Robin P. Goin-Kochel

A Multisite Study of the Clinical Diagnosis of Different Autism Spectrum Disorders

CONTEXT Best-estimate clinical diagnoses of specific autism spectrum disorders (autistic disorder, pervasive developmental disorder-not otherwise specified, and Asperger syndrome) have been used as the diagnostic gold standard, even when information from standardized instruments is available. OBJECTIVE To determine whether the relationships between behavioral phenotypes and clinical diagnoses of different autism spectrum disorders vary across 12 university-based sites. DESIGN Multisite observational study collecting clinical phenotype data (diagnostic, developmental, and demographic) for genetic research. Classification trees were used to identify characteristics that predicted diagnosis across and within sites. SETTING Participants were recruited through 12 university-based autism service providers into a genetic study of autism. PARTICIPANTS A total of 2102 probands (1814 male probands) between 4 and 18 years of age (mean [SD] age, 8.93 [3.5] years) who met autism spectrum criteria on the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule and who had a clinical diagnosis of an autism spectrum disorder. MAIN OUTCOME MEASURE Best-estimate clinical diagnoses predicted by standardized scores from diagnostic, cognitive, and behavioral measures. RESULTS Although distributions of scores on standardized measures were similar across sites, significant site differences emerged in best-estimate clinical diagnoses of specific autism spectrum disorders. Relationships between clinical diagnoses and standardized scores, particularly verbal IQ, language level, and core diagnostic features, varied across sites in weighting of information and cutoffs. CONCLUSIONS Clinical distinctions among categorical diagnostic subtypes of autism spectrum disorders were not reliable even across sites with well-documented fidelity using standardized diagnostic instruments. Results support the move from existing subgroupings of autism spectrum disorders to dimensional descriptions of core features of social affect and fixated, repetitive behaviors, together with characteristics such as language level and cognitive function.

How many doctors does it take to make an autism spectrum diagnosis

Parents of children with pervasive developmental disorders (n = 494) were surveyed to determine their level of satisfaction with the process of getting an autism spectrum diagnosis. Participants in this web-based study (mean age = 37.8 years) came from five countries and reported on children with an average age of 8.3 years (range = 1.7 to 22.1). All children had a diagnosis of either autism (59.9%), Asperger syndrome (23.5%), or PDD-NOS (16.6%). Higher levels of parental education and income were associated with earlier diagnosis and greater satisfaction with the diagnostic process. Parents were more satisfied with the diagnostic process when they saw fewer professionals to get the diagnosis and when the children received the diagnoses at younger ages.

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.

A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism

We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and γ-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2–4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.

“What Do You Like/Dislike About the Treatments You’re Currently Using?” A Qualitative Study of Parents of Children With Autism Spectrum Disorders

Children with autism spectrum disorders (ASD) often participate in many treatments, requiring parents’ dedication of time, money, and energy, and necessitating dealing with multiple service providers. To learn about parents’ experience in seeking and using treatments for their child with ASD, the authors asked them, “What do you like/dislike about the treatment(s) you’re currently using?” In this web-based, qualitative study, participants consisted of 486 parents (92% mothers) of children (80% boys; children’s M age = 8.3 years) with autism (n = 290, 59.7%), Asperger syndrome (n = 115, 23.6%), or pervasive developmental disorder—not otherwise specified (n = 81, 16.7%). The families lived in the United States, Canada, Australia, New Zealand, England, and Ireland. Parents’ written statements addressed more “dislikes” (70%) than “likes” (47%), and there were no universally liked or disliked interventions. Six themes emerged and are discussed: effectiveness of treatments, relationships with professionals, access to treatments, costs, medication concerns, and stress.

The Role of Parental Cognitive, Behavioral, and Motor Profiles in Clinical Variability in Individuals With Chromosome 16p11.2 Deletions

IMPORTANCE Most disorders caused by copy number variants (CNVs) display significant clinical variability, often referred to as incomplete penetrance and variable expressivity. Genetic and environmental sources of this variability are not well understood. OBJECTIVES To investigate the contributors to phenotypic variability in probands with CNVs involving the same genomic region; to measure the effect size for de novo mutation events; and to explore the contribution of familial background to resulting cognitive, behavioral, and motor performance outcomes in probands with de novo CNVs. DESIGN, SETTING, AND PARTICIPANTS Family-based study design with a volunteer sample of 56 individuals with de novo 16p11.2 deletions and their noncarrier parents and siblings from the Simons Variation in Individuals Project. MAIN OUTCOMES AND MEASURES We used linear mixed-model analysis to measure effect size and intraclass correlation to determine the influence of family background for a de novo CNV on quantitative traits representing the following 3 neurodevelopmental domains: cognitive ability (Full-Scale IQ), social behavior (Social Responsiveness Scale), and neuromotor performance (Purdue Pegboard Test). We included an anthropometric trait, body mass index, for comparison. RESULTS A significant deleterious effect of the 16p11.2 deletion was demonstrated across all domains. Relative to the biparental mean, the effect sizes were -1.7 SD for cognitive ability, 2.2 SD for social behavior, and -1.3 SD for neuromotor performance (P < .001). Despite large deleterious effects, significant positive correlations between parents and probands were preserved for the Full-Scale IQ (0.42 [P = .03]), the verbal IQ (0.53 [P = .004]), and the Social Responsiveness Scale (0.52 [P = .009]) scores. We also observed a 1-SD increase in the body mass index of probands compared with siblings, with an intraclass correlation of 0.40 (P = .07). CONCLUSIONS AND RELEVANCE Analysis of families with de novo CNVs provides the least confounded estimate of the effect size of the 16p11.2 deletion on heritable, quantitative traits and demonstrates a 1- to 2-SD effect across all neurodevelopmental dimensions. Significant parent-proband correlations indicate that family background contributes to the phenotypic variability seen in this and perhaps other CNV disorders and may have implications for counseling families regarding their childrens developmental and psychiatric prognoses. Use of biparental mean scores rather than general population mean scores may be more relevant to examine the effect of a mutation or any other cause of trait variation on a neurodevelopmental outcome and possibly on systems of diagnosis and trait ascertainment for developmental disorders.

