Autism Spectrum Disorder and Early Psychosis: a narrative review from a neurodevelopmental perspective.

Autism Spectrum Disorder (ASD), characterized by socio-communicative abnormalities and restricted, repetitive, and stereotyped behaviors, is part of Neurodevelopmental Disorders (NDDs), a diagnostic category distinctly in accordance with the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, (DSM-5), clearly separated from Schizophrenia Spectrum Disorder (SSD) (schizophrenia, schizophreniform disorder, schizoaffective disorder, schizotypal personality disorder). Over the last four decades, this clear distinction is gradually being replaced, describing ASD and SSD as two heterogeneous conditions but with neurodevelopmental origins and overlaps. Referring to the proposal of a neurodevelopmental continuum model, the current research's aim is to provide an update of the knowledge to date on the course of clinical symptoms and their overlaps among ASD and SSD. A narrative review of the literature published between January 2010 and June 2023 was conducted. Five studies were included. All studies show a global impairment in both conditions. Two studies show a focus on neurodevelopmental perspective in ASD and SSD. Only one study of these adopts a longitudinal prospective in terms of prognostic markers among ASD and SSD. Three studies underline the overlap between ASD and SSD in terms of negative, disorganized and positive symptomatology. To date, there is a gap in the current scientific literature focused on ASD-SSD course of clinical symptoms and their overlaps from a neurodevelopmental perspective. Future longitudinal studies to identify risk markers and tailored treatments are needed.

Effects of online tDCS and hf-tRNS on reading performance in children and adolescents with developmental dyslexia: a study protocol for a cross sectional, within-subject, randomized, double-blind, and sham-controlled trial.

Background: Developmental Dyslexia (DD) is a brain-based developmental disorder causing severe reading difficulties. The extensive data on the neurobiology of DD have increased interest in brain-directed approaches, such as transcranial direct current stimulation (tDCS), which have been proposed for DD. While positive outcomes have been observed, results remain heterogeneous. Various methodological approaches have been employed to address this issue. However, no studies have compared the effects of different transcranial electrical stimulation techniques (e.g., tDCS and transcranial random noise stimulation, tRNS), on reading in children and adolescents with DD. Methods: The present within-subject, double-blind, and sham-controlled trial aims to investigate the effects of tDCS and hf-tRNS on reading in children and adolescents with DD. Participants will undergo three conditions with a one-week interval session: (A) single active tDCS session; (B) single active hf-tRNS session; and (C) single sham session (tDCS/hf-tRNS). Left anodal/right cathodal tDCS and bilateral tRNS will be applied over the temporo-parietal regions for 20 min each. Reading measures will be collected before and during each session. Safety and blinding parameters will be recordered. Discussion: We hypothesize that tRNS will demonstrate comparable effectiveness to tDCS in improving reading compared to sham conditions. Additionally, we anticipate that hf-tRNS will exhibit a similar safety profile to tDCS. This study will contribute novel insights into the effectiveness of hf-tRNS, expediting the validation of brain-based treatments for DD.

Transcranial Direct Current Stimulation in neurogenetic syndromes: new treatment perspectives for Down syndrome?

This perspective review aims to explore the potential neurobiological mechanisms involved in the application of transcranial Direct Current Stimulation (tDCS) for Down syndrome (DS), the leading cause of genetically-based intellectual disability. The neural mechanisms underlying tDCS interventions in genetic disorders, typically characterized by cognitive deficits, are grounded in the concept of brain plasticity. We initially present the neurobiological and functional effects elicited by tDCS applications in enhancing neuroplasticity and in regulating the excitatory/inhibitory balance, both associated with cognitive improvement in the general population. The review begins with evidence on tDCS applications in five neurogenetic disorders, including Rett, Prader-Willi, Phelan-McDermid, and Neurofibromatosis 1 syndromes, as well as DS. Available evidence supports tDCS as a potential intervention tool and underscores the importance of advancing neurobiological research into the mechanisms of tDCS action in these conditions. We then discuss the potential of tDCS as a promising non-invasive strategy to mitigate deficits in plasticity and promote fine-tuning of the excitatory/inhibitory balance in DS, exploring implications for cognitive treatment perspectives in this population.

Association between child behavioural problems and parenting stress in autism spectrum disorders: the role of parenting self-efficacy.

