Searching for Potocki-Lupski syndrome phenotype: a patient with language impairment and no autism

Potocki-Lupski syndrome (PTLS; OMIM 610883) is a genomic syndrome that arises as a result of a duplication of 17p11.2. Although numerous cases of individuals with PTLS have been presented in the literature, its behavioral characterization is still ambiguous. We present a male child with a de novo dup(17)(p11.2p11.2) and he does not possess any autistic features, but is characterized by severe speech and language impairment. In the context of the analyses of this patient and other cases of PTLS, we argue that the central feature of the syndrome appears to be related to diminished speech and language capacity, rather than the specific social deficits central to autism.     

Factors associated with quality of life in individuals with autism spectrum disorders: A review of literature

This review study was conducted to synthesize the existing research on the level of quality of life (QoL) in individuals with autism spectrum disorders (ASD) and the factors associated with their QoL. A total of 16 studies were included for this review. This study found that (a) the majority of the individuals with ASD had poor QoL; (b) behavior problems and leisure activities were associated with the QoL of the majority of adults with ASD; (c) autism severity, age, behavior problems, social skills, adaptive behavior, education, and comorbid psychiatric conditions were associated with the QoL of the majority of children with ASD. These findings may provide critical information to parents/caregivers of individuals with ASD and practitioners providing services to them.     

Novel Submicroscopic Chromosomal Abnormalities Detected in Autism Spectrum Disorder

This autism CNV study on autism subjects used a 19K whole genome tiling path BAC microarray to identify 51 CNV in 46 (11.6%) of 397 subjects, which is significantly higher than the 5% identified using traditional cytogenetics. These smaller microdeletions and microduplications will allow a more focused effort to study the individual genes within these CNV. However, we are unable to differentiate for each specific CNV whether they 1) cause ASD, 2) contribute to ASD, or 3) have no phenotypic effect without analysis of much larger sample sizes or other methods of investigation.     

A molecular genetic study of autism and related phenotypes in extended pedigrees

Background

Efforts to uncover the risk genotypes associated with the familial nature of autism spectrum disorder (ASD) have had limited success. The study of extended pedigrees, incorporating additional ASD-related phenotypes into linkage analysis, offers an alternative approach to the search for inherited ASD susceptibility variants that complements traditional methods used to study the genetics of ASD.

Methods

We examined evidence for linkage in 19 extended pedigrees ascertained through ASD cases spread across at least two (and in most cases three) nuclear families. Both compound phenotypes (i.e., ASD and, in non-ASD individuals, the broad autism phenotype) and more narrowly defined components of these phenotypes, e.g., social and repetitive behavior, pragmatic language, and anxiety, were examined. The overarching goal was to maximize the aggregate information available on the maximum number of individuals and to disaggregate syndromic phenotypes in order to examine the genetic underpinnings of more narrowly defined aspects of ASD behavior.

Results

Results reveal substantial between-family locus heterogeneity and support the importance of previously reported ASD loci in inherited, familial, forms of ASD. Additional loci, not seen in the ASD analyses, show evidence for linkage to the broad autism phenotype (BAP). BAP peaks are well supported by multiple subphenotypes (including anxiety, pragmatic language, and social behavior) showing linkage to regions overlapping with the compound BAP phenotype. Whereas ''repetitive behavior’, showing the strongest evidence for linkage (Posterior Probability of Linkage = 62% at 6p25.2-24.3, and 69% at 19p13.3), appears to be linked to novel regions not detected with other compound or narrow phenotypes examined in this study.

Conclusions

These results provide support for the presence of key features underlying the complexity of the genetic architecture of ASD: substantial between-family locus heterogeneity, that the BAP appears to correspond to sets of subclinical features segregating with ASD within pedigrees, and that different features of the ASD phenotype segregate independently of one another. These findings support the additional study of larger, even more individually informative pedigrees, together with measurement of multiple, behavioral- and biomarker-based phenotypes, in both affected and non-affected individuals, to elucidate the complex genetics of familial ASD.     

