Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

Experiences with offering pro bono medical genetics services in the West Indies: Benefits to patients, physicians, and the community.

We describe our experiences with organizing pro bono medical genetics and neurology outreach programs on several different resource-limited islands in the West Indies. Due to geographic isolation, small population sizes, and socioeconomic disparities, most Caribbean islands lack medical services for managing, diagnosing, and counseling individuals with genetic disorders. From 2015 to 2019, we organized 2-3 clinics per year on various islands in the Caribbean. We also organized a week-long clinic to provide evaluations for children suspected of having autism spectrum disorder. Consultations for over 100 different individuals with suspected genetic disorders were performed in clinics or during home visits following referral by locally registered physicians. When possible, follow-up visits were attempted. When available and appropriate, clinical samples were shipped to collaborating laboratories for molecular analysis. Laboratory tests included karyotyping, cytogenomic microarray analysis, exome sequencing, triplet repeat expansion testing, blood amino acid level determination, biochemical assaying, and metabolomic profiling. We believe that significant contributions to healthcare by genetics professionals can be made even if availability is limited. Visiting geneticists may help by providing continuing medical education seminars. Clinical teaching rounds help to inform local physicians regarding the management of genetic disorders with the aim of generating awareness of genetic conditions. Even when only periodically available, a visiting geneticist may benefit affected individuals, their families, their local physicians, and the community at large.

Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.

PURPOSE: To maximize the discovery of potentially pathogenic variants to better understand the diagnostic utility of genome sequencing (GS) and to assess how the presence of multiple risk events might affect the phenotypic severity in autism spectrum disorders (ASD). METHODS: GS was applied to 180 simplex and multiplex ASD families (578 individuals, 213 patients) with exome sequencing and array comparative genomic hybridization further applied to a subset for validation and cross-platform comparisons. RESULTS: We found that 40.8% of patients carried variants with evidence of disease risk, including a de novo frameshift variant in NR4A2 and two de novo missense variants in SYNCRIP, while 21.1% carried clinically relevant pathogenic or likely pathogenic variants. Patients with more than one risk variant (9.9%) were more severely affected with respect to cognitive ability compared with patients with a single or no-risk variant. We observed no instance among the 27 multiplex families where a pathogenic or likely pathogenic variant was transmitted to all affected members in the family. CONCLUSION: The study demonstrates the diagnostic utility of GS, especially for multiple risk variants that contribute to the phenotypic severity, shows the genetic heterogeneity in multiplex families, and provides evidence for new genes for follow up.

Integrated Cognitive Behavioral Therapy for Comorbid Cannabis Use and Anxiety Disorders.

Cannabis use disorders (CUDs) co-occur with anxiety disorders at high rates, presumably because some individuals with anxiety disorders may rely on cannabis to manage anxiety. Motivation enhancement therapy (MET) combined with cognitive-behavioral therapy (CBT) is an efficacious intervention for CUD, yet outcomes are worse for patients with elevated anxiety. The integration of MET-CBT with False Safety Behavior Elimination Treatment (FSET) may be useful with anxious CUD patients, as the use of cannabis to manage anxiety can be targeted as a false safety behavior. Here, we describe the integrated treatment and the successful use of it among two patients-one with CUD and comorbid social anxiety disorder (SAD) and one with CUD and comorbid SAD and generalized anxiety disorder. Data support the feasibility of this integrated treatment as a viable approach to the treatment of CUD and comorbid anxiety disorders. Future controlled trials are now warranted to further evaluate the intervention.

Developmental Predictors of Cognitive and Adaptive Outcomes in Genetic Subtypes of Autism Spectrum Disorder.

Approximately one-fourth of autism spectrum disorder (ASD) cases are associated with a disruptive genetic variant. Many of these ASD genotypes have been described previously, and are characterized by unique constellations of medical, psychiatric, developmental, and behavioral features. Development of precision medicine care for affected individuals has been challenging due to the phenotypic heterogeneity that exists even within each genetic subtype. In the present study, we identify developmental milestones that predict cognitive and adaptive outcomes for five of the most common ASD genotypes. Sixty-five youth with a known pathogenic variant involving ADNP, CHD8, DYRK1A, GRIN2B, or SCN2A genes participated in cognitive and adaptive testing. Exploratory linear regressions were used to identify developmental milestones that predicted cognitive and adaptive outcomes within each gene group. We hypothesized that the earliest and most predictive milestones would vary across gene groups, but would be consistent across outcomes within each genetic subtype. Within the ADNP group, age of walking predicted cognitive outcomes, while age of first words predicted adaptive behaviors. Age of phrases predicted adaptive functioning in the CHD8 group, but cognitive outcomes were not clearly associated with early developmental milestones. Verbal milestones were the strongest predictors of cognitive and adaptive outcomes for individuals with mutations to DYRK1A, GRIN2B, or SCN2A. These trends inform decisions about treatment planning and long-term expectations for affected individuals, and they add to the growing body of research linking molecular genetic function to brain development and phenotypic outcomes. LAY SUMMARY: Researchers have found many genetic causes of autism including mutations to ADNP, CHD8, DYRK1A, GRIN2B, and SCN2A genes. We found that each genetic cause had different early developmental milestones that explained the overall functioning of the children when they were older. Depending on the genetic cause, the age that a child first starts walking and/or talking may help to better understand and support a child's development who has a mutation to one of the above genes. Autism Res 2020, 13: 1659-1669. © 2020 International Society for Autism Research and Wiley Periodicals LLC.

