Leandra Berry

The Cognitive and Behavioral Phenotype of the 16p11.2 Deletion in a Clinically Ascertained Population

BACKGROUND Deletion of the recurrent ~600 kb BP4-BP5 chromosomal region 16p11.2 has been associated with a wide range of neurodevelopmental outcomes. METHODS To clarify the phenotype of 16p11.2 deletion, we examined the psychiatric and developmental presentation of predominantly clinically referred individuals, with a particular emphasis on broader autism phenotype characteristics in individuals with recurrent ~600 kb chromosome 16p11.2 deletions. Using an extensive standardized assessment battery across three clinical sites, 85 individuals with the 16p11.2 deletion and 153 familial control subjects were evaluated for symptom presentation and clinical diagnosis. RESULTS Individuals with the 16p11.2 deletion presented with a high frequency of psychiatric and developmental disorders (>90%). The most commonly diagnosed conditions were developmental coordination disorder, phonologic processing disorder, expressive and receptive language disorders (71% of individuals >3 years old with a speech and language-related disorder), and autism spectrum disorder. Individuals with the 16p11.2 deletion not meeting diagnostic criteria for autism spectrum disorder had a significantly higher prevalence of autism-related characteristics compared with the familial noncarrier control group. Individuals with the 16p11.2 deletion had a range of intellectual ability, but IQ scores were 26 points lower than noncarrier family members on average. CONCLUSIONS Clinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly associated with the broader autism phenotype.

Clinical phenotype of the recurrent 1q21.1 copy-number variant

Purpose:To characterize the clinical phenotype of the recurrent copy-number variation (CNV) at 1q21.1, we assessed the psychiatric and medical phenotypes of 1q21.1 deletion and duplication carriers ascertained through clinical genetic testing and family member cascade testing, with particular emphasis on dimensional assessment across multiple functional domains.Methods:Nineteen individuals with 1q21.1 deletion, 19 individuals with the duplication, and 23 familial controls (noncarrier siblings and parents) spanning early childhood through adulthood were evaluated for psychiatric, neurologic, and other medical diagnoses, and their cognitive, adaptive, language, motor, and neurologic domains were also assessed. Twenty-eight individuals with 1q21.1 CNVs (15 deletion, 13 duplication) underwent structural magnetic resonance brain imaging.Results:Probands with 1q21.1 CNVs presented with a range of psychiatric, neurologic, and medical disorders. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. Increased frequency of Autism Spectrum Disorder (ASD) diagnosis, increased ASD symptom severity, and increased prevalence of macrocephaly were observed in the duplication relative to deletion carriers, whereas reciprocally increased prevalence of microcephaly was observed in the deletion carriers.Conclusions:Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.Genet Med 18 4, 341–349.

Brief measures of anxiety in non-treatment-seeking youth with autism spectrum disorder

This study investigated the accuracy of brief anxiety scales for non-treatment-seeking youth with autism spectrum disorder. In all, 54 youth (7–17 years; IQ: 67–158) with autism spectrum disorder and their parents completed (a) an expanded version of the Anxiety Disorders Interview Schedule—Child/Parent designed to capture typical and atypical fears and (b) brief scales of anxiety symptoms (Behavior Assessment Schedule for Children, Second Edition; Screen for Child Anxiety and Related Emotional Disorders; Negative Affective Self-Statement Questionnaire; Pediatric Anxiety Rating Scale). The results indicate that measures lacked adequate sensitivity and specificity, and the detection of atypical fears was particularly poor. Revised cut scores are offered, but refined and/or revised instruments are likely needed for research on youth with autism spectrum disorder.

The Cognitive and Behavioral Phenotypes of Individuals with CHRNA7 Duplications.

Chromosome 15q11q13 is among the least stable regions in the genome due to its highly complex genomic architecture. Low copy repeat elements at 15q13.3 facilitate recurrent copy number variants (CNVs), with deletions established as pathogenic and CHRNA7 implicated as a candidate gene. However, the pathogenicity of duplications of CHRNA7 is unclear, as they are found in affected probands as well as in reportedly healthy parents and unaffected control individuals. We evaluated 18 children with microduplications involving CHRNA7, identified by clinical chromosome microarray analysis (CMA). Comprehensive phenotyping revealed high prevalence of developmental delay/intellectual disability, autism spectrum disorder, and attention deficit/hyperactivity disorder. As CHRNA7 duplications are the most common CNVs identified by clinical CMA, this study provides anticipatory guidance for those involved with care of affected individuals.

