosure experience.Conclusions As expected this study highlights how difficult most parents find the diagnosis experience. Importantly, the data indicate that the personal experiences the parents have can have a long-term impact on how well they cope with telling their child about the diagnosis. It is important for clinicians to consider the long-term ramifications of the diagnosis experience and give the parents opportunities; through, for instance, psychoeducation to prepare for telling their child about the diagnosis. Further research is warranted to explore what type of information would be useful for parents to receive.
    Journal of Intellectual Disability Research 07/2014; · 1.88 Impact Factor
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    ABSTRACT: Purpose:The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1.Methods:Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data.Results:All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele.Conclusion:NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.Genet Med advance online publication 20 March 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.22.
    Genetics in medicine: official journal of the American College of Medical Genetics 03/2014; · 3.92 Impact Factor
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    ABSTRACT: OBJECTIVE Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants. METHOD The 1,402 participants with 22q11.2 deletion syndrome, ages 6-68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years. RESULTS Attention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were overrepresented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills. CONCLUSIONS To the authors' knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome.
    American Journal of Psychiatry 02/2014; · 14.72 Impact Factor
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    ABSTRACT: Abstract Children with 22q11.2 deletion syndrome exhibit high rates of social-behavioral problems, particularly in the internalizing domain, indicating an area in need of intervention. The current investigation was designed to obtain information regarding parent and teacher ratings of the social-emotional behavior of children with 22q11DS. Using the Child Behavior Checklist (CBCL), the sample included 67 children with 22q11DS and 59 control subjects. Results indicated significant differences in social-behavioral functioning of children with 22q11DS, as compared to a control group, based on rater type. Specifically, parents reported more difficulties with internalizing problems, withdrawal, and social problems in children with 22q11DS. In contrast, teachers perceived few differences between children with 22q11DS and unaffected children. Correlational analyses indicated weak concordance between parent and teacher reports, with no significant correlations on any of three summary scales. The findings support the use of multiple methods of assessment and multiple informants when collecting information regarding the social-behavioral functioning of children with 22q11DS, and that interpretations based on only one informant/setting need to be made cautiously.
    American Journal on Intellectual and Developmental Disabilities 09/2013; 118(5):339-352. · 2.08 Impact Factor
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    ABSTRACT: Purpose:The purpose of this study was to assess the diagnostic yield of the traditional, comprehensive clinical evaluation and targeted genetic testing, within a general genetics clinic. These data are critically needed to develop clinically and economically grounded diagnostic algorithms that consider presenting phenotype, traditional genetics testing, and the emerging role of next-generation sequencing (whole-exome/genome sequencing).Methods:We retrospectively analyzed a cohort of 500 unselected consecutive patients who received traditional genetic diagnostic evaluations at a tertiary medical center. We calculated the diagnosis rate, number of visits to diagnosis, genetic tests, and the cost of testing.Results:Thirty-nine patients were determined to not have a genetic disorder; 212 of the remaining 461 (46%) received a genetic diagnosis, and 72% of these were diagnosed on the first visit. The cost per subsequent successful genetic diagnosis was estimated at $25,000.Conclusion:Almost half of the patients were diagnosed using the traditional approach, most at the initial visit. For those remaining undiagnosed, next-generation sequencing may be clinically and economically beneficial. Estimating a 50% success rate for next-generation sequencing in undiagnosed genetic disorders, its application after the first clinical visit could result in a higher rate of genetic diagnosis at a considerable cost savings per successful diagnosis.Genet Med advance online publication 8 August 2013Genetics in Medicine (2013); doi:10.1038/gim.2013.99.
