Vandana Shashi

Duke University Medical Center, Durham, North Carolina, United States

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Publications (87)360.39 Total impact

  • Sarah J. Hart · Kelly Schoch · Vandana Shashi · Nancy Callanan
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    ABSTRACT: Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an increased chance of developing a psychiatric disorder. While parents of children affected by 22q11.2DS typically receive counseling about risk for non-psychiatric health concerns, genetic counselors may be reluctant to discuss psychiatric risk. Further education of genetic counselors may be necessary to encourage discussion of psychiatric risk with these families. The goal of this project was to develop recommendations for genetic counselors to provide psychiatric risk information to families affected by 22q11.2DS. The recommendations were developed by synthesizing resources in the literature about risk communication. These recommendations were refined following an online focus group meeting with five health care professionals who were recruited for participation from 22q11.2DS clinics across the U.S.A. The focus group data revealed three themes related to discussion of psychiatric risk: 1) Stepwise approach, 2) Discussing treatment options and reducing risks, and 3) Addressing stigma. These recommendations may be used as a foundation for a future clinical protocol to encourage discussion about the risk for psychiatric illness at an earlier point in the diagnostic process for 22q11.2DS and to provide improved information, support and resources to affected families.
    No preview · Article · Nov 2015 · Journal of Genetic Counseling
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    Preview · Article · Oct 2015
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    Preview · Article · Oct 2015
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    ABSTRACT: We report two patients with drug-resistant epilepsy, caused by KCNT1 mutations, who were treated with quinidine. Both mutations manifested gain of function In-vitro, showing increased current that was reduced by quinidine. One, who had epilepsy of infancy with migrating focal seizures, had 80% reduction in seizure frequency. The other, who had a novel phenotype, with severe nocturnal focal and secondary generalized seizures starting in early childhood with developmental regression, did not improve. While quinidine represents an encouraging opportunity for therapeutic benefits, our experience suggests caution in its application and supports the need to identify more targeted drugs for KCNT1 epilepsies. This article is protected by copyright. All rights reserved.
    No preview · Article · Sep 2015 · Annals of Neurology
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    ABSTRACT: Children with chromosome 22q11.2 deletion syndrome (22q11DS) often have deficits in social cognition and social skills that contribute to poor adaptive functioning. These deficits may be of relevance to the later occurrence of serious psychiatric illnesses such as schizophrenia. Yet, there are no evidence-based interventions to improve social cognitive functioning in children with 22q11DS. Using a customised social cognitive curriculum, we conducted a pilot small-group-based social cognitive training (SCT) programme in 13 adolescents with 22q11DS, relative to a control group of nine age- and gender-matched adolescents with 22q11DS. We found the SCT programme to be feasible, with high rates of compliance and satisfaction on the part of the participants and their families. Our preliminary analyses indicated that the intervention group showed significant improvements in an overall social cognitive composite index. SCT in a small-group format for adolescents with 22q11DS is feasible and results in gains in social cognition. A larger randomised controlled trial would permit assessment of efficacy of this promising novel intervention. © 2015 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.
    No preview · Article · Apr 2015 · Journal of Intellectual Disability Research

