Copy number variation plays an important role in clinical epilepsy.

OBJECTIVE: To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. METHODS: We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. RESULTS: Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34% were >500kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or "hotspots." We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. INTERPRETATION: Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy.

Optimizing Care for Autistic Patients in Health Care Settings: A Scoping Review and Call to Action.

OBJECTIVE: We conducted a scoping review of interventions designed to improve the health care experiences of autistic individuals and assessed the methodology and outcomes used to evaluate them. METHODS: Literature from January 2005 to October 2020 was searched using PubMed, Excerpta Medica dataBASE (EMBASE), Cumulated Index to Nursing and Allied Health Literature (CINAHL), PsycINFO as well as hand searching. Studies included described an intervention for autistic individuals in inpatient or outpatient settings and evaluated the intervention using standardized methodology. Results were exported to Covidence software. Ten reviewers completed abstract screening, full text review, and then systematic data extraction of the remaining articles. Two reviewers evaluated each article at each stage, with a third reviewer arbitrating differences. RESULTS: A total of 38 studies, including three randomized controlled trials (RCTs) were included. Twenty-six (68%) took place in dental, psychiatric, or procedural settings. Interventions primarily focused on visit preparation and comprehensive care plans or pathways (N = 29, 76%). The most frequent outcome was procedural compliance (N = 15), followed by intervention acceptability (N = 7) and parent satisfaction (N = 6). Two studies involved autistic individuals and caregivers in study design, and no studies assessed racial/ethnic diversity on intervention impact. CONCLUSIONS: Well-designed evaluations of interventions to support autistic individuals in pediatric health care settings are limited. There is a need to conduct large multi-site intervention implementation studies.

SOX12 and NRSN2 are candidate genes for 20p13 subtelomeric deletions associated with developmental delay.

20p13 telomeric/subtelomeric deletions are clinically significant but are currently under-investigated. So far only five molecularly delineated cases have been reported in literature and no candidate genes have been sufficiently implicated. Here, we present six new deletion cases identified by chromosomal microarray analysis (CMA). We also review 32 cases combined from literature and databases. We found that most 20p13 deletion patients exhibit significant developmental delay. Dysmorphic features are common but a consistent pattern was not recognized. Reduced cognitive ability was frequent. Based on pathogenic deletions delineated in this study, we mapped the smallest overlapping region and identified two nervous system expressing genes (SOX12 and NRSN2) as candidate genes that may be involved in the developmental defects in 20p13 microdeletion.

Keys to Success: A Professional Development Program to Support Care of Patients With Autism Spectrum Disorder.

Patients with autism spectrum disorder present with an extensive range of communication and social skills that require healthcare workers to have a comprehensive understanding of best practices for providing holistic care. This article presents the planning, curriculum development, implementation, and evaluation of a professional development program aimed at providing interprofessional staff with strategies and resources to use when caring for patients with autism spectrum disorder.

Development of a Training Curriculum for Hospital Security About Autism Spectrum Disorder.

OBJECTIVE: To evaluate whether a newly developed autism spectrum disorder (ASD)-training curriculum for hospital security officers improves comfort, knowledge, and practice. METHODS: Participants were security officers. The ASD-training curriculum was a 45-minute interactive session, adapted from trainings developed for other types of hospital providers. The curriculum included information regarding the presentation of, and challenges faced by, children with ASD in the hospital setting. Officers completed surveys before (T1), immediately after (T2), and 3 months after (T3) the training to assess comfort, knowledge, and practice. Comfort (Likert scale 1-5; 5 = highest) and knowledge (11 yes/no questions) questions were adapted from previous measures. Application of skills was assessed using case scenarios (at T1, T2, and T3) and with officers' report of using various strategies (at T1 and T3; Likert scale 1-5; 5 = always). Data were analyzed using repeated-measures analysis of variance and a series of paired contrast. RESULTS: For the 114 officers who completed surveys, mean comfort scores significantly increased from T1 to T2 (3.48 vs 3.9; p < 0.05), and these gains were maintained at T3 (4.1). Mean percent correct on knowledge questions significantly increased from T1 to T2 (74.6% vs 84.0%; p < 0.05) and was maintained at T3 (82.9%). Officers reported using 2 ASD-supportive strategies significantly more between T1 and T3: using pictures and written communication and asking the caregivers for advice. CONCLUSION: This newly developed ASD-training curriculum for hospital security officers resulted in an immediate increase of self-reported comfort and demonstrated knowledge with continued gains 3 months after training.