Novel copy number variants in children with autism and additional developmental anomalies

Autism is a neurodevelopmental disorder characterized by three core symptom domains: ritualistic-repetitive behaviors, impaired social interaction, and impaired communication and language development. Recent studies have highlighted etiologically relevant recurrent copy number changes in autism, such as 16p11.2 deletions and duplications, as well as a significant role for unique, novel variants. We used Affymetrix 250K GeneChip Microarray technology (either NspI or StyI) to detect microdeletions and duplications in a subset of children from the Autism Genetic Resource Exchange (AGRE). In order to enrich our sample for potentially pathogenic CNVs we selected children with autism who had additional features suggestive of chromosomal loss associated with developmental disturbance (positive criteria filter) but who had normal cytogenetic testing (negative criteria filter). We identified families with the following features: at least one child with autism who also had facial dysmorphology, limb or digit abnormalities, or ocular abnormalities. To detect changes in copy number we used a publicly available program, Copy Number Analyser for GeneChip® (CNAG) Ver. 2.0. We identified novel deletions and duplications on chromosomes 1q24.2, 3p26.2, 4q34.2, and 6q24.3. Several of these deletions and duplications include new and interesting candidate genes for autism such as syntaxin binding protein 5 (STXBP5 also known as tomosyn) and leucine rich repeat neuronal 1 (LRRN1 also known as NLRR1). Lastly, our data suggest that rare and potentially pathogenic microdeletions and duplications may have a substantially higher prevalence in children with autism and additional developmental anomalies than in children with autism alone.     

Neurodevelopmental phenotype associated with CHD8-SUPT16H duplication

Microdeletions encompassing 14q11.2 locus, involving SUPT16H and CHD8, were shown to cause developmental delay, intellectual disability, autism spectrum disorders and macrocephaly. Variations leading to CHD8 haploinsufficiency or loss of function were also shown to lead to a similar phenotype. Recently, a 14q11.2 microduplication syndrome, encompassing CHD8 and SUPT16H, has been described, highlighting the importance of a tight control of at least CHD8 gene-dosage for a normal development. There have been only a few reports of 14q11.2 microduplications. Patients showed variable neurodevelopmental issues of variable severity. Breakpoints of the microduplications were non-recurrent, making interpretation of the CNV and determination of their clinical relevance difficult. Here, we report on two patients with 14q11.2 microduplication encompassing CHD8 and SUPT16H, one of whom had normal intelligence. Review of previous reports describing patients with comparable microduplications allowed for a more precise delineation of the condition and widening of the phenotypic spectrum.

     

孤独症谱系障碍核心家系染色体核型分析研究

目的分析中国汉族人群孤独症谱系障碍核心家系的染色体核型特征,并筛查染色体畸变,探讨患者染色体畸变区域是否存在拷贝数变异和神经发育相关基因,为寻找孤独症谱系障碍的遗传病因提供线索。方法采用G带显色技术并依据人类细胞遗传学国际命名体制(International System for Human Cytogenetic Nomenclature,ISCN)对632个孤独症谱系障碍核心家系(包括632例患者及其健康生物学父母1264名)进行染色体核型分析,并根据各染色体带型特征筛查染色体数目和结构畸变情况。经与细胞遗传学芯片标准化联盟(International Standards for Cytogenomic Arrays,ISCA)数据库和人类亚微观结构基因组变异和疾病表型数据库(Database of genomic variation and Phenotype in Humans using Ensembl Resource,DECIPHER)比对,探讨检出的染色体畸变区域是否可能存在与孤独症谱系障碍和神经发育相关的致病性拷贝数变异和基因。结果共检出携带染色体畸变的患者22例,占患者3.48%(22/632)。其中5例为新生畸变,在患者中检出率为0.79%(5/632),包括1例重复,1例平衡易位,2例Turner综合征核型,1例21q22区域额外未知来源片段;另外17例染色体畸变为父母遗传,占患者2.69%(17/632)。经数据库比对,检出的染色体1q25和3p24畸变区域可能存在致病性较高的拷贝数变异,并累及TNR、ASTN1、NMNAT2等神经发育相关基因。结论部分孤独症谱系障碍患者存在新生染色体畸变;染色体畸变区域可能存在累及神经发育相关致病基因的拷贝数变异。染色体核型分析可为寻找孤独症谱系障碍的遗传病因提供线索。     

