Longitudinal Associations between Neurodevelopment and Psychosocial Health Status in Patients with Repaired D-Transposition of the Great Arteries.

OBJECTIVE: To examine associations between measurements of neurodevelopment and psychosocial health status at age 8 and 16 years in patients with repaired dextro-transposition of the great arteries. STUDY DESIGN: In the 16-year follow-up of the Boston Circulatory Arrest Study, 137 parents completed the Child Health Questionnaire-Parent Form-50, of whom 135 had completed the Child Health Questionnaire-Parent Form-50 when their child was age 8 years. Psychosocial and physical summary scores were used to assess change in health status from age 8 to 16 years. A comprehensive battery of neurodevelopmental testing was performed at ages 8 and 16 years to examine associations with adolescent health status. RESULTS: Lower psychosocial summary scores of 16 year old subjects with dextro-transposition of the great arteries were highly associated with numerous concurrent domains of neurodevelopmental function, most notably with higher (worse) scores on the Conners' Attention Deficit Hyperactivity Disorder/Diagnostic and Statistical Manual-4th Edition Scales (parent: r = -0.62, P < .001; adolescent: r = -0.43, P < .001) and the Behavior Rating Inventory of Executive Function Global Executive Composite (parent: r = -0.66, P < .001; adolescent: r = -0.39, P < .001). Psychosocial and physical summary scores tracked from ages 8 to 16 years (r = 0.44 and 0.47, respectively, P < .001 for each). Higher (worse) scores of multiple attention measures at age 8 years predicted worse psychosocial summary scores at age 16 years. CONCLUSIONS: Attention deficits at age 8 years were highly predictive of worse psychosocial health status in adolescence. Further studies are needed to assess whether treatment of childhood attention deficit hyperactivity disorder could improve adolescent well-being.

Updating the neurodevelopmental profile of Alazami syndrome: Illustrating the role of developmental assessment in rare genetic disorders.

Alazami syndrome, caused by biallelic pathogenic variants in LARP7, is a recently-described rare genetic disorder, with 17 patients currently reported in the literature. We present a case of a male infant referred for genetics evaluation at 5 months of age, found at 17 months of age to have Alazami syndrome. He was promptly referred for developmental evaluation, where he was found to be higher functioning than prior reports of individuals with this condition. This demonstrates the neurodevelopmental phenotypic variability seen in rare genetic disorders; it also demonstrates the important role of developmental programs to measure and track outcomes and provide support for infants with genetic disorders that put them at risk of developmental disabilities.

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 µg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Adolescents with d-transposition of the great arteries corrected with the arterial switch procedure: neuropsychological assessment and structural brain imaging.

BACKGROUND: We report neuropsychological and structural brain imaging assessments in children 16 years of age with d-transposition of the great arteries who underwent the arterial switch operation as infants. Children were randomly assigned to a vital organ support method, deep hypothermia with either total circulatory arrest or continuous low-flow cardiopulmonary bypass. METHODS AND RESULTS: Of 159 eligible adolescents, 139 (87%) participated. Academic achievement, memory, executive functions, visual-spatial skills, attention, and social cognition were assessed. Few significant treatment group differences were found. The occurrence of seizures in the postoperative period was the medical variable most consistently related to worse outcomes. The scores of both treatment groups tended to be lower than those of the test normative populations, with substantial proportions scoring ≥1 SDs below the expected mean. Although the test scores of most adolescents in this trial cohort are in the average range, a substantial proportion have received remedial academic or behavioral services (65%). Magnetic resonance imaging abnormalities were more frequent in the d-transposition of the great arteries group (33%) than in a referent group (4%). CONCLUSIONS: Adolescents with d-transposition of the great arteries who have undergone the arterial switch operation are at increased neurodevelopmental risk. These data suggest that children with congenital heart disease may benefit from ongoing surveillance to identify emerging difficulties. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000470.

Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.

Research has implicated mutations in the gene for neurexin-1 (NRXN1) in a variety of conditions including autism, schizophrenia, and nicotine dependence. To our knowledge, there have been no published reports describing the breadth of the phenotype associated with mutations in NRXN1. We present a medical record review of subjects with deletions involving exonic sequences of NRXN1. We ascertained cases from 3,540 individuals referred clinically for comparative genomic hybridization testing from March 2007 to January 2009. Twelve subjects were identified with exonic deletions. The phenotype of individuals with NRXN1 deletion is variable and includes autism spectrum disorders, mental retardation, language delays, and hypotonia. There was a statistically significant increase in NRXN1 deletion in our clinical sample compared to control populations described in the literature (P = 8.9 x 10(-7)). Three additional subjects with NRXN1 deletions and autism were identified through the Homozygosity Mapping Collaborative for Autism, and this deletion segregated with the phenotype. Our study indicates that deletions of NRXN1 predispose to a wide spectrum of developmental disorders.