    Genetics in medicine: official journal of the American College of Medical Genetics 08/2013; · 3.92 Impact Factor
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    ABSTRACT: BACKGROUND: Children with 22q11.2 deletion syndrome (22q11DS) are at risk for social-behavioural and neurocognitive sequelae throughout development. The current study examined the impact of family environmental characteristics on social-behavioural and cognitive outcomes in this paediatric population. METHOD: Guardians of children with 22q11DS were recruited through two medical genetics clinics. Consenting guardians were asked to complete several questionnaires regarding their child's social, emotional and behavioural functioning, as well as family social environment and parenting styles. Children with 22q11DS were asked to undergo a cognitive assessment, including IQ and achievement testing, and measures of attention, executive function and memory. RESULTS: Modest associations were found between aspects of the family social environment and parenting styles with social-behavioural and cognitive/academic outcomes. Regression models indicated that physical punishment, socioeconomic status, parental control and family organisation significantly predicted social-behavioural and cognitive outcomes in children with 22q11DS. CONCLUSION: Characteristics of the family social environment and parenting approaches appear to be associated with functional outcomes of children with 22q11DS. Understanding the impact of environmental variables on developmental outcomes can be useful in determining more effective targets for intervention. This will be important in order to improve the quality of life of individuals affected by 22q11DS.
    Journal of Intellectual Disability Research 06/2013; · 1.88 Impact Factor
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    ABSTRACT: Children with chromosome 22q11.2 deletion syndrome (22q11DS) are significantly impaired in their academic performance and functionality due to cognitive deficits, especially in attention, memory, and other facets of executive function. Compounding these cognitive deficits is the remarkably high risk of major psychoses, occurring in 25% of adolescents and adults with the disorder. There are currently no evidence-based interventions designed to improve the cognitive deficits in these individuals. We implemented a neuroplasticity-based computerized cognitive remediation program for 12 weeks in 13 adolescents with 22q11DS, assessed feasibility, and measured changes in cognition before and after the intervention compared to a control group of 10 age- and gender-matched children with 22q11DS. Our results indicated that despite their cognitive impairments, this intervention is feasible in children with 22q11DS, with high rates of adherence and satisfaction. Our preliminary analyses indicate that gains in cognition occur with the intervention. Further study in a larger randomized controlled trial would enable assessment of efficacy of this novel intervention.
    Research in developmental disabilities 06/2013; 34(9):2606-2613. · 4.41 Impact Factor
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    ABSTRACT: The present study sought to examine the longitudinal psychoeducational, neurocognitive, and psychiatric outcomes of children and adolescents with chromosome 22q11.2 deletion syndrome (22q11DS), a population with a high incidence of major psychiatric illnesses appearing in late adolescence/early adulthood. Little is known of the developmental changes that occur in the early teen years, prior to the age of highest psychosis risk. Data were collected from 71 participants (42 subjects with 22q11DS and 29 control subjects) at Time 1 (T1) and Time 2 (T2), approximately 3.5 years later. The 22q11DS group was significantly lower functioning than controls on IQ, neurocognition, and academic achievement at both T1 and T2. Children with 22q11DS also showed significantly greater social-behavioral difficulties and psychiatric symptoms, and were more likely to meet criteria for psychiatric disorders at both time points. In evaluating change over time from T1 to T2, the 22q11DS group did not show significant changes in psychoeducational or psychiatric outcomes relative to the controls, however, lack of expected age-related gains in attention regulation were noted. Within the 22q11DS group, an increase in the Attenuated Prodrome for Schizophrenia (number of psychiatric symptoms) was noted from T1 to T2 and four children with 22q11DS met criteria for Psychosis for the first time. Predictors at T1 that uncovered psychopathology symptoms at T2 included full-scale IQ, externalizing symptoms, and problem social behaviors. Overall, younger adolescent and preadolescent children with 22q11DS in this study exhibited slowed growth in attention regulation, with an increase in subclinical symptoms of schizophrenia, suggestive of increasing impairments in domains that are relevant to the high risk of Schizophrenia. Early predictors of later psychopathology included both cognitive and behavioral abnormalities. These findings begin to elucidate the trajectory of changes in psychopathology in children with 22q11DS in the years leading up to the onset of major psychiatric illnesses.
    Research in developmental disabilities 03/2013; 34(5):1758-1769. · 4.41 Impact Factor
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    ABSTRACT: Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.
