Deep psychophysiological phenotyping of adolescents and adults with 22q11.2 deletion syndrome: a multilevel approach to defining core disease processes.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal interstitial-deletion disorder, occurring in approximately 1 in 2000 to 6000 live births. Affected individuals exhibit variable clinical phenotypes that can include velopharyngeal anomalies, heart defects, T-cell-related immune deficits, dysmorphic facial features, neurodevelopmental disorders, including autism, early cognitive decline, schizophrenia, and other psychiatric disorders. Developing comprehensive treatments for 22q11.2DS requires an understanding of both the psychophysiological and neural mechanisms driving clinical outcomes. Our project probes the core psychophysiological abnormalities of 22q11.2DS in parallel with molecular studies of stem cell-derived neurons to unravel the basic mechanisms and pathophysiology of 22q11.2-related psychiatric disorders, with a primary focus on psychotic disorders. Our study is guided by the central hypothesis that abnormal neural processing associates with psychophysiological processing and underlies clinical diagnosis and symptomatology. Here, we present the scientific background and justification for our study, sharing details of our study design and human data collection protocol. METHODS: Our study is recruiting individuals with 22q11.2DS and healthy comparison subjects between the ages of 16 and 60 years. We are employing an extensive psychophysiological assessment battery (e.g., EEG, evoked potential measures, and acoustic startle) to assess fundamental sensory detection, attention, and reactivity. To complement these unbiased measures of cognitive processing, we will develop stem-cell derived neurons and examine neuronal phenotypes relevant to neurotransmission. Clinical characterization of our 22q11.2DS and control participants relies on diagnostic and research domain criteria assessments, including standard Axis-I diagnostic and neurocognitive measures, following from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and the North American Prodrome Longitudinal Study (NAPLS) batteries. We are also collecting measures of autism spectrum (ASD) and attention deficit/hyperactivity disorder (ADHD)-related symptoms. DISCUSSION: Studying 22q11.2DS in adolescence and adulthood via deep phenotyping across multiple clinical and biological domains may significantly increase our knowledge of its core disease processes. Our manuscript describes our ongoing study's protocol in detail. These paradigms could be adapted by clinical researchers studying 22q11.2DS, other CNV/single gene disorders, or idiopathic psychiatric syndromes, as well as by basic researchers who plan to incorporate biobehavioral outcome measures into their studies of 22q11.2DS.

Deep phenotyping in 3q29 deletion syndrome: recommendations for clinical care.

PURPOSE: To understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, brain structural, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care. METHODS: Thirty-two individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments. RESULTS: Medical manifestations were varied and reported across nearly every organ system. The most severe manifestations were congenital heart defects (25%) and the most common were gastrointestinal symptoms (81%). Physical examination revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), and attention deficit-hyperactivity disorder (ADHD) (63%). Neuroimaging revealed structural anomalies of the posterior fossa, but on neurological exam study subjects displayed only mild or moderate motor vulnerabilities. CONCLUSION: By direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.

Comprehensive phenotyping of neuropsychiatric traits in a multiplex 3q29 deletion family: a case report.