Social Communication Profiles of Children with Autism Spectrum Disorders Late in the Second Year of Life

This study examined social communication profiles from behavior samples videotaped between 18 and 24 months of age in three groups of children: 50 with autism spectrum disorders (ASD), 23 with developmental delays (DD), and 50 with typical development (TD). The ASD group scored significantly lower than the DD group on 5 social communication measures and the TD group on all 14 measures, indicating distinct profiles late in the second year. Understanding was the strongest predictor of developmental level and behavior regulation and inventory of gestures were the strongest predictors of autism symptoms at 3 years of age. The predictive relations suggest five pivotal skills late in the second year that have a cascading effect on outcomes of children with ASD.     

Parenting Stress in Mothers and Fathers of Toddlers with Autism Spectrum Disorders: Associations with Child Characteristics

Elevated parenting stress is observed among mothers of older children with autism spectrum disorders (ASD), but little is known about parents of young newly-diagnosed children. Associations between child behavior and parenting stress were examined in mothers and fathers of 54 toddlers with ASD (mean age = 26.9 months). Parents reported elevated parenting stress. Deficits/delays in children's social relatedness were associated with overall parenting stress, parent-child relationship problems, and distress for mothers and fathers. Regulatory problems were associated with maternal stress, whereas externalizing behaviors were associated with paternal stress. Cognitive functioning, communication deficits, and atypical behaviors were not uniquely associated with parenting stress. Clinical assessment of parental stress, acknowledging differences in parenting experiences for mothers and fathers of young children with ASD, is needed.     

Benign infantile convulsions (IC) and subsequent paroxysmal kinesigenic dyskinesia (PKD) in a patient with 16p11.2 microdeletion syndrome

Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) is caused by mutations in the gene PRRT2 located in 16p11.2. A deletion syndrome 16p11.2 is well established and is characterized by intellectual disability, speech delay, and autism. PKD/IC, however, is extremely rare in this syndrome. We describe a case of PKD/IC and 16p11.2 deletion syndrome and discuss modifiers of PRRT2 activity to explain the rare concurrence of both syndromes.     

What symptoms predict the diagnosis of autism or PDD-NOS in infants and toddlers with developmental delays using the Baby and Infant Screen for aUtIsm Traits

Purpose: Autism Spectrum Disorders (ASD) are characterized by life-long and severe symptoms such as stereotypies, social skills deficits and language delays. Previous research has demonstrated that children who receive early intensive behavioural intervention have a better prognosis than those who do not receive services. It is for this reason that assessments designed specifically for early identification of ASD are of paramount important.

Method: In Study 1, 957 infants with autism, PDD-NOS and atypical development were evaluated using an assessment screener for ASD traits, the Baby and Infant Screen for aUtIsm Traits (BISCUIT). In Study 2, only those with an autism or PDD-NOS diagnosis were evaluated.

Results: The BISCUIT was found to have an excellent overall classification rate for children in the target population. A sub-set of BISCUIT items was found that distinguished children with ASD from atypically developing children. Items were also found which could accurately predict autism vs PDD-NOS diagnosis.

Conclusions: These data suggest that the core features of ASD are distinct and can be identified early in life. Furthermore, the presence of specific core behaviours can allow for a more accurate clinical and diagnostic picture for young children with autism or PDD-NOS vs general developmental delays.     

