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Syndromic autism refers to autism spectrum disorder diagnosed in the context of a known genetic syndrome. The specific manifestations of any one of these syndromic autisms are related to a clinically defined genetic syndrome that can be traced to certain genes and variants, genetic deletions, or duplications at the chromosome level. The genetic mutations or defects in single genes associated with these genetic disorders result in a significant elevation of risk for developing autism relative to the general population and are related to recurrence with inheritance patterns. Additionally, these syndromes are associated with typical behavioral characteristics or phenotypes as well as an increased risk for specific behavioral or psychiatric disorders and clinical findings. Knowledge of these associations helps guide clinicians in identifying potentially treatable conditions that can help to improve the lives of affected patients and their families. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobehavioral disorders associated with developmental impairments in social communication skills and stereotypic, rigid or repetitive behaviors. We review common behavioral, psychiatric and genetic associations related to ASD. Autism affects about 2% of children with 4:1 male-to-female ratio and a heritability estimate between 70 and 90%. The etiology of ASD involves a complex interplay between inheritance and environmental factors influenced by epigenetics. Over 800 genes and dozens of genetic syndromes are associated with ASD. Novel gene–protein interactions with pathway and molecular function analyses have identified at least three functional pathways including chromatin modeling, Wnt, Notch and other signaling pathways and metabolic disturbances involving neuronal growth and dendritic spine profiles. An estimated 50% of individuals with ASD are diagnosed with chromosome deletions or duplications (e.g., 15q11.2, BP1-BP2, 16p11.2 and 15q13.3), identified syndromes (e.g., Williams, Phelan-McDermid and Shprintzen velocardiofacial) or single gene disorders. Behavioral and psychiatric conditions in autism impacted by genetics influence clinical evaluations, counseling, diagnoses, therapeutic interventions and treatment approaches. Pharmacogenetics testing is now possible to help guide the selection of psychotropic medications to treat challenging behaviors or co-occurring psychiatric conditions commonly seen in ASD. In this review of the autism spectrum disorder, behavioral, psychiatric and genetic observations and associations relevant to the evaluation and treatment of individuals with ASD are discussed. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e.g., diseases, tissues or functional pathways). Twenty-three genes were common to all three disorders and mapped to nine biological Superpathways including Circadian entrainment (10 genes, score = 37.0), Amphetamine addiction (five genes, score = 24.2), and Sudden infant death syndrome (six genes, score = 24.1). Brain tissues included the medulla oblongata (11 genes, score = 2.1), thalamus (10 genes, score = 2.0) and hypothalamus (nine genes, score = 2.0) with six common genes (BDNF, DRD2, CHRNA7, HTR2A, SLC6A3, and TPH2). Overlapping genes impacted dopamine and serotonin homeostasis and signal transduction pathways, impacting mood, behavior and physical activity level. Converging effects on pathways governing circadian rhythms support a core etiological relationship between neuropsychiatric illnesses and sleep disruption with hypoxia and central brain stem dysfunction. [ABSTRACT FROM AUTHOR]

Mammalian chromosomes are comprised of complex chromatin architecture with the specific assembly and configuration of each chromosome influencing gene expression and function in yet undefined ways by varying degrees of heterochromatinization that result in Giemsa (G) negative euchromatic (light) bands and G-positive heterochromatic (dark) bands. We carried out morphometric measurements of high-resolution chromosome ideograms for the first time to characterize the total euchromatic and heterochromatic chromosome band length, distribution and localization of 20,145 known protein-coding genes, 790 recognized autism spectrum disorder (ASD) genes and 365 obesity genes. The individual lengths of G-negative euchromatin and G-positive heterochromatin chromosome bands were measured in millimeters and recorded from scaled and stacked digital images of 850-band high-resolution ideograms supplied by the International Society of Chromosome Nomenclature (ISCN) 2013. Our overall measurements followed established banding patterns based on chromosome size. G-negative euchromatic band regions contained 60% of protein-coding genes while the remaining 40% were distributed across the four heterochromatic dark band sub-types. ASD genes were disproportionately overrepresented in the darker heterochromatic sub-bands, while the obesity gene distribution pattern did not significantly differ from protein-coding genes. Our study supports recent trends implicating genes located in heterochromatin regions playing a role in biological processes including neurodevelopment and function, specifically genes associated with ASD. [ABSTRACT FROM AUTHOR]