BACKGROUND: 3q29 deletion syndrome is associated with a range of medical, neurodevelopmental, and psychiatric phenotypes. The deletion is usually de novo but cases have been reported where the deletion is inherited from apparently unaffected parents. The presence of these unaffected or mildly affected individuals suggests there may be an ascertainment bias for severely affected cases of 3q29 deletion syndrome, thus the more deleterious consequence of the 3q29 deletion may be overestimated. However, a substantial fraction of 3q29 deletion syndrome morbidity is due to psychiatric illness. In many case reports, probands and transmitting parents are not systematically evaluated for psychiatric traits. Here we report results from a systematic phenotyping protocol for neurodevelopmental and neuropsychiatric traits applied to all 3q29 deletion carriers in a multiplex family. CASE PRESENTATION: Through the 3q29 registry at Emory University, a multiplex family was identified where three offspring had a paternally inherited 3q29 deletion. We evaluated all 4 3q29 deletion family members using our previously described standardized, systematic phenotyping protocol. The transmitting parent reported no psychiatric history, however upon evaluation he was discovered to meet criteria for multiple psychiatric diagnoses including previously undiagnosed schizoaffective disorder. All four 3q29 deletion individuals in the pedigree had multiple psychiatric diagnoses that interfered with quality of life and prohibited successful academic and occupational functioning. Cognitive ability for all individuals was average or below average, but within the normal range. CONCLUSIONS: This is the first case report of inherited 3q29 deletion syndrome where all affected individuals in the pedigree have been comprehensively and systematically evaluated for neurodevelopmental and psychiatric symptoms, using a standard battery of normed instruments administered by expert clinicians. Our investigation reveals that individuals with 3q29 deletion syndrome may have psychiatric morbidity that is debilitating, but only apparent through specialized evaluation by an expert. In the absence of appropriate evaluation, individuals with 3q29 deletion syndrome may suffer from psychiatric illness but lack avenues for access to care. The individuals evaluated here all have cognition in the normal range alongside multiple psychiatric diagnoses each, suggesting that cognitive ability alone is not a representative proxy for 3q29 deletion-associated disability. These results require replication in a larger cohort of individuals with 3q29 deletion syndrome.

Study protocol for The Emory 3q29 Project: evaluation of neurodevelopmental, psychiatric, and medical symptoms in 3q29 deletion syndrome.

BACKGROUND: 3q29 deletion syndrome is caused by a recurrent hemizygous 1.6 Mb deletion on the long arm of chromosome 3. The syndrome is rare (1 in 30,000 individuals) and is associated with mild to moderate intellectual disability, increased risk for autism and anxiety, and a 40-fold increased risk for schizophrenia, along with a host of physical manifestations. However, the disorder is poorly characterized, the range of manifestations is not well described, and the underlying molecular mechanism is not understood. We designed the Emory 3q29 Project to document the range of neurodevelopmental and psychiatric manifestations associated with 3q29 deletion syndrome. We will also create a biobank of samples from our 3q29 deletion carriers for mechanistic studies, which will be a publicly-available resource for qualified investigators. The ultimate goals of our study are three-fold: first, to improve management and treatment of 3q29 deletion syndrome. Second, to uncover the molecular mechanism of the disorder. Third, to enable cross-disorder comparison with other rare genetic syndromes associated with neuropsychiatric phenotypes. METHODS: We will ascertain study subjects, age 6 and older, from our existing registry ( 3q29deletion.org ). Participants and their families will travel to Atlanta, GA for phenotypic assessments, with particular emphasis on evaluation of anxiety, cognitive ability, autism symptomatology, and risk for psychosis via prodromal symptoms and syndromes. Evaluations will be performed using standardized instruments. Structural, diffusion, and resting-state functional MRI data will be collected from eligible study participants. We will also collect blood from the 3q29 deletion carrier and participating family members, to be banked at the NIMH Repository and Genomics Resource (NRGR). DISCUSSION: The study of 3q29 deletion has the potential to transform our understanding of complex disease. Study of individuals with the deletion may provide insights into long term care and management of the disorder. Our project describes the protocol for a prospective study of the behavioral and clinical phenotype associated with 3q29 deletion syndrome. The paradigm described here could easily be adapted to study additional CNV or single gene disorders with high risk for neuropsychiatric phenotypes, and/or transferred to other study sites, providing a means for data harmonization and cross-disorder analysis.

Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills.

The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7-60 y) and sex. A common SNP in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range -0.6 to -1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans.