Autism Spectrum Disorder Parent Report for Outcome Monitoring: A Preliminary Report of Development and Clinical Utility.

OBJECTIVE: Children with autism spectrum disorder (ASD) face challenges across many functional domains. A tool that gathers relevant clinical information before visits, emphasizing symptoms that are likely to change over development and inform clinical interventions, could improve health care quality, allowing for more patient-centered and efficient care. This study evaluated the clinical utility and preliminary psychometrics of the ASD Parent Report for Outcome Monitoring (ASD-PROM), a web-based measure assessing competence in core features of ASD, along with the breadth of concerns and comorbidities that frequently co-occur with ASD. METHODS: An interdisciplinary team drafted the ASD-PROM and made iterative revisions based on parent feedback. Parents of 62 children completed the ASD-PROM before their autism-specialty clinical visit, 53 completed the ASD-PROM twice, and 48 completed the Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) concurrently. Parents (n = 25) and clinicians (n = 13) completed postvisit surveys to assess utility (phase 1). The ASD-PROM was then released for general clinical use (phase 2). RESULTS: On a Likert scale (1 = very poorly, 10 = very well), parents found that ASD-PROM items described their child's abilities well (median = 8.0; interquartile range [IQR]: 7.0-9.5) and had a positive effect on care (median = 8.0; IQR: 7.0-10.0). Clinicians found the ASD-PROM effective in assessing parent-reported patient abilities (median = 9.0, IQR: 7.0-9.0) and felt the ASD-PROM helped make their care more patient-centered and efficient (both median = 8.0, IQR: 6.0-9.0). Two-week test-retest reliability was acceptable (0.95). ASD-PROM scores correlated positively with scores from similar domains on the Vineland-II (Pearson r 0.30-0.50, medium to large effects). CONCLUSION: The ASD-PROM is a freely available tool to gather information on developmental and behavioral functioning in children with ASD before autism-specialty clinical visits. Clinical utility and preliminary psychometrics are promising, although limitations (including a low response rate during clinical use and a need for additional in-depth assessments and potential resulting modifications to the tool) remain to be addressed. Ultimately, the ASD-PROM may help promote patient-centered and efficient care for children across a wide range of ages and developmental levels.

Development and Evaluation of an Educational Initiative to Improve Hospital Personnel Preparedness to Care for Children with Autism Spectrum Disorder.

OBJECTIVE: To evaluate the effectiveness of a multimodal educational curriculum on increasing hospital personnel's awareness of successful strategies and comfort in caring for children with autism spectrum disorder (ASD). METHODS: We developed a 3-part training for front-line staff (i.e., front desk, clinical assistants, and phlebotomists) in 8 outpatient hospital departments frequented by patients with ASD. Following a needs assessment, participants completed an online educational module and then attended an in-person seminar tailored to each department. To evaluate training effectiveness, we administered pre-, immediate post-, and 1 month post-training surveys assessing personnel attitudes, comfort, perceived knowledge, and behaviors around caring for patients with ASD. RESULTS: We trained 168 staff members from 8 departments. On the needs assessment, participants (N = 129) reported a mean 2.5 behavioral incidents involving patients with ASD over the previous 3 months; 92% believed that the training would be helpful for their work. Across pre-, immediate- and 1-month post-training surveys, scores improved on all questions related to personnel attitudes about the importance of ASD-friendly care, comfort interacting with patients with ASD, perceived knowledge about ASD, and self-reported frequency of behaviors intended to help children with ASD adjust to the hospital setting (p < 0.05). There was no difference in baseline scores or change in scores between clinical and nonclinical personnel. On a program evaluation (N = 57), 81% rated the training as "very good" or "excellent," and 87% reported that they would be able to apply training material immediately to their role. CONCLUSION: This training initiative led to improvement in attitudes, comfort level, perceived knowledge, and self-reported behaviors of hospital personnel working with patients with ASD, which was maintained over 1 month.