    The American Journal of Human Genetics 02/2013; · 11.20 Impact Factor
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    ABSTRACT: Most children with chromosome 22q11.2 deletion syndrome (22q11DS) have an IQ in the range that may allow them to be capable of understanding a genetic diagnosis despite mild intellectual disabilities. However, there are no publications that relate to the disclosure of a 22q11DS diagnosis to the affected child, or the factors that influence parents' disclosure to the child. A pilot study was conducted including eight semi-structured interviews with caregivers of children with 22q11DS, 10 to 17 years of age, to investigate the factors that influence how parents inform their children of the diagnosis. Six of eight participants had disclosed the diagnosis to the child, and most of these parents felt they could have benefited from additional advice from professionals to increase their confidence and success, as well as the child's comprehension of the information. Those who had not informed the child were uncertain about the words to use, how to initiate the conversation, or were concerned about the child's level of understanding. Our results demonstrate that genetics professionals should help prepare caregivers for conversations with their children about the diagnosis of 22q11DS, monitor the understanding of the diagnosis over time, and provide ongoing support.
    Journal of Genetic Counseling 08/2012; · 1.45 Impact Factor
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    ABSTRACT: Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with neurocognitive impairments. The neural substrates of cognitive impairments in 22q11DS remain poorly understood. Because the corpus callosum (CC) is found to be abnormal in a variety of neurodevelopmental disorders, we obtained volumetric measurements of the CC and its subregions, examined the relationship between these regions and neurocognition and selected genotypes within candidate genes in the 22q11.2 interval in 59 children with 22q11DS and 53 control subjects. The total CC, splenium and genu were significantly larger in children with 22q11DS and the enlargement was associated with better neurocognitive functioning in the 22q11DS group, suggestive of a compensatory increase in the CC volumes. The expected age-related increase in the volume of the CC was not seen in children with 22q11DS, indicative of dysmaturation of the CC in these children. The increased volumes in the genu, splenium and total CC in the 22q11DS group were associated with polymorphisms within the candidate genes: COMT (rs4680), ZDHHC8 (rs175174) and UFD1L (rs5992403). These findings indicate that alterations in the CC volume in children with 22q11DS are associated with cognition and specific genotypes in the 22q11.2 interval.
    European journal of human genetics: EJHG 07/2012; 20(10):1051-7. · 3.56 Impact Factor
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    ABSTRACT: Chromosome 22q11.2 deletion syndrome (22q11DS), the most common microdeletion in humans, is associated with multiple medical features, almost universal cognitive deficits, and a high risk of schizophrenia. The metabolic basis of the psychological/psychiatric features is not well understood. Volumetric brain imaging studies have shown that gray matter abnormalities in the dorsolateral prefrontal cortex (DLPFC), an area that is believed to be integral for higher neurocognition, as well as being involved in schizophrenia, are associated with the psychological manifestations. However, studies have not characterized any possible metabolite alterations within the DLPFC of children with 22q11DS and their correlations with the psychological findings. We conducted a short echo time, single-voxel, in vivo proton spectroscopy study involving children with 22q11DS (n = 26) and matched control subjects (n = 23). Absolute N-acetylaspartate (NAA) levels from the DLPFC were significantly elevated in children with 22q11DS compared with control subjects and the elevations were associated with poor global functioning and higher rates of comorbid attention-deficit/hyperactivity disorder. Children with 22q11DS had a lack of an age-associated decrease in NAA levels, a trend seen in the control subjects. However, the results did not remain statistically significant after corrections for multiple comparisons were made. These findings represent the first report of proton spectroscopy in children with 22q11DS. The elevated DLPFC NAA levels and the lack of decreasing trends in NAA with age in the 22q11DS group relative to control subjects suggest an alteration in cortical development. Also, such neuronal dysmaturation is associated with psychopathology in children with 22q11DS.