Examining the Overlap between Autism Spectrum Disorder and 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is a genomic disorder reported to associate with autism spectrum disorders (ASDs) in 15-50% of cases; however, others suggest that individuals with 22q11.2DS present psychiatric or behavioral features associated with ASDs, but do not meet full criteria for ASD diagnoses. Such wide variability in findings may arise in part due to methodological differences across studies. Our study sought to determine whether individuals with 22q11.2DS meet strict ASD diagnostic criteria using research-based guidelines from the Collaborative Programs of Excellence in Autism (CPEA), which required a gathering of information from three sources: the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observational Schedule (ADOS), and a clinician's best-estimate diagnosis. Our study examined a cohort of children, adolescents, and young adults (n = 56) with 22q11.2DS, who were ascertained irrespective of parents' behavioral or developmental concerns, and found that 17.9% (n = 10) of the participants met CPEA criteria for an ASD diagnosis, and that a majority showed some level of social-communication impairment or the presence of repetitive behaviors. We conclude that strictly defined ASDs occur in a substantial proportion of individuals with 22q11.2DS, and recommend that all individuals with 22q11.2DS be screened for ASDs during early childhood.

Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity.

RATIONALE: Dopamine ß-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine in the central nervous system and peripherally. DBH variants are associated with large changes in circulating DBH and implicated in multiple disorders; yet causal relationships and tissue-specific effects remain unresolved. OBJECTIVE: To characterize regulatory variants in DBH, effect on mRNA expression, and role in modulating sympathetic tone and disease risk. METHODS AND RESULTS: Analysis of DBH mRNA in human tissues confirmed high expression in the locus coeruleus and adrenal gland, but also in sympathetically innervated organs (liver>lung>heart). Allele-specific mRNA assays revealed pronounced allelic expression differences in the liver (2- to 11-fold) attributable to promoter rs1611115 and exon 2 rs1108580, but only small differences in locus coeruleus and adrenals. These alleles were also associated with significantly reduced mRNA expression in liver and lung. Although DBH protein is expressed in other sympathetically innervated organs, mRNA levels were too low for analysis. In mice, hepatic Dbh mRNA levels correlated with cardiovascular risk phenotypes. The minor alleles of rs1611115 and rs1108580 were associated with sympathetic phenotypes, including angina pectoris. Testing combined effects of these variants suggested protection against myocardial infarction in 3 separate clinical cohorts. CONCLUSIONS: We demonstrate profound effects of DBH variants on expression in 2 sympathetically innervated organs, liver and lung, but not in adrenals and brain. Preliminary results demonstrate an association of these variants with clinical phenotypes responsive to peripheral sympathetic tone. We hypothesize that in addition to endocrine effects via circulating DBH and norepinephrine, the variants act in sympathetically innervated target organs.

The effect of hypocalcemia in early childhood on autism-related social and communication skills in patients with 22q11 deletion syndrome.

22q11 deletion syndrome (22qDS), also known as DiGeorge syndrome, is a copy number variant disorder that has a diverse clinical presentation including hypocalcaemia, learning disabilities, and psychiatric disorders. Many patients with 22q11DS present with signs that overlap with autism spectrum disorder (ASD) yet the possible physiological mechanisms that link 22q11DS with ASD are unknown. We hypothesized that early childhood hypocalcemia influences the neurobehavioral phenotype of 22q11DS. Drawing on a longitudinal cohort of 22q11DS patients, we abstracted albumin-adjusted serum calcium levels from 151 participants ranging in age from newborn to 19.5 years (mean 2.5 years). We then examined a subset of 20 infants and toddlers from this group for the association between the lowest calcium level on record and scores on the Communication and Symbolic Behavior Scales-Developmental Profile Infant-Toddler Checklist (CSBS-DP ITC). The mean (SD) age at calcium testing was 6.2 (8.5) months, whereas the mean (SD) age at the CSBS-DP ITC assessment was 14.7 (3.8) months. Lower calcium was associated with significantly greater impairment in the CSBS-DP ITC Social (p < 0.05), Speech (p < 0.01), and Symbolic domains (p < 0.05), in regression models adjusted for sex, age at blood draw, and age at the psychological assessment. Nevertheless, these findings are limited by the small sample size of children with combined data on calcium and CSBS-DP ITC, and hence will require replication in a larger cohort with longitudinal assessments. Considering the role of calcium regulation in neurodevelopment and neuroplasticity, low calcium during early brain development could be a risk factor for adverse neurobehavioral outcomes.