Recently, autism-related research has focused on the identification of various genes and disturbed pathways causing the genetically heterogeneous group of autism spectrum disorders (ASD). The list of autism-related genes has significantly increased due to better awareness with advances in genetic technology and expanding searchable genomic databases. We compiled a master list of known and clinically relevant autism spectrum disorder genes identified with supporting evidence from peer-reviewed medical literature sources by searching key words related to autism and genetics and from authoritative autism-related public access websites, such as the Simons Foundation Autism Research Institute autism genomic database dedicated to gene discovery and characterization. Our list consists of 792 genes arranged in alphabetical order in tabular form with gene symbols placed on high-resolution human chromosome ideograms, thereby enabling clinical and laboratory geneticists and genetic counsellors to access convenient visual images of the location and distribution of ASD genes. Meaningful correlations of the observed phenotype in patients with suspected/confirmed ASD gene(s) at the chromosome region or breakpoint band site can be made to inform diagnosis and gene-based personalized care and provide genetic counselling for families. [ABSTRACT FROM AUTHOR]

Patients with the 15q11.2 BP1-BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen. The 15q11.2 BP1-BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%-1.27% of patients presenting for microarray analysis which is a two to four fold increase compared with controls. Review of clinical features from about 200 individuals were grouped into five categories and included developmental (73%) and speech (67%) delays; dysmorphic ears (46%) and palatal anomalies (46%); writing (60%) and reading (57%) difficulties, memory problems (60%) and verbal IQ scores ≤75 (50%); general behavioral problems, unspecified (55%) and abnormal brain imaging (43%). Other clinical features noted but not considered as common were seizures/epilepsy (26%), autism spectrum disorder (27%), attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) (35%), schizophrenia/paranoid psychosis (20%) and motor delay (42%). Not all individuals with the deletion are clinically affected, yet the collection of findings appear to share biological pathways and presumed genetic mechanisms. Neuropsychiatric and behavior disturbances and mild dysmorphic features are associated with genomic imbalances of the 15q11.2 BP1-BP2 region, including microdeletions, but with an apparent incomplete penetrance and variable expressivity. [ABSTRACT FROM AUTHOR]

Classical autism or autistic disorder belongs to a group of genetically heterogeneous conditions known as Autism Spectrum Disorders (ASD). Heritability is estimated as high as 90% for ASD with a recently reported compilation of 629 clinically relevant candidate and known genes. We chose to undertake a descriptive next generation whole exome sequencing case study of 30 well-characterized Caucasian females with autism (average age, 7.7 ± 2.6 years; age range, 5 to 16 years) from multiplex families. Genomic DNA was used for whole exome sequencing via paired-end next generation sequencing approach and X chromosome inactivation status. The list of putative disease causing genes was developed from primary selection criteria using machine learning-derived classification score and other predictive parameters (GERP2, PolyPhen2, and SIFT). We narrowed the variant list to 10 to 20 genes and screened for biological significance including neural development, function and known neurological disorders. Seventy-eight genes identified met selection criteria ranging from 1 to 9 filtered variants per female. Five females presented with functional variants of X-linked genes (IL1RAPL1, PIR, GABRQ, GPRASP2, SYTL4) with cadherin, protocadherin and ankyrin repeat gene families most commonly altered (e.g., CDH6, FAT2, PCDH8, CTNNA3, ANKRD11). Other genes related to neurogenesis and neuronal migration (e.g., SEMA3F, MIDN), were also identified. [ABSTRACT FROM AUTHOR]