Introduction: The present study build on previous research that found a bidirectional relation of parenting stress and negative behavioural outcomes in children with Autism Spectrum Disorders. Aim: To investigate the mediating role of parenting self-efficacy in the relationship of parenting stress and children's behavioural and emotional problems. Materials and methods: The sample included 32 young children and their families. Sociodemographic and clinical data were collected. Hierarchical regression analysis revealed direct and indirect mediating effects. Results: Parenting self-efficacy mediated the relationship between parenting stress and children's behavioural and emotional problems in fathers only. Conclusions: We discuss potential ways targeted parenting self-efficacy intervention can support fathers. Results contribute to gain father-informed knowledge in, a research branch generally focused on mothers.

What Factors Predict Adaptive Functioning in Preschool Children with Autism Spectrum Disorder? A Longitudinal Study.

Adaptive functioning constitutes a fundamental aspect of the phenotype associated with autism spectrum disorder (ASD) in preschool-aged children, exerting a significant influence on both the child and the family's overall quality of life. The aim of this study was to investigate the predictors of the adaptive functioning domains in preschool-age children with ASD at two time points, providing a snapshot of this fundamental developmental step. Methods: Ninety-five children with ASD (M = 3.89, SD = 1.13) were included in the study and longitudinal data (the mean length of the longitudinal data collection was 1 year) on ASD features such as social communication and social interaction, repetitive and restricted behavior, cognitive level, and adaptive functioning were collected. We considered autistic features, cognitive level, and sociodemographic factors as possible predictors of the different adaptive functioning domains one year later. Results: Data obtained showed a worsening of the ASD features and adaptive functioning after one year. Furthermore, the severity of repetitive and restricted behavior predicted adaptive functioning, especially in the social and practical domains of the child, one year later. This prediction was observed alongside the child's cognitive level. Conclusions: The study identifies some potential predictive factors of specific adaptive functioning domains in preschoolers with ASD. Considering how critical adaptive functioning is for the well-being of both the child and their family, it becomes imperative to design early-stage interventions focused on nurturing adaptive skills in children with ASD.

Corrigendum: PTCHD1 gene mutation/deletion: the cognitive-behavioral phenotyping of four case reports.

[This corrects the article DOI: 10.3389/fpsyt.2023.1327802.].

Evolution of neuropsychological and behavioral profile in a cohort of pediatric patients with Becker muscular dystrophy in a longitudinal study.

It has long been reported that neuropsychological deficits may be present in dystrophinopathies, specifically non-progressive cognitive impairment and a global deficit in executive functions; this neurocognitive profile has been less explored in patients with Becker than Duchenne muscular dystrophy (BMD/DMD). We conducted a longitudinal study to explore the evolution of neuropsychological and behavioural profile in a cohort of paediatric BMD. Seventeen patients with BMD without intellectual disability were assessed using a full battery of tests, including intellectual, adaptive and executive functioning, language and behavioral features. Tests were performed at baseline and after 12 months. The results showed adequate cognitive and adaptive profile with falls in Working Memory, as well as lower scores in executive functions. An improvement was observed in Processing Speed. Behavioral questionnaires confirmed a negative trend, while in normal ranges. We found a statistically significant difference between T0 and T1 in some items exploring executive functions. No statistically significant difference was observed stratifying patients by mutation site or IQ level. In conclusion, our study suggests that BMD patients have a stable neurocognitive profile, while a deflection in the executive functions may be observed. We recommend a careful monitoring to intercept learning disabilities and promptly start a multimodal rehabilitation.

Childhood Clinical Features Preceding the Onset of Bipolar Versus Major Depressive Disorders During Adolescence.

OBJECTIVE: To identify childhood psychopathological features that predict the onset of adolescent Bipolar (BD) versus Unipolar Major Depressive Disorder (UD) during adolescence. METHOD: We analyzed clinical data from 495 juveniles diagnosed with DSM-5 UD (n = 359), and BD (n = 136), using bivariate analysis and multivariate logistic regression model. RESULTS: BD subjects exhibited earlier onset of any psychiatric feature compared to UD. Antecedents associated with later BD were: oppositional defiant > specific phobias > ADHD > obsessive compulsive (OCD). Antecedents selectively associated with later UD were: social anxiety and separation anxiety. Factors significantly and independently associated with later BD diagnosis were: [a] emotional dysregulation at onset of the mood disorder; [b] first depressive episode with mixed features; [c] antecedent ADHD; [d] antecedent OCD, and [e] antecedent oppositional-defiance. CONCLUSION: Identifying developmental differences in BD and UD symptoms can aid clinicians in early identification and treatment planning for bipolar disorder in youth.