Reduced amplitude and slowed latency of the acoustic startle response in adolescents and adults with 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is one of the most robust genetic predictors of psychosis and other psychiatric illnesses. In this study, we examined 22q11DS subjects' acoustic startle responses (ASRs), which putatively index psychosis risk. Latency of the ASR is a presumptive marker of neural processing speed and is prolonged (slower) in schizophrenia. ASR measures correlate with increased psychosis risk, depend on glutamate and dopamine receptor signaling, and could serve as translational biomarkers in interventions for groups at high psychosis risk. METHODS: Startle magnitude, latency, and prepulse inhibition were assessed with a standard acoustic startle paradigm in 31 individuals with 22q11.2DS and 32 healthy comparison (HC) subjects. Surface electrodes placed on participants' orbicularis oculi recorded the electromyographic signal in ASR eyeblinks. Individuals without measurable startle blinks in the initial habituation block were classified as non-startlers. RESULTS: Across the startle session, the ASR magnitude was significantly lower in 22q11DS subjects than HCs because a significantly higher proportion of 22q11DS subjects were non-startlers. Latency of the ASR to pulse-alone stimuli was significantly slower in 22q11DS than HC subjects. Due to the overall lower 22q11DS startle response frequency and magnitudes prepulse inhibition could not be analyzed. CONCLUSIONS: Reduced magnitude and slow latency of 22q11DS subjects' responses suggest reduced central nervous system and neuronal responsiveness. These findings are consistent with significant cognitive impairments observed in 22q11DS subjects. Further research is needed to untangle the connections among basic neurotransmission dysfunction, psychophysiological responsiveness, and cognitive impairment.

Psychosis spectrum symptoms among individuals with schizophrenia-associated copy number variants and evidence of cerebellar correlates of symptom severity.

The 3q29 deletion (3q29Del) is a copy number variant (CNV) with one of the highest effect sizes for psychosis-risk (>40-fold). Systematic research offers avenues for elucidating mechanism; however, compared to CNVs like 22q11.2Del, 3q29Del remains understudied. Emerging findings indicate that posterior fossa abnormalities are common among carriers, but their clinical relevance is unclear. We report the first in-depth evaluation of psychotic symptoms in participants with 3q29Del (N=23), using the Structured Interview for Psychosis-Risk Syndromes, and compare this profile to 22q11.2Del (N=31) and healthy controls (N=279). We also explore correlations between psychotic symptoms and posterior fossa abnormalities. Cumulatively, 48% of the 3q29Del sample exhibited a psychotic disorder or attenuated positive symptoms, with a subset meeting criteria for clinical high-risk. 3q29Del had more severe ratings than controls on all domains and only exhibited less severe ratings than 22q11.2Del in negative symptoms; ratings demonstrated select sex differences but no domain-wise correlations with IQ. An inverse relationship was identified between positive symptoms and cerebellar cortex volume in 3q29Del, documenting the first clinically-relevant neuroanatomical connection in this syndrome. Our findings characterize the profile of psychotic symptoms in the largest 3q29Del sample reported to date, contrast with another high-impact CNV, and highlight cerebellar involvement in psychosis-risk.

Alcohol and alcohol-related harm in China: policy changes needed.

In China, alcohol consumption is increasing faster than anywhere else in the world. A steady increase in alcohol production has also been observed in the country, together with a rise in alcohol-related harm. Despite these trends, China's policies on the sale and consumption of alcoholic beverages are weak compared with those of other countries in Asia. Weakest of all are its policies on taxation, drink driving laws, alcohol sale to minors and marketing licenses. The authors of this descriptive paper draw attention to the urgent need for public health professionals and government officials in China to prioritize population surveillance, research and interventions designed to reduce alcohol use disorders. They describe China's current alcohol policies and recent trends in alcohol-related harm and highlight the need for health officials to conduct a thorough policy review from a public health perspective, using as a model the World Health Organization's global strategy to reduce the harmful use of alcohol.