Copy number variations involving the 17q12 region have been associated with developmental and speech delay, autism, aggression, self-injury, biting and hitting, oppositional defiance, inappropriate language, and auditory hallucinations. We present a tallappearing 17-year-old boy with marfanoid habitus, hypermobile joints, mild scoliosis, pectus deformity, widely spaced nipples, pes cavus, autism spectrum disorder, intellectual disability, and psychiatric manifestations including physical and verbal aggression, obsessive-compulsive behaviors, and oppositional defiance. An echocardiogram showed borderline increased aortic root size. An abdominal ultrasound revealed a small pancreas, mild splenomegaly with a 1.3 cm accessory splenule, and normal kidneys and liver. A testing panel for Marfan, aneurysm, and related disorders was negative. Subsequently, a 400 K array-based comparative genomic hybridization (aCGH) + SNP analysis was performed which identified a de novo suspected pathogenic deletion on chromosome 17q12 encompassing 28 genes. Despite the limited number of cases described in the literature with 17q12 rearrangements, our proband's phenotypic features both overlap and expand on previously reported cases. Since syndrome-specific DNA sequencing studies failed to provide an explanation for this patient's unusual habitus, we postulate that this case represents an expansion of the 17q12 microdeletion phenotype. Further analysis of the deleted interval is recommended for new genotype-phenotype correlations. [ABSTRACT FROM AUTHOR]

In clinical settings, the information provided by genetic testing can explain the triggers and processes underlying clinical presentations, such as neurodevelopmental disorders, in up to one third of affected individuals. However, translating this knowledge into better and more personalized clinical management to many appears a distant target. This article presents three paradigmatic cases to exemplify how this translational effort can, at least in some instances, be undertaken today with very positive results: (a) a young girl carrying a chr. 16p11.2 duplication can be screened using targeted exams and undertake therapeutic/preventive interventions related to her genetic diagnosis; (b) a 13-year-old boy with intellectual disability and autism spectrum disorder carries a chr. 11q14.1 deletion, partly spanning the DLG2 gene important for synaptic function, and gained over 20 I.Q. points ostensibly due to carbolithium, prescribed in the absence of affective symptoms, exclusively following the pathophysiology pointed out by the genetic results; (c) a 58-year-old woman carries a COL3A1 gene variant responsible for the vascular form of Ehler–Danlos syndrome with colon rupture. Detection of this variant in six members of her extended family allows for better clinical management of the proband and targeted genetic counselling for family members at risk of this connective tissue disorder. The unprecedented flow of genetic information available today through new technologies, if interpreted in the light of current knowledge in clinical diagnosis and care of those with connective tissue disorders and neurodevelopmental disturbances, in biology and in neuropsychopharmacology, can promote better clinical and pharmacological treatment, disease surveillance, and management provided and incorporated into the clinical setting. [ABSTRACT FROM AUTHOR]

SHANK3 encodes a scaffold protein involved in postsynaptic receptor density in glutamatergic synapses, including those in the parvalbumin (PV)+ inhibitory neurons—the key players in the generation of sensory gamma oscillations, such as 40-Hz auditory steady-state response (ASSR). However, 40-Hz ASSR was not studied in relation to SHANK3 functioning. Here, we present a 15-year-old girl (SH01) with previously unreported duplication of the first seven exons of the SHANK3 gene (22q13.33). SH01's electroencephalogram (EEG) during 40-Hz click trains of 500 ms duration binaurally presented with inter-trial intervals of 500–800 ms were compared with those from typically developing children (n = 32). SH01 was diagnosed with mild mental retardation and learning disabilities (F70.88), dysgraphia, dyslexia, and smaller vocabulary than typically developing (TD) peers. Her clinical phenotype resembled the phenotype of previously described patients with 22q13.33 microduplications (≈30 reported so far). SH01 had mild autistic symptoms but below the threshold for ASD diagnosis and microcephaly. No seizures or MRI abnormalities were reported. While SH01 had relatively preserved auditory event-related potential (ERP) with slightly attenuated P1, her 40-Hz ASSR was totally absent significantly deviating from TD's ASSR. The absence of 40-Hz ASSR in patients with microduplication, which affected the SHANK3 gene, indicates deficient temporal resolution of the auditory system, which might underlie language problems and represent a neurophysiological biomarker of SHANK3 abnormalities. [ABSTRACT FROM AUTHOR]

The 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15q1l.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FAT3) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes ( x ¯ = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype. [ABSTRACT FROM AUTHOR]