    Biological psychiatry 05/2012; 72(8):684-91. · 8.93 Impact Factor
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    ABSTRACT: There is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations. The authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met. This undertaking resulted in a likely genetic diagnosis in 6 of the 12 probands, including the identification of apparently causal mutations in four genes known to cause Mendelian disease (TCF4, EFTUD2, SCN2A and SMAD4) and one gene related to known Mendelian disease genes (NGLY1). Of particular interest is that at the time of this study, EFTUD2 was not yet known as a Mendelian disease gene but was nominated as a likely cause based on the observation of de novo mutations in two unrelated probands. In a seventh case with multiple disparate clinical features, the authors were able to identify homozygous mutations in EFEMP1 as a likely cause for macular degeneration (though likely not for other features). This study provides evidence that next-generation sequencing can have high success rates in a clinical setting, but also highlights key challenges. It further suggests that the presentation of known Mendelian conditions may be considerably broader than currently recognised.
    Journal of Medical Genetics 05/2012; 49(6):353-61. · 5.70 Impact Factor
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    ABSTRACT: Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion in humans. Nonverbal learning disability (NLD) has been used to describe the strengths and deficits of children with 22q11DS, but the applicability of the label for this population has seldom been systematically evaluated. The goal of the current study was to address how well the NLD diagnosis characterizes children and adolescents with 22q11DS. A total of 74 children and adolescents with 22q11DS were given neurocognitive, socioemotional, and academic assessments to measure aspects of NLD. Of the cohort, 20% met at least 7 of 9 assessed criteria for NLD; 25% showed verbal skills exceeding their nonverbal skills as assessed by an IQ test; and 24% showed the good rote verbal capacity commonly associated with NLD. Hypothesizing that if the entire cohort did not show consistent NLD characteristics, the descriptor might be more accurate for a distinct subgroup, the authors used latent class analysis to divide participants into three subgroups. However, the lines along which the groups broke out were more related to general functioning level than to NLD criteria. All three groups showed a heightened risk for psychiatric illness, highlighting the importance of careful mental health monitoring for all children with 22q11DS.
    Journal of learning disabilities 05/2012; · 1.77 Impact Factor
  • Translational psychiatry. 02/2012; 2:e124.
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    ABSTRACT: Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans. It is typified by highly variable symptoms, which might be explained by epigenetic regulation of genes in the interval. Using computational algorithms, our laboratory previously predicted that DiGeorge critical region 6 (DGCR6), which lies within the deletion interval, is imprinted in humans. Expression and epigenetic regulation of this gene have not, however, been examined in 22q11DS subjects. The purpose of this study was to determine if the expression levels of DGCR6 and its duplicate copy DGCR6L in 22q11DS subjects are associated with the parent-of-origin of the deletion and childhood psychopathologies. Our investigation showed no evidence of parent-of-origin-related differences in expression of both DGCR6 and DGCR6L. However, we found that the variability in DGCR6 expression was significantly greater in 22q11DS children than in age and gender-matched control individuals. Children with 22q11DS who had anxiety disorders had significantly lower DGCR6 expression, especially in subjects with the deletion on the maternal chromosome, despite the lack of imprinting. Our findings indicate that epigenetic mechanisms other than imprinting contribute to the dysregulation of these genes and the associated childhood psychopathologies observed in individuals with 22q11DS. Further studies are now needed to test the usefulness of DGCR6 and DGCR6L expression and alterations in the epigenome at these loci in predicting childhood anxiety and associated adult-onset pathologies in 22q11DS subjects.
    Translational psychiatry. 02/2012; 2:e105.
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    ABSTRACT: Privigen(®) (immune globulin intravenous [human], 10% liquid) and Hizentra(®) (immune globulin subcutaneous [human], 20% liquid) are stabilized by proline. The clinical implications of administering proline-containing immunoglobulin products to patients with defects of proline metabolism have not been addressed; Privigen and Hizentra are contraindicated in these patients. Some patients with chromosome 22q11.2 deletion syndrome have elevated proline levels; however, only 3-4% of patients also have an immunodeficiency that requires IgG therapy. This review summarizes the evidence related to the safety and pharmacokinetics of proline assessed in Privigen and Hizentra preclinical and clinical studies, and subsequent implications for patients with defects in proline metabolism. Clinical data indicate that proline does not accumulate after Privigen or Hizentra treatment and is not associated with adverse events. There is no evidence to suggest that patients with defects of proline metabolism would be affected by transient elevations in plasma proline following Privigen and/or Hizentra treatment.