En Chine, la consommation d'alcool augmente plus rapidement que partout ailleurs dans le monde. Une augmentation constante de la production d'alcool a également observée dans le pays, ainsi qu'une augmentation des méfaits de l'alcool. Malgré ces tendances, les politiques de la Chine en matière de vente et de consommation de boissons alcoolisées sont faibles comparées à celles des autres pays d'Asie. Les plus faibles de toutes sont ses politiques sur la taxation, les lois relatives à l'alcool au volant, la vente d'alcool aux mineurs et la commercialisation des licences. Les auteurs de cet article descriptif attirent l'attention sur la nécessité urgente pour les professionnels de la santé publique et les fonctionnaires gouvernementaux chinois d'accorder la priorité à la surveillance de la population, la recherche et les interventions destinées à réduire les troubles liés à la consommation d'alcool. Ils décrivent les politiques actuelles sur l'alcool en Chine et les tendances récentes des méfaits de l'alcoolisme. Ils soulignent également la nécessité pour les autorités sanitaires de procéder à un examen approfondi de la politique dans une perspective de santé publique, en prenant comme modèle la stratégie globale de l'Organisation mondiale de la Santé afin de réduire l'usage nocif de l'alcool.

En China, el consumo de alcohol está aumentando con mayor rapidez que en cualquier otro lugar del mundo, y también se ha observado un crecimiento constante de la producción de alcohol en el país, junto con un aumento de los daños relacionados con esta sustancia. A pesar de estas tendencias, las políticas chinas sobre la venta y consumo de bebidas alcohólicas son débiles en comparación con las de otros países asiáticos. Las políticas más débiles son las que regulan los impuestos, las leyes de consumo y conducción, la venta de alcohol a menores de edad y las licencias para la venta de alcohol. Los autores de este artículo descriptivo llaman la atención sobre la necesidad urgente de que los funcionarios gubernamentales y los profesionales de la sanidad pública chinos den prioridad a la vigilancia de la población, a la investigación y a las intervenciones diseñadas para reducir los trastornos provocados por el consumo de alcohol. Describen las políticas actuales chinas relativas al alcohol, así como las tendencias presentes de los daños relacionados con el alcohol y destacan la necesidad de que los funcionarios de salud lleven a cabo una revisión de toda la política desde la perspectiva de la sanidad pública, usando como modelo la estrategia global de la Organización Mundial de la Salud para reducir el uso nocivo de alcohol.

The gut microbiome: a new frontier in autism research.

The human gut harbors a complex community of microbes that profoundly influence many aspects of growth and development, including development of the nervous system. Advances in high-throughput DNA sequencing methods have led to rapidly expanding knowledge about this gut microbiome. Here, we review fundamental emerging data on the human gut microbiome, with a focus on potential interactions between the microbiome and autism spectrum disorders (ASD) and consider research on atypical patterns of feeding and nutrition in ASD and how they might interact with the microbiome. Finally we selectively survey results from studies in rodents on the impact of the microbiome on neurobehavioral development. The evidence reviewed here suggests that a deeper understanding of the gut microbiome could open up new avenues of research on ASD, including potential novel treatment strategies.

Sex dependent influence of a functional polymorphism in steroid 5-α-reductase type 2 (SRD5A2) on post-traumatic stress symptoms.