Pediatric acute hospitalization for anorexia nervosa: an economic evaluation.

BACKGROUND: Anorexia nervosa (AN) is a psychiatric disorders which may potentially led to a high risk of health medical complications, suicide and self-harming behaviour. Since Covid-19 pandemic onset in March 2020, evidence suggested an increase occurrence of AN. The main aim of the retrospective analysis is to define the cost of hospitalization in the acute phase (HAP) at IRCCS Bambino Gesù Children Hospital, Rome, Italy, over 2 years study. Secondary purposes are defining the main risk factors for a prolonged hospitalization (including age, sex and comorbidities) and the possible influence of Covid-19 pandemic on AN admission and hospital stay. METHODS: for the purpose of the study, we included children and adolescents aged less than 18 years, admitted to IRCCS Bambino Gesù Children Hospital, Rome, Italy, with a diagnosis of AN. Medical costs were calculated consulting the Lazio Regional Health Service Tariffs. Basing on the date of hospital admission, patients were later divided into two subgroups: subgroup A included patients hospitalized prior than Covid-19 onset (from March 2019 to February 2020) and subgroup B those admitted after (from March 2020 to October 2022). RESULTS: a total of 260 patients has been included in the study with a median age of 15 years (range 6-18 years). The total health care cost of AN hospitalized patients was of EUR 3,352,333 with a median cost of EUR 11,124 for each admission (range EUR 930 - 45,739) and a median daily cost of EUR 593 (range EUR 557-930). Median cost was higher in case of comorbidities, guarded patients, enteral feeding. A prolonged hospitalization has been documented in subgroup A with a higher economic burden. CONCLUSIONS: the economic burden of eating disorders is of note. Adequate sanitary policies as well as health economic analyses are required to gain insight into the cost-effectiveness of AN management. TRIAL REGISTRATION: 2526-OPBG-2021.

Neurocognitive and adaptive phenotypes in adolescent inpatients with mood disorders: an exploratory study on disruptive mood dysregulation disorder in the framework of depressive disorders.

Introduction: Few studies on adolescents have investigated intelligence quotient (IQ) in mood disorders. Evidence on Disruptive Mood Dysregulation Disorder (DMDD), a controversial entity among depressive disorders, is more limited. Materials and methods: We performed an exploratory study on adolescent inpatients with unipolar mood disorders to test specific impairment in cognitive and adaptive profile. We also considered common psychopathological comorbidities. We retrospectively collected data on inpatients with a diagnosis of major depressive disorder (MDD), DMDD or Depressive Disorder - Not Otherwise Specified (DD-NOS) evaluated with Wechsler Scales of Intelligence, Adaptive Behavior Assessment System (ABAS-II), and Children's Global Assessment Scale (C-GAS). Results: Out of 198 inpatients (85.9% females), 33.3% had MDD, 60.1% DD-NOS and 6.6% DMDD. DMDD patients had higher rates of ADHD (15.4%) and learning disorders (LD, 23.1%), a lower mean IQ (87.8 ± 10.7; p = 0.001) and ABAS-II scores (general composite 68.8 ± 16.8; p = 0.002) than other groups. In linear regression analysis, DMDD retained a significant correlation with lower IQ and adaptive abilities when controlling for sex, and comorbidities. Among comorbidities, LD correlated with lower perceptual reasoning and IQ, and ADHD with lower conceptual adaptive abilities. In all diagnosis groups, working memory and processing speed were lower than verbal comprehension and perceptual reasoning. Discussion: While impairment in working memory and processing speed is a non-specific correlate of active mood disorder, DMDD is burdened by lower general intelligence and adaptive abilities and higher rate of neurodevelopmental comorbidities. Lower IQ in the normal range is a correlate of DMDD among variables examined, not explained by the effect of neurodevelopmental comorbidities. These findings are discussed with regards to possible implications for the consideration of DMDD as a bridge condition between neurodevelopmental disorders and mood disorders.