Human genetic studies have implicated more than a hundred genes in Autism Spectrum Disorder (ASD). Understanding how variation in implicated genes influence expression of co-occurring conditions and drug response can inform more effective, personalized approaches for treatment of individuals with ASD. Rapidly translating this information into the clinic requires efficient algorithms to sort through the myriad of genes implicated by rare gene-damaging single nucleotide and copy number variants, and common variation detected in genome-wide association studies (GWAS). To pinpoint genes that are more likely to have clinically relevant variants, we developed a functional annotation pipeline. We defined clinical relevance in this project as any ASD associated gene with evidence indicating a patient may have a complex, co-occurring condition that requires direct intervention (e.g., sleep and gastrointestinal disturbances, attention deficit hyperactivity, anxiety, seizures, depression), or is relevant to drug development and/or approaches to maximizing efficacy and minimizing adverse events (i.e., pharmacogenomics). Starting with a list of all candidate genes implicated in all manifestations of ASD (i.e., idiopathic and syndromic), this pipeline uses databases that represent multiple lines of evidence to identify genes: (1) expressed in the human brain, (2) involved in ASD-relevant biological processes and resulting in analogous phenotypes in mice, (3) whose products are targeted by approved pharmaceutical compounds or possessing pharmacogenetic variation and (4) whose products directly interact with those of genes with variants recommended to be tested for by the American College of Medical Genetics (ACMG). Compared with 1000 gene sets, each with a random selection of human protein coding genes, more genes in the ASD set were annotated for each category evaluated (p ≤ 1.99 × 10−2). Of the 956 ASD-implicated genes in the full set, 18 were flagged based on evidence in all categories. Fewer genes from randomly drawn sets were annotated in all categories (x = 8.02, sd = 2.56, p = 7.75 × 10−4). Notably, none of the prioritized genes are represented among the 59 genes compiled by the ACMG, and 78% had a pathogenic or likely pathogenic variant in ClinVar. Results from this work should rapidly prioritize potentially actionable results from genetic studies and, in turn, inform future work toward clinical decision support for personalized care based on genetic testing. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) consists of a genetically heterogenous group of neurobehavioral disorders characterized by impairment in three behavioral domains including communication, social interaction, and stereotypic repetitive behaviors. ASD affects more than 1% of children in Western societies, with diagnoses on the rise due to improved recognition, screening, clinical assessment, and diagnostic testing. We reviewed the role of genetic and metabolic factors which contribute to the causation of ASD with the use of new genetic technology. Up to 40 percent of individuals with ASD are now diagnosed with genetic syndromes or have chromosomal abnormalities including small DNA deletions or duplications, single gene conditions, or gene variants and metabolic disturbances with mitochondrial dysfunction. Although the heritability estimate for ASD is between 70 and 90%, there is a lower molecular diagnostic yield than anticipated. A likely explanation may relate to multifactorial causation with etiological heterogeneity and hundreds of genes involved with a complex interplay between inheritance and environmental factors influenced by epigenetics and capabilities to identify causative genes and their variants for ASD. Behavioral and psychiatric correlates, diagnosis and genetic evaluation with testing are discussed along with psychiatric treatment approaches and pharmacogenetics for selection of medication to treat challenging behaviors or comorbidities commonly seen in ASD. We emphasize prioritizing treatment based on targeted symptoms for individuals with ASD, as treatment will vary from patient to patient based on diagnosis, comorbidities, causation, and symptom severity. [ABSTRACT FROM AUTHOR]

To identify whether parent-of-origin effects (POE) of the 15q11.2 BP1-BP2 microdeletion are associated with differences in clinical features in individuals inheriting the deletion, we collected 71 individuals reported with phenotypic data and known inheritance from a clinical cohort, a research cohort, the DECIPHER database, and the primary literature. Chi-squared and Mann-Whitney U tests were used to test for differences in specific and grouped clinical symptoms based on parental inheritance and proband gender. Analyses controlled for sibling sets and individuals with additional variants of uncertain significance (VOUS). Among all probands, maternal deletions were associated with macrocephaly (p = 0.016) and autism spectrum disorder (ASD; p = 0.02), while paternal deletions were associated with congenital heart disease (CHD; p = 0.004). Excluding sibling sets, maternal deletions were associated with epilepsy as well as macrocephaly (p < 0.05), while paternal deletions were associated with CHD and abnormal muscular phenotypes (p < 0.05). Excluding sibling sets and probands with an additional VOUS, maternal deletions were associated with epilepsy (p = 0.019) and paternal deletions associated with muscular phenotypes (p = 0.008). Significant gender-based differences were also observed. Our results supported POEs of this deletion and included macrocephaly, epilepsy and ASD in maternal deletions with CHD and abnormal muscular phenotypes seen in paternal deletions. [ABSTRACT FROM AUTHOR]