The MTHFR 677C→T polymorphism and behaviors in children with autism: exploratory genotype–phenotype correlations

New evidence suggests that autism may be associated with (a) varied behavioral responses to folate therapy and (b) metabolic anomalies, including those in folate metabolism, that contribute to hypomethylation of DNA. We hypothesized that children with autism who are homozygous for the MTHFR 677 T allele (TT) and, to a lesser extent those with the CT variant, would exhibit more behavioral problems and/or more severe problematic behaviors than homozygous wild‐type (CC) individuals because of difficulties in effectively converting 5,10‐MTHF to 5‐MTHF. Data from the Autism Genetic Resource Exchange (AGRE) collection were analyzed for all children who met strict criteria for autism per the Autism Diagnostic Interview—Revised (ADI‐R) and the Autism Diagnostic Observation Schedule (ADOS) and who had been genotyped for the 677 C to T MTHFR polymorphism (n=147). Chi‐square tests, logistic regression, and one‐way ANOVAs were used to determine whether differences existed among MTHFR genotypes for specific behaviors on the ADI‐R and indices for level of functioning. Exploratory results indicated four behaviors from the ADI‐R that were more common and problematic (95% CI) among those with at least one copy of the T allele as compared to homozygous wild‐type individuals: direct gaze, current complex body movements, a history of self‐injurious behavior, and current overactivity (ORs=2.72, 2.33, 2.12, 2.47, respectively). No differences existed among genotypes for level of functioning as measured with the Peabody Picture Vocabulary Test—Third Edition, Ravens Colored Progressive Matrices, or the Vineland Adaptive Behavior Scales. Findings call for further investigation of the relationship between folate metabolism and problem behaviors among children with autism.

Expanding the clinical spectrum of the 16p11.2 chromosomal rearrangements: three patients with syringomyelia

16p11.2 rearrangements are associated with developmental delay, cognitive impairment, autism spectrum disorder, behavioral problems (especially attention-deficit hyperactivity disorder), seizures, obesity, dysmorphic features, and abnormal head size. In addition, congenital anomalies and abnormal brain findings were frequently observed in patients with these rearrangements. We identified and performed a detailed microarray, phenotypic, and radiological characterization of three new patients with 16p11.2 rearrangements: two deletion patients and one patient with the reciprocal duplication. All patients have a heterozygous loss (deletion) or gain (duplication) corresponding to chromosomal coordinates (chr16: 29 528 190–30 107 184) with a minimal size of 579 kb. The deletion patients had language delay and learning disabilities and one met criteria for pervasive developmental disorder not otherwise specified. The duplication patient received a diagnosis of autism and had academic deficits and behavioral problems. The patients with deletion had long cervicothoracic syringomyelia and the duplication patient had long thoracolumbar syringomyelia. The syringomyelia in one patient with deletion was associated with Chiari malformation. Our findings highlight the broad spectrum of clinical and neurological manifestations in patients with 16p11.2 rearrangements. Our observation suggests that genes (or a single gene) within the implicated interval have significant roles in the pathogenesis of syringomyelia. A more comprehensive and systematic research is warranted to study the frequency and spectrum of malformations in the central nervous system in these patients.

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

IMPORTANCE The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI). OBJECTIVES To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD. DESIGN, SETTING, AND PARTICIPANTS This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives. MAIN OUTCOMES AND MEASURES Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data. RESULTS Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies. CONCLUSIONS AND RELEVANCE The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.

Lack of evidence for increased genetic loading for autism among families of affected females: A replication from family history data in two large samples

Both the broad and narrow phenotypes of autism have been consistently observed in family members of affected individuals. Additionally, autism spectrum disorders (ASDs) present four times more often in males than in females, for reasons that are currently unknown. In this study, we examined whether there were differences in familial loading of ASD among families of male versus female probands. Analyses were conducted with existing data from two distinct samples. The first sample contained 417 individuals with autism and Aspergers disorder and included information on the ASD diagnoses of their first- and second-degree relatives. The second sample consisted of 405 sibships participating in the Autism Genetic Resource Exchange, of which one or more siblings had an ASD diagnosis. Results from both samples did not suggest significant differences in the prevalence of ASD among relatives of affected males versus females.