Autism after DSM 5: the potential impact in one child's case.

CASE: Max is a 21-month old boy with speech and language delay presenting for diagnostic clarification and treatment recommendations. Max was born at 37 weeks after a twin gestation. He is medically healthy and lives at home with supportive parents and a typically developing twin sister. Max began speech and language therapy when he was 14 months old.Max spoke his first word at 16 months. He uses fewer than 10 words or word approximations; however, he does not use these words spontaneously to communicate. Max has decreased use of eye contact and rarely uses nonverbal means of communication. Max whines but does not point or reference his parents to request their help when he wants something out of reach. Max responds to 1-step directions about 50% of the time. An audiology assessment was normal. Max does not bring objects of interest to show others, rarely initiates interactions and does not consistently respond to social overtures.Max is described as an easy-going child. He is content to play on his own and shows little interest in other children. He likes to spin wheels for the purpose of watching them. Max has no rigidities or rituals and is easy to redirect. He has no sensory seeking behaviors or aversions. He does not engage in any repetitive motor mannerisms.On formal evaluation, Max's cognitive skills were assessed within the average range; language and gross motor skills were below average. Performance on the Autism Diagnostic Observation Schedule, Toddler Module was concerning for an Autism Spectrum Disorder (ASD).Max's evaluation was concerning for deficits in social and communication functioning. A new Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) was recently published, resulting in a change in the diagnostic criteria for ASDs. Max meets criteria for autistic disorder under DSM, 4th edition, text revision (DSM-4-TR), but does not meet criteria for an ASD under DSM-5. Specifically by DSM-4-TR, he met all criteria under social interaction, 2 criteria under communication, and 1 under restricted and repetitive behaviors. By DSM-5, he met all of criteria A and just 1 of criteria B. How would you proceed diagnostically and what treatment recommendations would you make?

"He is just a little shy like me": screening for autism in a young child.

CASE: Jacob is a 22-month-old wonderful boy, who is being seen a few months late for his 18-month-old visit because of scheduling snafus, as both parents work outside the home. At this visit, it is routine in our practice to administer the Modified Checklist for Autism in Toddlers (MCHAT) and the Parents' Evaluation of Developmental Status (PEDS). On the PEDS, in response to the question, "Do you have any concerns about how your child talks or makes speech sounds?" the parents respond "He only says 2 words in Hebrew and none in English." On the MCHAT, they reply "no" to 3 items: (1) "Does your child ever pretend, for example, to talk on the phone or take care of a doll or pretend other things?" (2) "Does your child respond to his/her name when you call?" and (3) "Does your child sometimes stare at nothing or wander with no purpose?" This results in failing 1 critical and 3 total items. Our practice protocol recommends a referral for a diagnostic evaluation. Jacob has been a healthy child, and this is the first time that his parents have fallen behind in routine health care maintenance visits. His medical history is unremarkable. He was born at term, weighing 3.2 kg, without any perinatal complications. His parents had emigrated from the Poland in their teenage years and have been married for 8 years. They also have a 5-year-old daughter. They both report that, in Poland, there are some relatives who were "very late talkers," but they do not know about any definitive family history of autism. At the 15-month visit, the parents reported that Jacob had expressive jargoning but no recognizable words. They stated then that he was not interested in toys but liked to play with the television remote control. He is in full-time child care--initially with a nanny in their home, but at 15 months started 3 days a week in a center-based childcare with many families from their community, where children speak Polish, English, and Hebrew at home. His mother works full time as an accountant and father as a physicist in a commercial laboratory. Both have graduate degrees and are trilingual. The parents are conflicted in their interpretation of Jacob's behavior. His father is concerned that he is autistic and his mother feels that "he is just a little shy like me." His physical examination is normal. He is somewhat inhibited and anxious but will sit still on the examination table and alone during the examination. You update his immunizations and then struggle with where to head next.

Clinical genetic testing for patients with autism spectrum disorders.

BACKGROUND: Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established. PATIENTS AND METHODS: A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared. RESULTS: Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%-2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%-0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%-21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%-8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients. CONCLUSIONS: CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.