Co-occurring medical conditions among individuals with ASD-associated disruptive mutations.

Children with autism spectrum disorder (ASD) are at risk for co-occurring medical conditions, many of which have also been reported among individuals with mutations in ASD-associated genes. This study examined rates of co-occurring medical conditions across 301 individuals with disruptive mutations to 1 of 18 ASD-risk genes in comparison to rates of conditions in an idiopathic ASD sample. Rates of gastrointestinal problems, seizures, physical anomalies, and immune problems were generally elevated, with significant differences in rates observed between groups. Results may inform medical care of individuals with ASD-associated mutations and research into mechanisms of co-occurring medical conditions in ASD.

Clinical Phenotypes of Carriers of Mutations in CHD8 or Its Conserved Target Genes.

BACKGROUND: Variants disruptive to CHD8 (which codes for the protein CHD8 [chromodomain-helicase-DNA-binding protein 8]) are among the most common mutations revealed by exome sequencing in autism spectrum disorder (ASD). Recent work has indicated that CHD8 plays a role in the regulation of other ASD-risk genes. However, it is unclear whether a possible shared genetic ontology extends to the phenotype. METHODS: This study (N = 143; 42.7% female participants) investigated clinical and behavioral features of individuals ascertained for the presence of a known disruptive ASD-risk mutation that is 1) CHD8 (CHD8 group) (n = 15), 2) a gene targeted by CHD8 (target group) (n = 22), or 3) a gene without confirmed evidence of being targeted by CHD8 (other gene group) (n = 106). RESULTS: Results indicated shared features between the CHD8 and target groups that included less severe adaptive deficits in communication skills, similar functional language, more social motivation challenges in those with ASD, larger head circumference, higher weight, and lower seizure prevalence relative to the other gene group. CONCLUSIONS: These similarities suggest broader genetic ontology accounts for aspects of phenotypic heterogeneity. Improved understanding of the relationships between related disruptive gene events may lead us to improved understanding of shared mechanisms and lead to more focused treatments for individuals with known genetic mutations.

Comorbid psychopathology rates in children diagnosed with autism spectrum disorders according to the DSM-IV-TR and the proposed DSM-5.

OBJECTIVE: To investigate differences in comorbid psychopathology rates between individuals who meet criteria of Autism Spectrum Disorders (ASDs) according to DSM-5 or the DSM-IV-TR. METHODS: Comorbid psychopathology was measured using the Autism Spectrum Disorders- Comorbid for Children. 424 individuals between the ages of 2 and 18 years of age; including children who met criteria for an ASD according to the DSM-5, the DSM-IV-TR only, and a control group that did not meet either set of criteria. RESULTS: Of the ASD participants, 36% would no longer meet criteria according to proposed DSM-5. Comorbidity rates for the ASD groups were significantly different from the control group; however, ASD groups were not significantly different in terms of total comorbid psychopathology. CONCLUSION: The results elucidate the need for further research regarding services and treatments for those individuals that will no longer meet criteria for an ASD but still have significant rates of comorbid psychopathology.

Autism spectrum disorder severity as a predictor of Battelle Developmental Inventory - second edition (BDI-2) scores in toddlers.

OBJECTIVE: The study aimed to evaluate the relationship between the severity of autism spectrum disorder (ASD) symptomology and scores on the Battelle Developmental Inventory, Second Edition (BDI-2) in toddlers (n = 325). METHODS: Total scores on the BDI-2 and individual domain scores were examined to explore the relationship between severity of ASD and developmental quotient, impairment in personal-social skills, adaptive functioning, cognition, and communication. RESULTS: Regression analyses controlled for the impact of age and IQ on results, indicating that higher autism severity scores were associated with overall greater impairment and in the total scores and the individual domains of the BDI-2. The domains were found to be differentially affected by severity of ASD. CONCLUSION: These findings suggest severity of ASD may influence symptom presentation. Clinical implications of study findings are discussed.

An investigation of self-injurious behaviors in adults with severe intellectual disabilities.