Attention-deficit/hyperactivity disorder (AD/HD) in autism spectrum disorder

The purpose of this review is to provide an overview of the research on attention-deficit/hyperactivity disorder (AD/HD) in individuals with autism spectrum disorder (ASD). Topics explored are the prevalence of AD/HD, the importance of studying AD/HD, as well as the questionnaire measures used to measure AD/HD in individuals with ASD. Research on the relationship between AD/HD in ASD and parental stress and psychological distress, developmental regression, language and communication, adaptive behavior, social skills, autism severity, challenging behavior, comorbid psychopathology, gastrointestinal symptoms, sleep problems, epilepsy, sensory issues, motor difficulties, and quality of life are also discussed. Research on cardiac reactivity and executive functioning are also explored. Finally, recommendations for treatment are given as well as areas where future research is needed.     

Epilepsy,neuropsychiatric phenotypes,neuroimaging findings,and genotype-neurophenotype correlation in 22q11.2 deletion syndrome

Objectives:To describe the epilepsy, neuropsychiatric manifestations, and neuroimaging findings in a group of patients with 22q11.2 DS, and to correlate the size of the deleted genetic material with the severity of the phenotype.Methods:We retrospectively analyzed the medical records of 28 patients (21 pediatric patients and 7 adults) with a genetically confirmed diagnosis of 22q11.2 DS. Clinical data (epilepsy, neurological exam, neuropsychological and developmental assessment, and psychiatric disorders), neuroimaging, and cytogenetic tests were analyzed.Results:Of the 28 patients with 22q11.2 DS, 6 (21.4%) had epileptic seizures, 2 had symptomatic hypocalcemic seizures, 4 (14.2%) had a psychiatric disorder, which comprised of attention deficit hyperactivity disorder, autism spectrum disorder, psychosis, and mood disorder, and 17 (60.7%) had developmental delay. All patients with epilepsy had a developmental delay. Twelve patients underwent a neuropsychology assessment. Intellectual levels ranged from moderate intellectual disability (7/12, 58%) to average (5/12, 41.6%). Of the 16 patients, 6 (37.5%) had a normal brain, while 10 (62.5%) had abnormal neuroimaging findings. No significant correlation was found between the size of the deleted genetic material and the severity of the phenotype.Conclusion:22q11.2DS patients are at high risk to develop epilepsy, neuropsychiatric manifestations, and structural brain abnormalities. This indicates that this defined genetic locus is crucial for the development of the nervous system, and patients with 22q11.2 DS have genetic susceptibility to develop epilepsy.

22q11.2 deletion syndrome (22q11.2DS) has to many names such as velocardiofacial syndrome and DiGeorge syndrome, which is the most common microdeletion syndrome.1 It is due to hemizygous microdeletions on chromosome 22q11.2, it occurs 1 in 4000 live births, and 90% occur de novo. Most individuals with 22q11.2 DS lost about 3 Megabases (Mb) of DNA on chromosome 22 at position 22q11.2 in each cell.2 Some affected individuals have smaller deleted genetic material in this region. The clinical picture has a markedly different expression and incomplete penetrance. Therefore, 22q11.2DS has symptoms affecting several systems in the body, including congenital heart anomalies, palatal anomalies, hypocalcemia due to hypoplasia of parathyroid glands, immunodeficiency due to hypoplastic thymus, facial dysmorphism, disorders of cognition and behavior, and psychiatric disorders.3 However, few studies have been conducted on the epilepsy, neurological, neuroimaging, and neuropsychiatric features of 22q11.2 DS.This study aimed to examine the epilepsy, neurological, neuropsychiatric phenotypes, and neuroimaging findings in a series of individuals with 22q11.2 DS and to correlate the genotype with the neurophenotype.     