Reintroducing Dyslexia: Early Identification and Implications for Pediatric Practice.

Dyslexia is a common learning disorder that renders children susceptible to poor health outcomes and many elements of socioeconomic difficulty. It is commonly undiagnosed until a child has repeatedly failed to learn to read in elementary school; this late diagnosis not only places the child at an academic disadvantage but also can be a precursor to psychiatric comorbidities such as anxiety and depression. Genetic and neuroimaging research have revealed that dyslexia is heritable and that it is undergirded by brain differences that are present even before reading instruction begins. Cognitive-behavioral research has revealed that there are early literacy skill deficits that represent red flags for dyslexia risk and can be measured at a preschool age. Altogether, this evidence points to dyslexia as a disorder that can be flagged by a pediatrician before school entry, during a period of heightened brain plasticity when interventions are more likely to be effective. In this review, we discuss the clinical implications of the most recent advances in dyslexia research, which converge to indicate that early identification and screening are crucial to the prevention or mitigation of adverse secondary consequences of dyslexia. We further highlight evidence-based and practical strategies for the implementation of early risk identification in pediatric practice so that physicians can be empowered in their ability to treat, educate, and advocate for their patients and families with dyslexia.

Twelve-Month Outcomes of Stand-Alone Excisional Goniotomy in Mild to Severe Glaucoma.

PURPOSE: To describe 12-month intraocular pressure (IOP) and medication use outcomes following excisional goniotomy (EG) as a stand-alone procedure in eyes with medically uncontrolled glaucoma. METHODS: This was a retrospective analysis of data from surgeons at 8 centers (6 US, 2 Mexico). Eyes with glaucoma undergoing standalone EG with a specialized instrument (Kahook Dual Blade, New World Medical, Rancho Cucamonga, CA) for IOP reduction and followed for 12 months postoperatively were included. Data were collected preoperatively, intraoperatively, and 1 day, 1 week, and 1, 3, 6, and 12 months postoperatively. The primary outcome was reduction from baseline in IOP, and key secondary outcomes included IOP-lowering medication reduction as well as adverse events. RESULTS: A total of 42 eyes were analyzed, of which 36 (85.7%) had mild to severe primary open-angle glaucoma (POAG). Mean (standard error) IOP at baseline was 21.6 (0.8) mmHg, and mean number of medications used at baseline was 2.6 (0.2). At 3, 6, and 12 months postoperatively, mean IOP reductions from baseline were 4.6 mmHg (22.3%), 5.6 mmHg (27.7%), and 3.9 mmHg (19.3%) (p≤0.001 at each time point). At the same time points, mean medications reductions of 0.7 (25.8%), 0.9 (32.6%), and 0.3 (12.5%) medications were seen (p<0.05 at months 3 and 6, not significant at month 12). Six eyes (14.3%) underwent additional glaucoma surgery during the 12-month follow-up period. DISCUSSION: Standalone EG with KDB can reduce IOP, and in many cases reduce medication use, through up to 12 months in eyes with mild to severe glaucoma. Statistically significant and clinically relevant reductions in IOP were seen at every time point. While the goal of surgery was not to reduce medication burden, mean medication use was significantly reduced at all but the last time point. In the majority of eyes, the need for a bleb-based glaucoma procedure was delayed or prevented for at least 12 months.

Behaviour at eight years in children with surgically corrected transposition: The Boston Circulatory Arrest Trial.

Uncertainty exists regarding the degree to which infants with congenitally malformed hearts are at risk of behavioural disorders in childhood. Data was collected as part of a randomized clinical trial involving 155 children with surgically corrected transposition (concordant atrioventricular and ventriculo-arterial connections or alignments). As infants, they underwent the arterial switch operation, involving deep hypothermia with predominantly total circulatory arrest or predominantly low-flow continuous cardiopulmonary bypass as the method of providing support to the vital organs. Parents completed the Child Behavior Checklist when the patients were aged 4 and 8 years, and the Connors' Parent Rating Scale at the age of 8 years. When the children were aged 8, teachers completed the Teacher's Report Form and the Connors' Teacher Rating Scale. In the cohort as a whole, the frequencies of behavioural problems identified by both parents and teachers were elevated, particularly on the scales for competence of the Child Behavior Checklist, and the Adaptive scales of the Teacher's Report Form. Approximately 1 in 5 patients had scores for Total Problem Behavior in the range of clinical concern on both the Child Behavior Checklist and the Teacher's Report Form. Few differences were found, however, according to the method of operative treatment. Postoperative seizures were associated with social and attention problems. Children experiencing academic problems at the age of 8 showed a larger increase in behavioural problems between the ages of 4 and 8 than did children making adequate academic progress. Children with congenitally malformed hearts who underwent reparative surgery in infancy using a strategy of severe haemodilution and alpha stat are at increased risk of behavioural problems in middle childhood.