    Expert Review of Clinical Immunology 02/2012; 8(2):169-78. · 2.89 Impact Factor
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    ABSTRACT: Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with numerous and variable clinical manifestations including conotruncal heart abnormalities, palatal anomalies, hypoparathyroidism, immune deficiency, and cognitive deficits. The clinical suspicion of this syndrome is often heightened by the presence of characteristic facial features. A previous report highlighted the under-diagnosis of this condition in African Americans, thought to be related to a paucity of typical facial features. We ascertained the largest cohort (n = 50) of African-American individuals with 22q11DS reported thus far, across five genetics centers in the United States and report on their facial and other phenotypic features. About 3/4 of our cohort has at least one dysmorphic facial feature. Auricular abnormalities, especially small ears, are the most common dysmorphic facial feature followed by nasal and ocular abnormalities. Skeletal findings are seen in about 2/3 of our cohort, higher than the typical frequency reported in 22q11DS. Cardiac anomalies, developmental delay, and palatal abnormalities are seen at a lower frequency in our cohort. Thus, it is evident that the features traditionally associated with 22q11DS are difficult to recognize in African-American individuals with this syndrome, due to both altered frequencies of major anomalies and a non-classic facial appearance. Therefore, a high index of suspicion is needed to recognize 22q11DS in African-American individuals.
    American Journal of Medical Genetics Part A 09/2011; 155A(9):2186-95. · 2.30 Impact Factor
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    ABSTRACT: Although distinctive neuropsychological impairments have been delineated in children with chromosome 22q11 deletion syndrome (22q11DS), social skills and social cognition remain less well-characterised. To examine social skills and social cognition and their relationship with neuropsychological function/behaviour and psychiatric diagnoses in children with 22q11DS. Sixty-six children with 22q11DS and 54 control participants underwent neuropsychological testing and were administered the Diagnostic Analysis of Non-Verbal Accuracy (DANVA) for face and auditory emotion recognition, a measure of social cognition: their parents/guardians were administered the Social Skills Rating System (SSRS) - parent version, Child Behavior Checklist (CBCL) - parent version and the Computerised Diagnostic Interview Schedule for Children (C-DISC). The 22q11DS group exhibited significantly lower social skills total score and more problem social behaviours, lower neurocognitive functioning, higher rates of anxiety disorders and more internalising symptoms than the control group. Participants with 22q11DS also exhibited significant deficits in their ability to read facial expressions compared with the control group, but performed no differently than the control participants in the processing of emotions by tone of voice. Within the 22q11DS group, higher social competency was correlated with higher global assessment of functioning and parental socio-economic status. Social competency was worse in those with anxiety disorders, attention deficit hyperactivity disorder, more than two psychiatric diagnoses on the C-DISC and higher internalising symptoms. No significant correlations of SSRS scores were seen with IQ, executive functions, attention, or verbal learning and memory. No correlations were found between social cognition and social skill scores. Our results indicate that social skills in children with 22q11DS are associated with behaviour/emotional functioning and not with neurocognition. Thus, treating the behaviour or emotional problems such as attention deficit hyperactivity disorder and anxiety disorders may provide a pathway for improving social skills in these children.
    Journal of Intellectual Disability Research 08/2011; 56(9):865-78. · 1.88 Impact Factor
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    ABSTRACT: To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.
    Nature Genetics 08/2011; 43(9):838-46. · 35.21 Impact Factor

Publication Stats

849 Citations
230.79 Total Impact Points

Institutions

  • 2010–2014
    • Duke University
      • Department of Psychology and Neuroscience
      Durham, North Carolina, United States
  • 2009–2013
    • Duke University Medical Center
      • Division of Medical Genetics
      Durham, NC, United States
  • 2007–2012
    • University of North Carolina at Greensboro
      • Department of Psychology
      Greensboro, NC, United States
  • 1999–2007
    • Wake Forest School of Medicine
      • • Department of Pediatrics
      • • Section on Medical Genetics
      Winston-Salem, North Carolina, United States
  • 1994–1995
    • University of Virginia
      • Department of Pediatrics
      Charlottesville, Virginia, United States