Modulation of mu attenuation to social stimuli in children and adults with 16p11.2 deletions and duplications

Background

Copy number variations (CNV) within the recurrent ~600 kb chromosomal locus of 16p11.2 are associated with a wide range of neurodevelopmental disorders, including autism spectrum disorder (ASD). However, little is known about the social brain phenotype of 16p11.2 CNV and how this phenotype is related to the social impairments associated with CNVs at this locus. The aim of this preliminary study was to use molecular subtyping to establish the social brain phenotype of individuals with 16p11.2 CNV and how these patterns relate to typical development and ASD.

Methods

We evaluated the social brain phenotype as expressed by mu attenuation in 48 children and adults characterized as duplication carriers (n = 12), deletion carriers (n = 12), individuals with idiopathic ASD (n = 8), and neurotypical controls (n = 16). Participants watched videos containing social and nonsocial motion during electroencephalogram (EEG) acquisition.

Results

Overall, only the typical group exhibited predicted patterns of mu modulation to social information (e.g., greater mu attenuation for social than nonsocial motion). Both 16p11.2 CNV groups exhibited more mu attenuation for nonsocial than social motion. The ASD group did not discriminate between conditions and demonstrated less mu attenuation compared to the typical and duplication carriers. Single-trial analysis indicated that mu attenuation decreased over time more rapidly for 16p11.2 CNV groups than the typical group. The duplication group did not diverge from typical patterns of mu attenuation until after initial exposure.

Conclusions

These results indicate atypical but unique patterns of mu attenuation for deletion and duplication carriers, highlighting the need to continue characterizing the social brain phenotype associated with 16p11.2 CNVs.

Electronic supplementary material

The online version of this article (doi:10.1186/s11689-015-9118-5) contains supplementary material, which is available to authorized users.     

Syntax and Morphology in Danish-Speaking Children with Autism Spectrum Disorder

The current study examined delays in syntax and morphology, and vocabulary, in autism spectrum disorder (ASD). Children ages 4–6 years with ASD (n?=?21) and typical development (n?=?21), matched on nonverbal mental age, completed five language tasks. The ASD group had significant delays in both syntax and morphology, and vocabulary measures, with significant within-group heterogeneity; furthermore, syntactic and morphological measures were impaired even for subgroups matched on vocabulary. Children in the ASD group without early language delay showed syntactic and morphological impairment, with intact performance on vocabulary and sentence repetition. Findings indicate that syntactic and morphological impairments are a significant concern for high-functioning children with ASD, and may be overlooked if language evaluation focuses exclusively on vocabulary.     

Spontaneous communication in autism spectrum disorder: A review of topographies and interventions

Lack of spontaneous communicative initiations appears to be a consistent problem in individuals with a diagnosis of autism spectrum disorder (ASD; Fujiki & Brinton, 2009). Spontaneous communication is emitted at a much lower frequency compared to individuals with language impairment and typically developing persons. Deficits of spontaneity in social interaction have been identified explicitly in the diagnostic criteria for autism, regardless of communication level or ability (American Psychiatric Association, 1994). In addition, without intervention 21–66% of children with ASD do not develop communicative speech (Lord & McGee, 2001). Individuals with autism rarely initiate appropriate speech and often fail to engage in typical social interactions such as asking questions, requesting information, expressing affection or requesting interactions (Carr & Kologinsky, 1983). This paper provides a review of the communicative topographies used to ameliorate spontaneous communication functions in individuals with autism and addresses the behavioral interventions that are used to induce such spontaneity.     

Adaptive Behavior Ratings Correlate With Symptomatology and IQ Among Individuals With High-Functioning Autism Spectrum Disorders

Caregiver report on the Adaptive Behavior Assessment System-II (ABAS) for 40 high-functioning individuals with Autism Spectrum Disorders (ASD) and 30 typically developing (TD) individuals matched for age, IQ, and sex ratio revealed global adaptive behavior deficits in ASD, with social skills impairments particularly prominent. Within the ASD group, adaptive communication skills were positively related to IQ while global adaptive functioning was negatively associated with autism symptomatology. Autistic behavior ratings related negatively to ABAS scores in the TD but not the ASD group. This investigation demonstrates: the utility of an adaptive functioning checklist for capturing impairments, even in high-functioning individuals with ASD; and that a relationship between social abilities and autism exists independently of intelligence.     