Six-Month Outcomes of Goniotomy Performed with the Kahook Dual Blade as a Stand-Alone Glaucoma Procedure.

INTRODUCTION: To characterize the reduction in intraocular pressure (IOP) and IOP-lowering medication use following goniotomy via trabecular meshwork excision performed using the Kahook Dual Blade as a stand-alone procedure in adult eyes with glaucoma uncontrolled on a regimen of 1-3 topical IOP-lowering medications. METHODS: In this retrospective analysis, data from consecutive patients undergoing goniotomy with the Kahook Dual Blade by 11 surgeons were analyzed. Preoperative, intraoperative, and postoperative follow-up data through 6 months of follow-up were collected. The primary efficacy endpoint was IOP reduction from preoperative baseline; reduction in IOP-lowering medication use was a secondary endpoint. RESULTS: Data were collected from 53 eyes of 42 subjects. Mean (± SE) preoperative IOP was 23.5 ± 1.1 mmHg, and from day 1 through 6 months of postoperative follow-up mean IOP reductions of 7.0-10.3 mmHg (29.8-43.8%; p < 0.001 at each time point) were observed. Mean preoperative medication use was 2.5 ± 0.2 medications per eye and was reduced by month 6 to 1.5 ± 0.2 (a 40.0% reduction; p < 0.05). Eyes with higher baseline IOP experienced mean IOP reductions of 13.7 mmHg (- 46.4%) at month 6, while eyes with lower baseline IOP experienced mean IOP reductions of 3.8 mmHg (- 21.0%) at month 6. Mean medications were reduced by 1.3 medications in high-IOP eyes and by 0.9 in low-IOP eyes at month 6. No significant sight-threatening adverse events were observed. CONCLUSIONS: Goniotomy via trabecular meshwork excision performed using the Kahook Dual Blade effectively and safely lowered IOP when performed as a stand-alone procedure in eyes with glaucoma. The significant drop in IOP met or exceeded the recommended targets for these glaucoma patients. FUNDING: New World Medical, Inc.

Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: the Boston Circulatory Arrest Trial.

OBJECTIVES: Our goal was to determine which of the two major methods of vital organ support used in infant cardiac surgery, total circulatory arrest and low-flow cardiopulmonary bypass, results in better neurodevelopmental outcomes at school age. METHODS: In a single-center trial, infants with dextrotransposition of the great arteries underwent the arterial switch operation after random assignment to either total circulatory arrest or low-flow cardiopulmonary bypass. Developmental, neurologic, and speech outcomes were assessed at 8 years of age in 155 of 160 eligible children (97%). RESULTS: Treatment groups did not differ in terms of most outcomes, including neurologic status, Full-Scale or Performance IQ score, academic achievement, memory, problem solving, and visual-motor integration. Children assigned to total circulatory arrest performed worse on tests of motor function including manual dexterity with the nondominant hand (P =.003), apraxia of speech (P =.01), visual-motor tracking (P =.01), and phonologic awareness (P =.003). Assignment to low-flow cardiopulmonary bypass was associated with a more impulsive response style on a continuous performance test of vigilance (P <.01) and worse behavior as rated by teachers (P =.05). Although mean scores on most outcomes were within normal limits, neurodevelopmental status in the cohort as a whole was below expectation in many respects, including academic achievement, fine motor function, visual-spatial skills, working memory, hypothesis generating and testing, sustained attention, and higher-order language skills. CONCLUSIONS: Use of total circulatory arrest to support vital organs during heart surgery in infancy is generally associated with greater functional deficits than is use of low-flow cardiopulmonary bypass, although both strategies are associated with increased risk of neurodevelopmental vulnerabilities.

The effect of duration of deep hypothermic circulatory arrest in infant heart surgery on late neurodevelopment: the Boston Circulatory Arrest Trial.