Self-injurious behavior (SIB) is commonly observed among individuals with intellectual disability (ID) living in state-run supports and services centers. Specific examples of SIB include poking oneself in the eye; harming oneself by hitting, scratching, or pinching; and pica (i.e., swallowing objects causing bodily harm). Previous research has focused on SIB in individuals with ID more generally without focusing on specific levels of ID or taking into account other important personal variables. This study examined 45 adults with severe ID living in two large state-run facilities in the Southeastern United States who were separated into groups for comparison (ASD and non ASD; verbal and nonverbal). Data was collected on the presence of SIB using the Autism Spectrum Disorder-Problem Behavior Adult Version (ASD-PBA). A two-way analysis of variance (ANOVA) was conducted to determine if there were significant differences between groups on rates of SIB. Individuals with ID and ASD exhibited significantly higher rates of SIB than individuals with only ID, F (1,43)=50.84, p<0.05. Furthermore, verbal individuals had significantly higher rates of SIB than nonverbal individuals, F (1,43)=57.612, p<0.05. There was a significant interaction between the effects of ASD diagnosis and verbal ability on rates of SIB, F (1,43)=50.84, p<0.05. The implications of these findings in the context of other research on ID, ASD, SIB, and verbal abilities are discussed.

Food selectivity in children with and without an autism spectrum disorder: investigation of diagnosis and age.

Feeding problems are common in children with autism spectrum disorders (ASDs), with food selectivity being the most frequently reported. Selectivity based on type and/or texture of food is of concern in those with ASD. Variations in symptom presentation of food selectivity in children with different autism spectrum diagnoses across childhood have not often been investigated. Parent-report of food selectivity was examined in 525 children age 2-18 years diagnosed with autistic disorder, PDD-NOS, Asperger's disorder, atypical development, and typical development using information garnered from the Autism Spectrum Disorder-Comorbidity for Children (ASD-CC), a tool to assess emotional issues and comorbid psychopathology. Individuals with an ASD were reported to have significantly more food selectivity than both the atypically developing group and the typically developing group. In addition, the ASD groups, when looked at together, showed a decrease in food selectivity across childhood with significant decrease in the Asperger's disorder group.

Comparing challenging behavior in children diagnosed with autism spectrum disorders according to the DSM-IV-TR and the proposed DSM-5.

OBJECTIVE: The aim of the current study is to investigate challenging behavior in children who may no longer meet criteria for an autism spectrum disorder (ASD) diagnosis according to the proposed fifth edition of the Diagnostic and Statistical Manual (DSM-5). METHOD: Children and adolescents (n = 459) were separated into three groups including those who met criteria for ASD according to the DSM-5 criteria (n = 219); those who will no longer qualify for an ASD diagnosis according to the DSM-5 but met criteria according to the DSM-IV-TR (n = 109); and a control group (n = 131). Scores on the Autism Spectrum Disorders - Problem Behaviors for Children (ASD-PB-C) were compared among groups. RESULTS: The DSM-5 captured a slightly more impaired population in terms of problem behavior. CONCLUSION: Implications regarding access to treatment for those no longer meeting criteria need to be taken into consideration in the coming months.

The effects of developmental quotient and diagnostic criteria on challenging behaviors in toddlers with developmental disabilities.

Previous research has found that individuals with intellectual disability and/or autism spectrum disorder (ASD), and those with greater symptom severity within these diagnoses, show higher rates of aggressive/destructive behavior, stereotypic behavior, and self-injurious behavior. In this exploratory cross-sectional study, toddlers at-risk for a developmental disorder (n=1509) ranging from 17 to 36 months fell into one of three diagnostic categories: Autistic Disorder, Pervasive Developmental Disorder-Not Otherwise Specified [PDD-NOS], and atypically developing - no ASD diagnosis. Mental health professionals from EarlySteps, Louisiana's Early Intervention System, interviewed parents and guardians using the Baby and Infant Screen for Children with aUtIsm Traits (BISCUIT) -Part 3 (Matson, Boisjoli, & Wilkins, 2007) to obtain measures of challenging behaviors and the Battelle Developmental Inventory, 2nd Edition (BDI-2) (Newborg, 2005) to obtain developmental quotients (DQ). Toddlers diagnosed with Autistic Disorder or PDD-NOS showed a positive relationship between total DQ and challenging behavior; whereas, atypically developing toddlers with no ASD diagnosis showed a more adaptive, negative relationship. The DQ domains that were most influential on challenging behaviors varied by diagnosis, with communication and motor domains playing greater roles for toddlers with Autistic Disorder or PDD-NOS, and personal-social and cognitive domains playing greater roles for atypically developing toddlers with no ASD diagnosis.

Comorbidity of physical and motor problems in children with autism.

Autism and the related pervasive developmental disorders are a heavily researched group of neurodevelopmental conditions. In addition to core symptoms, there are a number of other physical and motor conditions that co-occur at high rates. This paper provides a review of factors and behaviors that correlate highly with disorders on the autism spectrum. Among these conditions are premature birth, birth defects, gross and fine motor skills, and obesity. Each of these topics is addressed, and what researchers have found are presented. These data have important implications for the types of collateral behaviors that should be assessed and treated, along with the core symptoms of autism.