Exploring the relation between brain response to speech at 6-months and language outcomes at 24-months in infants at high and low risk for autism spectrum disorder: A preliminary functional near-infrared spectroscopy study

Infants at high familial risk for autism spectrum disorder (ASD) are at increased risk for language impairments. Studies have demonstrated that atypical brain response to speech is related to language impairments in this population, but few have examined this relation longitudinally. We used functional near-infrared spectroscopy (fNIRS) to investigate the neural correlates of speech processing in 6-month-old infants at high (HRA) and low risk (LRA) for autism. We also assessed the relation between brain response to speech at 6-months and verbal developmental quotient (VDQ) scores at 24-months. LRA infants exhibited greater brain response to speech in bilateral anterior regions of interest (ROIs) compared to posterior ROIs, while HRA infants exhibited similar brain response across all ROIs. Compared to LRA infants, HRA+ infants who were later diagnosed with ASD had reduced brain response in bilateral anterior ROIs, while HRA- infants who were not later diagnosed with ASD had increased brain response in right posterior ROI. Greater brain response in left anterior ROI predicted VDQ scores for LRA infants only. Findings highlight the importance of studying HRA+ and HRA- infants separately, and implicate a different, more distributed neural system for speech processing in HRA infants that is not related to language functioning.     

Parental Depression and Child Behavior Problems: A Pilot Study Examining Pathways of Influence

Parents of children with autism spectrum disorders (ASD) have higher rates of depressive symptoms than parents of typically developing children and parents of children with other developmental disorders. Parental depressive symptoms are strongly associated with problem behaviors in children; however, the mechanisms through which parental depression influences child behavior in families of children with ASD are unclear. The purpose of this study was to examine the relationship between parental depression and child behavior problems among families of children with ASD, more specifically to investigate the mediating variables that may explain the processes through which parental depression and child behavior problems are associated. The sample consisted of 33 parents of children with ASD (ages 2 to 5 years old). Findings suggested that authoritative parenting style significantly mediated the relationship between parental depression and behavior problems. This study highlights the importance of considering parental mental health and its impact on parenting behavior in interventions targeting child behavior problems.     

Associations between cytokines,endocrine stress response,and gastrointestinal symptoms in autism spectrum disorder

Many children and adolescents with autism spectrum disorder (ASD) have significant gastrointestinal (GI) symptoms, but the etiology is currently unknown. Some individuals with ASD show altered reactivity to stress and altered immune markers relative to typically-developing individuals, particularly stress-responsive cytokines including tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). Acute and chronic stress is associated with the onset and exacerbation of GI symptoms in those without ASD. The present study examined whether GI symptoms in ASD were associated with increases in cortisol, a stress-associated endocrine marker, and TNF-α and IL-6 in response to stress. As hypothesized, a greater amount of lower GI tract symptoms were significantly associated with post-stress cortisol concentration. The relationship between cortisol response to stress and GI functioning was greater for children who had a history of regressive autism. Exploratory analyses revealed significant correlations between cortisol response, intelligence, and inappropriate speech. In contrast, symptoms of the lower GI tract were not associated with levels of TNF-α or IL-6. Significant correlations were found, however, between TNF-α and IL-6 and irritability, socialization, and intelligence. These findings suggest that individuals with ASD and symptoms of the lower GI tract may have an increased response to stress, but this effect is not associated with concomitant changes in TNF-α and IL-6. The relationship between cortisol stress response and lower GI tract symptoms in children with regressive autism, as well as the relationships between cortisol, IL-6, and intelligence in ASD, warrant further investigation.