OBJECTIVES: Despite the technical advantages of total circulatory arrest for vital organ support during infant heart surgery, many centers have moved away from its use because of the demonstrated effects of circulatory arrest of long duration on neurodevelopmental outcomes. Our goal was to determine the functional form of the association between duration of circulatory arrest and risk of neurodevelopmental dysfunction. METHODS: From 1988 to 1992, in a single-center trial, infants with d-transposition of the great arteries underwent the arterial switch operation after random assignment to circulatory arrest or low-flow bypass. The alpha-stat method was used, and hematocrit on bypass was maintained at 20%. Developmental, neurologic, and speech outcomes were assessed at 8 years of age in 155 of 160 eligible children (97%). Outcomes selected for analysis were Full-Scale, Verbal, and Performance IQ, Reading and Mathematics Composite, time to complete the Grooved Pegboard (dominant hand), and the Mayo Test for Apraxia. RESULTS: Nonparametric regression and piecewise linear models indicated that neurodevelopmental outcomes were generally not adversely affected unless the duration of circulatory arrest exceeded a threshold of 41 minutes (95% 1-sided lower confidence limit of 32 minutes). CONCLUSIONS: We found that the effect of duration of total circulatory arrest on later neurodevelopmental outcomes is nonlinear, with little influence at shorter durations and with steadily worsening outcomes after longer durations of circulatory arrest. Because the effects of duration of circulatory arrest may vary according to diagnosis, age at surgery, and other bypass and perioperative variables, this study cannot ascertain a universally "safe" duration of total circulatory arrest.

The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial in infants.

BACKGROUND: We hypothesized that cognitive impairment and hemodynamic instability after infant cardiac surgery with cardiopulmonary bypass might be exacerbated by hemodilution. METHODS: In a single-center randomized trial with blinded assessment of outcomes, we compared use of 2 hemodilution protocols during hypothermic cardiopulmonary bypass with infant cardiac surgery. The primary perioperative end point was lowest cardiac index in the first 24 hours postoperatively, and primary end points at age 1 year were scores on the Psychomotor Development Index and Mental Developmental Index of the Bayley Scales. RESULTS: Among 147 subjects, 74 were assigned to the lower-hematocrit strategy (21.5% +/- 2.9%, mean +/- SD at onset of low-flow bypass) and 73 to the higher-hematocrit strategy (27.8% +/- 3.2%). In intent-to-treat analyses the lower-hematocrit group had lower nadirs of cardiac index (P =.02), higher serum lactate levels 60 minutes after cardiopulmonary bypass (P =.03), and a greater percentage increase in total body water on the first postoperative day (P =.006). Blood product use and adverse events were similar in the 2 groups. At age 1 year (113 children), the lower-hematocrit group had worse scores on the Psychomotor Development Index (81.9 +/- 15.7 vs 89.7 +/- 14.7, P =.008), as well as more Psychomotor Development Index scores at least 2 SDs below the population mean (16/56 [29%] vs 5/53 [9%], P =.01). The groups had similar Mental Developmental Index scores and findings on neurologic examination. Inferences using hematocrit as a continuous variable were similar to those based on intent-to-treat analyses. CONCLUSIONS: Hemodilution to a hematocrit level in wide use for cardiopulmonary bypass and thought to be safe is associated with adverse perioperative and developmental outcomes in infants.

Measuring quality of life in children with attention-deficit/hyperactivity disorder and their families: development and evaluation of a new tool.

OBJECTIVE: To psychometrically evaluate a new parent-completed questionnaire that measures the effect of attention-deficit/hyperactivity disorder (ADHD) on the everyday well-being of children and their families. SETTING: Using a mail-out/mail-back method, the sample was drawn from the registry of an outpatient developmental and behavioral program of a large tertiary pediatric hospital. All children received medication for ADHD. PARTICIPANTS: Responses were received for 81 children of whom 60 (74%) were boys. An even split of questionnaires was returned for children with ADHD primarily inattentive (50%) and ADHD combined (50%). The condition of 70 patients (86%) had been diagnosed for 1 year or longer; 69 patients (89%) reported receiving medication. MAIN OUTCOME MEASURE: The ADHD Impact Module, HealthAct, Boston, Mass, developed with input from families, measures the effect of the disorder on the child's emotional-social well-being (Child Scale, 8 items) and the family (Home Scale, 10 items). RESULTS: The scales exceeded standard criteria for item convergent and discriminant validity. No floor effects and minimal (2%) ceiling effects were observed. Cronbach alpha was 0.88 and 0.93 (Child and Home Scales), respectively. Raw scale scores are transformed on a 0 through 100 continuum; a higher score indicates more favorable findings. Statistically significant differences (P<.000) were observed for ADHD inattentive vs ADHD combined on both scales (Child, 65.26 vs 48.86; Home, 72.79 vs 51.26). Better "success at home" scores were reported by parents of ADHD inattentive children (Child Scale, 62.12 vs 47.36, P =.00; Home Scale, 70.58 vs 47.01, P =.000). CONCLUSIONS: The ADHD Impact Module meets stringent psychometric standards. Further validation is required, but current evidence suggests it is a promising new questionnaire.