  • No preview · Article · Mar 2015 · Clinical Genetics
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    ABSTRACT: Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age. To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS. Prospective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with ≥1 assessment at age 8-24 years). Diagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test. Among 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P < .001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (odds ratio = 2.49; 95% CI, 1.24-5.00; P = .01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from age 11 years onward. In 22q11DS, early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis.
    Full-text · Article · Feb 2015 · JAMA Psychiatry
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    ABSTRACT: Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s). Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    No preview · Article · Feb 2015 · The American Journal of Human Genetics
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    ABSTRACT: Despite the exciting advent of whole exome sequencing (WES) in medical genetics practices, the optimal interpretation of results requires further actions such as reconsidering clinical information and obtaining further laboratory testing. There are no published data to guide clinicians in this process. In a retrospective study on 93 patients who underwent clinical WES, we set out to assess and resolve these practical challenges. With the laboratories reporting a molecular diagnostic rate of 25.8%, the medical geneticists and the laboratories were 90% concordant in their interpretation of the WES results. Divergence occurred when the medical geneticist reconsidered clinical information and/or additional information regarding pathogenicity of a variant. Variants of uncertain significance were reported in 86% of patients, with 53.7% needing follow-up, such as additional laboratory tests and genotyping of family members. By layering clinical data (e.g. mode of inheritance and phenotypic fit) on to the laboratory results, we developed clinical categories for the WES results. These categories of Definite diagnosis (14/93), Likely diagnosis (8/93), Possible diagnosis (13/93) and No diagnosis (58/93) could be used to uniformly convey results to patients. Our framework for a clinically informed interpretation of the results enhances the utility of WES within medical genetics practices. This article is protected by copyright. All rights reserved.
    Full-text · Article · Feb 2015 · Clinical Genetics
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    ABSTRACT: Purpose:Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene-disease associations.Methods:We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients.Results:We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice (P = 3.4 × 10(-8)). This enrichment is only partially explained by mutations found in known disease-causing genes.Conclusion:This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications.Genet Med advance online publication 15 January 2015Genetics in Medicine (2015); doi:10.1038/gim.2014.191.
    No preview · Article · Jan 2015 · Genetics in medicine: official journal of the American College of Medical Genetics
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    ABSTRACT: 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion in humans. There have been few studies assessing the impact of this condition on the family and no previous studies conducted on unaffected siblings of children with 22q11DS. The goal of this study was to determine the frequency, method, and content of information being communicated by parents to unaffected siblings about the condition and to assess unaffected siblings' knowledge of 22q11DS and perceptions of the impact of the condition on their affected sibling and themselves. Families were recruited from several 22q11DS educational and support organizations and asked to complete a single anonymous online survey. Families were eligible to participate if they had one child with 22q11DS and at least one unaffected child between the ages of 12 and 17. Survey questions were developed based on previous literature and authors' expertise with individuals with 22q11DS. Responses to quantitative and qualitative questions were analyzed to calculate frequencies and proportions and to extract themes, respectively. A total of 25 families (defined as a unit of at least one parent, one affected child, and at least one unaffected child) participated in the study. Parents shared genetic information less often as compared to behavioral and medical information. Siblings of children with 22q11DS had both positive and negative experiences in having a brother or sister with this condition. Genetic counselors can use the results of this study to develop anticipatory guidance for parents of children with 22q11DS in talking with their unaffected children about the condition.
    No preview · Article · Dec 2014 · Journal of Genetic Counseling
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    ABSTRACT: A novel X-linked intellectual disability (XLID) syndrome with moderate intellectual disability and distinguishing craniofacial dysmorphisms had been previously mapped to the Xq26-q27 interval. On whole exome sequencing in the large family originally reported with this disorder, we identified a 23 bp frameshift deletion in the RNA Binding Motif Protein X-linked (RBMX) gene at Xq26 in the affected males (n = 7), one carrier female, absent in unaffected males (n = 2) and in control databases (7800 exomes). The RBMX gene has not been previously causal of human disease. We examined the genic intolerance scores for the coding regions and the non-coding regions of RBMX; the findings were indicative of RBMX being relatively intolerant to loss of function variants, a distinctive pattern seen in a subset of XLID genes. Prior expression and animal modeling studies indicate that loss of function of RBMX results in abnormal brain development. Our finding putatively adds a novel gene to the loci associated with XLID and may enable the identification of other individuals affected with this distinctive syndrome.
    Full-text · Article · Sep 2014 · Clinical Genetics
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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.
    Full-text · Article · Jul 2014 · Journal of Intellectual Disability Research
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    ABSTRACT: As indicated by several recent studies, magnetic susceptibility of the brain is influenced mainly by myelin in the white matter and by iron deposits in the deep nuclei. Myelination and iron deposition in the brain evolve both spatially and temporally. This evolution reflects an important characteristic of normal brain development and ageing. In this study, we assessed the changes of regional susceptibility in the human brain in vivo by examining the developmental and ageing process from 1 to 83 years of age. The evolution of magnetic susceptibility over this lifespan was found to display differential trajectories between the gray and the white matter. In both cortical and subcortical white matter, an initial decrease followed by a subsequent increase in magnetic susceptibility was observed, which could be fitted by a Poisson curve. In the gray matter, including the cortical gray matter and the iron-rich deep nuclei, magnetic susceptibility displayed a monotonic increase that can be described by an exponential growth. The rate of change varied according to functional and anatomical regions of the brain. For the brain nuclei, the age-related changes of susceptibility were in good agreement with the findings from R2(*) measurement. Our results suggest that magnetic susceptibility may provide valuable information regarding the spatial and temporal patterns of brain myelination and iron deposition during brain maturation and ageing. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
    No preview · Article · Jun 2014 · Human Brain Mapping
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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.
    Full-text · Article · Mar 2014 · Genetics in medicine: official journal of the American College of Medical Genetics
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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.
    Full-text · Article · Feb 2014 · American Journal of Psychiatry
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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.
    No preview · Article · Sep 2013 · American Journal on Intellectual and Developmental Disabilities
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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.
    Full-text · Article · Aug 2013 · Genetics in medicine: official journal of the American College of Medical Genetics
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    T M Allen · J Hersh · K Schoch · K Curtiss · S R Hooper · V Shashi
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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.
    Preview · Article · Jun 2013 · Journal of Intellectual Disability Research
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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.
    No preview · Article · Jun 2013 · Research in developmental disabilities

Publication Stats

2k Citations
360.39 Total Impact Points

Institutions

  • 2009-2015
    • Duke University Medical Center
      • • Division of Medical Genetics
      • • Department of Pediatrics
      Durham, North Carolina, United States
    • Duke University
      Durham, North Carolina, United States
  • 1999-2009
    • Wake Forest School of Medicine
      • • Department of Pediatrics
      • • Section on Medical Genetics
      • • Department of Otolaryngology
      Winston-Salem, North Carolina, United States
  • 2007
    • Wake Forest University
      Winston-Salem, North Carolina, United States
  • 1994-1995
    • University of Virginia
      • Division of Pediatrics
      Charlottesville, Virginia, United States