The complex behavioral phenotype of 15q13.3 microdeletion syndrome.

Background:Chromosome 15q13.3 represents a hotspot for genomic rearrangements due to repetitive sequences mediating nonallelic homologous recombination. Deletions of 15q13.3 have been identified in the context of multiple neurological and psychiatric disorders, but a prospective clinical and behavioral assessment of affected individuals has not yet been reported.Methods:Eighteen subjects with 15q13.3 microdeletion underwent a series of behavioral assessments, along with clinical history and physical examination, to comprehensively define their behavioral phenotypes.Results:Cognitive deficits are the most prevalent feature in 15q13.3 deletion syndrome, with an average nonverbal IQ of 60 among the patients studied. Autism spectrum disorder was highly penetrant, with 31% of patients meeting clinical criteria and exceeding cutoff scores on both ADOS-2 and ADI-R. Affected individuals exhibited a complex pattern of behavioral abnormalities, most notably hyperactivity, attention problems, withdrawal, and externalizing symptoms, as well as impairments in functional communication, leadership, adaptive skills, and activities of daily living.Conclusions:The 15q13.3 deletion syndrome encompasses a heterogeneous behavioral phenotype that poses a major challenge to parents, caregivers, and treating providers. Further work to more clearly delineate genotype–phenotype relationships in 15q13.3 deletions will be important for anticipatory guidance and development of targeted therapies.Genet Med 18 11, 1111–1118.

Prevalence of Autism Spectrum Disorder in Children Referred for Diagnostic Autism Evaluation

Increased public awareness of autism spectrum disorders (ASD) and routine screening in primary care have contributed to increased requests for diagnostic ASD evaluations. However, given the scarcity of subspecialty autism diagnostic resources, overreferral of children suspected of having ASD may be contributing to long waiting lists at tertiary care autism centers and delaying diagnosis for those children who truly have ASD. To determine whether children are being excessively referred to ASD-specific diagnostic clinics, our objective was to determine the prevalence of true ASD diagnoses in children referred for diagnostic ASD evaluation. Charts of all patients referred to a regional autism center between April 2011 and August 2012 for suspicion of a possible ASD were retrospectively reviewed and demographic and clinical diagnoses abstracted. Only 214 of 348 patients evaluated (61%) received an ASD diagnosis. Thus, concerns about autism are not confirmed by an ASD diagnosis in a significant number of children.

Early Intervention Before Autism Diagnosis in Children Referred to a Regional Autism Clinic.

Objective: To determine the prevalence of receipt of early intervention and therapeutic services in children suspected of having possible autism spectrum disorder (ASD) before their diagnostic ASD evaluations. Methods: The electronic medical records of all children ⩽5 years of age evaluated at a single regional ASD clinic between September 2012 and June 2014 were reviewed. Information regarding type of services, clinical diagnoses, and demographic information was abstracted for each patient. Results: Five hundred sixty-one children (mean age = 44 mo [SD, 10 mo]; 80% [N = 450] male; 20% [N = 111] female) completed a diagnostic ASD evaluation. Of these children, 497 (89%) were already receiving early intervention services, and only 64 (11%) were not receiving any services. Receipt of services did not vary based on race, ethnicity, insurance type, or primary language. Children who were already receiving services were more likely to receive an ASD diagnosis (67%, N = 332) than those not receiving services (44% [N = 28]; p ⩽ .001). Conclusion: Despite concerns that long wait lists for diagnostic ASD evaluations may delay initiation of critical early interventions, our data indicate that most children are receiving early intervention services before their diagnostic ASD evaluations, particularly if an ASD diagnosis is confirmed. This may be attributable to increased awareness among primary care providers and families of the importance of early interventions. Further investigation into access to more intensive interventions (such as applied behavioral analysis) once an ASD diagnosis is established is warranted.

Neurocognitive and Neurobehavioral Phenotype of Youth with Schaaf-Yang Syndrome

Truncating variants of the MAGEL2 gene, one of the protein-coding genes within the Prader-Willi syndrome (PWS) critical region on chromosome 15q11, cause Schaaf-Yang syndrome (SYS)—a neurodevelopmental disorder that shares several clinical features with PWS. The current study sought to characterize the neurobehavioral phenotype of SYS in a sample of 9 patients with molecularly-confirmed SYS. Participants received an assessment of developmental/intellectual functioning, adaptive functioning, autism symptomatology, and behavioral/emotional functioning. Compared to individuals with PWS, patients with SYS manifested more severe cognitive deficits, no obsessions or compulsions, and increased rates of autism spectrum disorder.