Complementary and alternative therapies in childhood attention and hyperactivity problems.

To determine the prevalence and factors associated with complementary and alternative medicine (CAM) use for childhood attention and hyperactivity problems, we surveyed parents of children referred for evaluation of attention-deficit hyperactivity disorder (ADHD). Parents indicated whether they had used CAM therapies (e.g., acupuncture, nutritional supplements) in the past year and rated how important different reasons were in making their therapy decisions. Overall, 62 of 114 (54%) parents reported using CAM, most commonly expressive therapies, vitamins, and dietary manipulation, to treat their child's attention problems. Parents who used CAM rated a "natural therapy" and "having more control over treatments" significantly more important in their choice of therapy than parents who did not use CAM. Only 11% of parents discussed using CAM with their child's physician. Because parents often use CAM to treat their child's attention and hyperactivity problems without their pediatrician's knowledge, pediatricians need to initiate discussions of CAM use with patients and families.

Visual-spatial skills in children after open-heart surgery.

This study was part of a randomized clinical trial comparing the central nervous system effects of the two vital organ-support methods used in infant cardiac surgery: total circulatory arrest and low-flow cardiopulmonary bypass. The extent to which visual-spatial deficits are (1). associated with surgical and perioperative variables, (2). attributable to visual-perceptual, motor control, or metacognitive deficits, and (3). associated with adaptive difficulties at home or school was evaluated. The subjects were 155 8-year-old children with D-transposition of the great arteries who underwent the arterial switch operation before 3 months of age. As part of a comprehensive evaluation, the Rey-Osterrieth Complex Figure (ROCF) was administered. ROCF copy productions were classified as having a Basal Organization Level of 1 (low) or 2 or greater. A five-category clinical rating was also assigned. More than half of the children in the cohort (52%) had copy productions scored at Level 1, more than twice the expected frequency. The risk of having a low score was not associated with vital organ support method or other surgical variables. On the basis of comparisons of the relative fits of nested logistic regression models, poor visual-perceptual abilities were more predictive of having a Level 1 score than either motor control or metacognitive deficits. Children with poor copy production scores had lower mathematics scores, but not lower reading scores or poorer parent and teacher ratings of adaptive competence. The percentage of children receiving remedial school services was associated with ROCF clinical rating, ranging from 58% in the worst category to 8% in the best category. Visual-spatial deficits are common among children after infant heart surgery and seem to reflect visual-perceptual rather than motor control or metacognitive deficits. In addition, these deficits do not seem to be clearly associated with the intraoperative methods or postoperative events evaluated.

Influence of parental stress and social support on the behavioral adjustment of children with transposition of the great arteries.

The joint role of parent stress and social support in the emotional adjustment of children was examined prospectively in a group of children with d-transposition of the great arteries (d-TGA). Questionnaires on parent perceptions of stress and social support were administered when children were 1 and 4 years of age (n = 143-153). Parent ratings of child behavior problems were collected at 4 years (n = 152). The findings indicate a favorable outcome for parents and children with congenital heart disease (CHD). Compared with normative samples, parents experienced less stress and more social support, and they rated children as showing fewer behavior problems. Parents with more stress at both ages reported more behavior problems. Families with less social support reported more stress at both 1 and 4 years. Social support, however, did not moderate the relationship between stress and child behavior problems. Early detection of distressed families may assist in alleviating stress and reducing behavior problems.

Neurobehavioral factors associated with referral for learning problems in a community sample: evidence for an adaptational model for learning disorders.

We evaluated community general education (CGE; n = 178), community special education (CSE; n = 30) and hospital-referred (HR, n = 145) children (ages 7-6 to 11-11) prospectively over a 2-year period. During this period, 17 CGE children were referred for evaluation (community referred; CR). Prior to referral, CR children performed more poorly than community-nonreferred (CNR) children on cognitive ability, academic achievement, attention problems, and information processing. CR group performance was equivalent to that of CSE and HR groups, but HR children showed poorer academic achievement. Referred children performed more poorly on all measures than nonreferred, whether they met formal diagnostic criteria for a learning disorder or not. Learning disorders may be better conceptualized as a context-dependent problem of functional adaptation than as a disability analogous to physical disabilities, raising questions about the validity of using psychometric test scores as the criterion for identification.

Using whole-exome sequencing to identify inherited causes of autism.

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.