A non-synonymous, single nucleotide polymorphism (SNP) in the gene coding for steroid 5-α-reductase type 2 (SRD5A2) is associated with reduced conversion of testosterone to dihydrotestosterone (DHT). Because SRD5A2 participates in the regulation of testosterone and cortisol metabolism, hormones shown to be dysregulated in patients with PTSD, we examined whether the V89L variant (rs523349) influences risk for post-traumatic stress disorder (PTSD). Study participants (N = 1,443) were traumatized African-American patients of low socioeconomic status with high rates of lifetime trauma exposure recruited from the primary care clinics of a large, urban hospital. PTSD symptoms were measured with the post-traumatic stress symptom scale (PSS). Subjects were genotyped for the V89L variant (rs523349) of SRD5A2. We initially found a significant sex-dependent effect of genotype in male but not female subjects on symptoms. Associations with PTSD symptoms were confirmed using a separate internal replication sample with identical methods of data analysis, followed by pooled analysis of the combined samples (N = 1,443, sex × genotype interaction P < 0.002; males: n = 536, P < 0.001). These data support the hypothesis that functional variation within SRD5A2 influences, in a sex-specific way, the severity of post-traumatic stress symptoms and risk for diagnosis of PTSD.

Adaptive behavior deficits in individuals with 3q29 deletion syndrome.

Background: 3q29 deletion syndrome (3q29del) is associated with a significantly increased risk for neurodevelopmental and neuropsychiatric phenotypes. Mild to moderate intellectual disability (ID) is common in this population, and previous work by our team identified substantial deficits in adaptive behavior. However, the full profile of adaptive function in 3q29del has not been described, nor has it been compared to other genomic syndromes associated with elevated risk for neurodevelopmental and neuropsychiatric phenotypes. Methods: Individuals with 3q29del (n=32, 62.5% male) were evaluated using the Vineland Adaptive Behavior Scales, Third Edition, Comprehensive Parent/Caregiver Form (Vineland-3). We explored the relationship between adaptive behavior and cognitive function, executive function, and neurodevelopmental and neuropsychiatric comorbidities in our 3q29del study sample, and we compared subjects with 3q29del to published data on Fragile X syndrome, 22q11.2 deletion syndrome, and 16p11.2 deletion and duplication syndromes. Results: Individuals with 3q29del had global deficits in adaptive behavior that were not driven by specific weaknesses in any given domain. Individual neurodevelopmental and neuropsychiatric diagnoses had a small effect on adaptive behavior, and the cumulative number of comorbid diagnoses was significantly negatively associated with Vineland-3 performance. Both cognitive ability and executive function were significantly associated with adaptive behavior, and executive function was a better predictor of Vineland-3 performance than cognitive ability. Finally, the severity of adaptive behavior deficits in 3q29del was distinct from previously published data on comparable genomic disorders. Conclusions: Individuals with 3q29del have significant deficits in adaptive behavior, affecting all domains assessed by the Vineland-3. Executive function is a better predictor of adaptive behavior than cognitive ability in this population and suggests that interventions targeting executive function may be an effective therapeutic strategy.

Visual-Motor Integration Deficits in 3q29 Deletion Syndrome.

3q29 deletion syndrome (3q29del) is associated with neuropsychiatric and neurodevelopmental phenotypes. We previously reported that graphomotor weakness is present in up to 78% of individuals with 3q29del. We have now explored nuances of the graphomotor phenotype and its association with other comorbidities in this population. Participants were recruited from the online 3q29 registry (3q29deletion.org) for two days of deep phenotyping. 32 individuals with 3q29del (62.5% male) were evaluated with the Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI) to assess visual-motor integration. Participants were also evaluated with measures of cognitive ability, executive function, adaptive behavior, and school function. Males with 3q29del performed significantly worse than females on the VMI and Motor Coordination subtest. VMI performance was significantly associated with ADHD diagnosis and cognitive ability. Compared to published data from individuals with 22q11.2 deletion syndrome, individuals with 3q29del showed significantly more impairment. The 3q29 deletion is associated with substantial deficits in visual-motor integration, Visual Perception, and Motor Coordination. Our data suggests that 3q29del may qualify as a nonverbal learning disability. Future studies should assess whether individuals with 3q29del would benefit from early interventions, including occupational therapy.

Depression and anxiety symptoms among women who carry the FMR1 premutation: impact of raising a child with fragile X syndrome is moderated by CRHR1 polymorphisms.