Objectives: Our clinical experience with low dose loxapine (5-15 mg/day) suggests promising efficacy and safety for irritability in autism spectrum disorders (ASD). We studied low dose loxapine prospectively in adolescents and adults with ASD and irritability. Additionally, we measured loxapine and metabolite concentrations, and brain-derived neurotrophic factor (BDNF) as a biomarker of neuromodulation. Methods: We performed a 12 week open trial of add-on loxapine in subjects, ages 13-65 years, diagnosed with ASD, and Aberrant Behavior Checklist-Irritability (ABC-I) subscale scores >14. Loxapine was dosed flexibly up to 15 mg daily, starting with 5 mg on alternate days. From weeks 1 to 6, other psychoactive medications were tapered if possible; from weeks 6 to 12, all medication doses were held stable. The primary outcome was the Clinical Global Impressions-Improvement subscale (CGI-I), ratings of Much Improved or Very Much Improved. Secondary outcomes were the ABC-I, Repetitive Behavior Scale-Revised, and Schalock Quality of Life scale. Serum BDNF and loxapine and metabolite concentrations were assayed. BDNF rs6265 was genotyped. Results: Sixteen subjects were enrolled; 12 completed all visits. Median age was 18 years (range 13-39). Median final loxapine dose was 7.5 mg/day (2.5-15). All 14 subjects (100%) with data at week 12 were rated as Much Improved on CGI-I at 12 weeks. Mean change on ABC-I at 12 weeks was −31%, p=0.01. Mean body mass index (BMI)- Z decreased between weeks 6 and 12, p=0.03. Side effects were minimal, and prolactin elevation occurred in only one subject. BDNF concentrations measured in 11 subjects increased significantly ( p=0.04). Subjects with AG genotype for BDNF rs6265 required a lower dose of loxapine at study end, but had similar behavioral and BDNF concentration changes as the GG genotype. Conclusions: Low dose loxapine shows promise as a repurposed drug for irritability in ASD. Loxapine effects on BDNF warrant further study. [ABSTRACT FROM AUTHOR]

Abstract: Chromosomal microarray analysis is now commonly used in clinical practice to identify copy number variants (CNVs) in the human genome. We report our experience with the use of the 105K and 180K oligonucleotide microarrays in 215 consecutive patients referred with either autism or autism spectrum disorders (ASD) or developmental delay/learning disability for genetic services at the University of Kansas Medical Center during the past 4years (2009–2012). Of the 215 patients [140 males and 75 females (male/female ratio=1.87); 65 with ASD and 150 with learning disability], abnormal microarray results were seen in 45 individuals (21%) with a total of 49 CNVs. Of these findings, 32 represented a known diagnostic CNV contributing to the clinical presentation and 17 represented non-diagnostic CNVs (variants of unknown significance). Thirteen patients with ASD had a total of 14 CNVs, 6 CNVs recognized as diagnostic and 8 as non-diagnostic. The most common chromosome involved in the ASD group was chromosome 15. For those with a learning disability, 32 patients had a total of 35 CNVs. Twenty-six of the 35 CNVs were classified as a known diagnostic CNV, usually a deletion (n=20). Nine CNVs were classified as an unknown non-diagnostic CNV, usually a duplication (n=8). For the learning disability subgroup, chromosomes 2 and 22 were most involved. Thirteen out of 65 patients (20%) with ASD had a CNV compared with 32 out of 150 patients (21%) with a learning disability. The frequency of chromosomal microarray abnormalities compared by subject group or gender was not statistically different. A higher percentage of individuals with a learning disability had clinical findings of seizures, dysmorphic features and microcephaly, but not statistically significant. While both groups contained more males than females, a significantly higher percentage of males were present in the ASD group. [Copyright &y& Elsevier]