The fragile X mental retardation gene, FMR1, contains a polymorphic CGG repeat in the 5'-untranslated region of exon 1. Once unstable, this repeat is capable of expansion across generations. Women who carry a premutation allele (55-199 repeats) are at risk of passing on a full mutation allele (>200 repeats) to their offspring. A full mutation leads to the most common form of inherited intellectual disability, fragile X syndrome (FXS). Mounting evidence suggests that premutation carriers may be vulnerable to symptoms of anxiety and depression. The goal of this study was to test the hypothesis that among women who carry a premutation, the stress of raising a child with FXS would be moderated by genetic factors influencing endogenous cortisol responses, which could in turn modulate anxiety and depression symptoms. To this end, we genotyped single nucleotide polymorphisms (SNPs) at the corticotrophin releasing hormone receptor 1 locus (CRHR1) in 460 women. Participants completed self-report questionnaires assessing symptoms of depression [Centers for Epidemiological Studies Depression Scale (CESD)], anxiety [State-Trait Anxiety Inventory (STAI) and Social Phobia and Anxiety Inventory (SPAI)], and mood [Positive and Negative Affect Schedule (PANAS)]. Results indicate a statistically significant interaction between CRHR1 genotype and the status of raising a child with FXS to predict social anxiety symptoms reported on the SPAI (rs7209436, P = 0.0001). Our data suggest that genetic variants in CRHR1 that associate with differential cortisol activation may also modulate levels of anxiety related to the stress of raising a child with FXS among women who carry an FMR1 premutation.

Autism spectrum disorder symptom expression in individuals with 3q29 deletion syndrome.

BACKGROUND: The 1.6 Mb 3q29 deletion is associated with neurodevelopmental and neuropsychiatric phenotypes, including a 19-fold increased risk for autism spectrum disorder (ASD). Previous work by our team identified elevated social disability in this population via parent-report questionnaires. However, clinical features of ASD in this population have not been explored in detail. METHODS: Thirty-one individuals with 3q29 deletion syndrome (3q29del, 61.3% male) were evaluated using two gold-standard clinical ASD evaluations: the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), and the Autism Diagnostic Interview, Revised (ADI-R). Four matched comparators for each subject were ascertained from the National Database for Autism Research. Item-level scores on the ADOS-2 and ADI-R were compared between subjects with 3q29del and matched comparators. RESULTS: Subjects with 3q29del and no ASD (3q29del-ASD) had greater evidence of social disability compared to typically developing (TD) comparison subjects across the ADOS-2. Subjects with 3q29del and ASD (3q29del + ASD) were largely indistinguishable from non-syndromic ASD (nsASD) subjects on the ADOS-2. 3q29del + ASD performed significantly better on social communication on the ADI-R than nsASD (3q29 + ASD mean = 11.36; nsASD mean = 15.70; p = 0.01), and this was driven by reduced deficits in nonverbal communication (3q29 + ASD mean = 1.73; nsASD mean = 3.63; p = 0.03). 3q29del + ASD reported significantly later age at the first two-word phrase compared to nsASD (3q29del + ASD mean = 43.89 months; nsASD mean = 37.86 months; p = 0.01). However, speech delay was not related to improved nonverbal communication in 3q29del + ASD. LIMITATIONS: There were not enough TD comparators with ADI-R data in NDAR to include in the present analysis. Additionally, our relatively small sample size made it difficult to assess race and ethnicity effects. CONCLUSIONS: 3q29del is associated with significant social disability, irrespective of ASD diagnosis. 3q29del + ASD have similar levels of social disability to nsASD, while 3q29del-ASD have significantly increased social disability compared to TD individuals. However, social communication is reasonably well preserved in 3q29del + ASD relative to nsASD. It is critical that verbal ability and social disability be examined separately in this population to ensure equal access to ASD and social skills evaluations and services.

A normative chart for cognitive development in a genetically selected population.

Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQ-scores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p < 0.01). Our findings suggest that using variant-specific normative IQ data significantly reduces required sample size in a research context, and may facilitate a more clinically informative interpretation of IQ data. This approach allows identification of individuals that deviate from their expected, variant-specific, trajectory. This group may be at increased risk for comorbid conditions, such as schizophrenia in the case of 22q11DS.

Linkage analysis of plasma dopamine ß-hydroxylase activity in families of patients with schizophrenia.

Dopamine ß-hydroxylase (DßH) catalyzes the conversion of dopamine to norepinephrine. DßH enters the plasma after vesicular release from sympathetic neurons and the adrenal medulla. Plasma DßH activity (pDßH) varies widely among individuals, and genetic inheritance regulates that variation. Linkage studies suggested strong linkage of pDßH to ABO on 9q34, and positive evidence for linkage to the complement fixation locus on 19p13.2-13.3. Subsequent association studies strongly supported DBH, which maps adjacent to ABO, as the locus regulating a large proportion of the heritable variation in pDßH. Prior studies have suggested that variation in pDßH, or genetic variants at DßH, associate with differences in expression of psychotic symptoms in patients with schizophrenia and other idiopathic or drug-induced brain disorders, suggesting that DBH might be a genetic modifier of psychotic symptoms. As a first step toward investigating that hypothesis, we performed linkage analysis on pDßH in patients with schizophrenia and their relatives. The results strongly confirm linkage of markers at DBH to pDßH under several models (maximum multipoint LOD score, 6.33), but find no evidence to support linkage anywhere on chromosome 19. Accounting for the contributions to the linkage signal of three SNPs at DBH, rs1611115, rs1611122, and rs6271 reduced but did not eliminate the linkage peak, whereas accounting for all SNPs near DBH eliminated the signal entirely. Analysis of markers genome-wide uncovered positive evidence for linkage between markers at chromosome 20p12 (multi-point LOD = 3.1 at 27.2 cM). The present results provide the first direct evidence for linkage between DBH and pDßH, suggest that rs1611115, rs1611122, rs6271 and additional unidentified variants at or near DBH contribute to the genetic regulation of pDßH, and suggest that a locus near 20p12 also influences pDßH.

Predictors of neonatal hypothalamic-pituitary-adrenal axis activity at delivery.

OBJECTIVE: Clinical and preclinical studies indicate that maternal stress during pregnancy may exert long-lasting adverse effects on offspring. This investigation sought to identify factors mediating the relationship between maternal and neonatal hypothalamic-pituitary-adrenal (HPA) axes in pregnant women with past or family psychiatric history. PATIENTS: Two hundred and five pairs of maternal and umbilical cord blood samples from a clinical population were collected at delivery. MEASUREMENTS: Maternal and neonatal HPA axis activity measures were plasma adrenocorticotrophic hormone (ACTH), total cortisol, free cortisol and cortisol-binding globulin concentrations. The effects of maternal race, age, body mass index, psychiatric diagnosis (DSM-IV), birth weight, delivery method and estimated gestational age (EGA) at delivery on both maternal and neonatal HPA axis measures were also examined. Incorporating these independent predictors as covariates where necessary, we evaluated whether neonatal HPA axis activity measures could be predicted by the same maternal measure using linear regression. RESULTS: Delivery method was associated with umbilical cord plasma ACTH and both total and free cord cortisol concentrations (T = 10·53-4·21; P < 0·0001-0·010). After accounting for method of delivery and EGA, we found that maternal plasma ACTH concentrations predicted 23·9% of the variance in foetal plasma ACTH concentrations (T = 6·76; P < 0·0001), and maternal free and total plasma cortisol concentrations predicted 39·8% and 32·3% of the variance in foetal plasma free and total cortisol concentrations (T = 5·37-6·90; P < 0·0001), respectively. CONCLUSION: These data suggest that neonatal response is coupled with maternal HPA axis activity at delivery. Future investigations will scrutinize the potential long-term sequelae for the offspring.