Vertebral Fractures in Pediatric Suicidal Jumpers: A Retrospective Study with Epidemiological and Clinical Analysis before and after the COVID-19 Pandemic.

BACKGROUND: From the beginning of the COVID-19 pandemic, reports in the literature confirm a significant increase in suicide attempts in children and adolescents. At the Bambino Gesù Pediatric Hospital Emergency Department (Rome, Italy), there was a dramatic increase in suicidal jumpers. Many of these presented vertebral fractures. METHODS: This retrospective study includes all suicidal jumpers with vertebral fractures treated from April 2017 to March 2023. We collected and compared data from three years before to three years after the pandemic, analyzing vertebral fractures. RESULTS: From April 2019 to March 2020, 141 cases of suicide attempt arrived at the emergency department. Five of these were suicidal jumpers without vertebral fractures. From April 2020 to March 2023, 362 cases of suicide were hospitalized and 19 were suicidal jumpers; 12 reported vertebral fractures (mean age 14 years). Seven patients were treated by percutaneous pedicle fixation. Three patients needed an open spinal surgery by posterior approach. One case with cervical fractures was treated by Halo-Vest. CONCLUSIONS: This is the first report that shows a sharp increase in vertebral body fractures due to suicide jumping attempts in children and adolescents. This could be a new epidemiological phenomenon persisting or even increasing over time in the pediatric population as a consequence of the COVID-19 pandemic.

Psychiatric Hospitalization for Psychopathological Disorders and Self-Injurious Behaviors in Italian Children and Adolescents during COVID-19.

The evidence shows that the COVID-19 pandemic dramatically increased the number of urgent psychiatric consultations for children and adolescents in hospital emergency departments (EDs). However, what needs to be further investigated are the characteristics of psychiatric hospitalization in children and adolescents admitted to the Child and Adolescent Neuropsychiatry Unit wards in EDs. Specifically, this retrospective study aimed to examine changes in (i) the number of inpatients and (ii) the distribution of psychopathological disorders and self-injurious behaviors in our Child and Adolescent Neuropsychiatry Unit ward during the COVID-19 lockdown in Italy (March-June 2020; October 2020-January 2021) compared with the same months of previous years. We found a significantly lower number of inpatients during the first four quarantine months than the first four reference months and a higher number of inpatients during the second four quarantine months than the second four reference months. Additionally, we found an increased frequency of mood disorders, non-suicidal self-injurious behavior, and suicidal ideation during the COVID-19 lockdown compared to the reference periods. Our findings underline the need to develop psychological healthcare services for future emergency periods in order to identify and treat psychological distress in children and adolescents early, reducing the risk of psychiatric hospitalization.

Clinical features and comorbidity in very early-onset schizophrenia: a systematic review.

Background: Very early-onset schizophrenia (VEOS) is a form of schizophrenia that manifests before the age of 13 years and is characterized by the presence of positive, negative, and disorganized symptoms. The condition is exceptionally rare and, to date, limited studies have been conducted, resulting in incomplete information about its clinical features. Methods: The present study involves a systematic review of the existing literature regarding the clinical features and comorbidities of VEOS. Results: The first search retrieved 384 studies. Of these, 366 were removed following the application of exclusion criteria, resulting in 18 studies for the final set. Conclusion: The results highlight that VEOS shares similarities with early-onset and adult-onset schizophrenia but also exhibits distinct and recognizable characteristics, including a more severe clinical profile (particularly in females), increased visual hallucinations, and high comorbidities with neurodevelopmental disorders. These findings may support clinicians in formulating early diagnoses and developing effective treatment strategies for pediatric and adolescent patients with psychosis.

Psychiatric Disorders in Children and Adolescents: Clinical Issue and Strategies for Intervention.

Mental health plays a crucial role in an individual's overall well-being, and it is widely recognized that many adult mental health disorders originate during childhood and adolescence. It is imperative to promptly recognize signs of psychological distress and clinically significant symptoms that can affect an individual's functioning from an early age. The growing prevalence of psychiatric disorders in children and adolescents indeed highlights the significance of identifying both risk and protective factors. Finally, a personalized and integrated treatment approach is essential to prevent the chronicity and pervasiveness of symptoms.

The efficacy of non-invasive brain stimulation in the treatment of children and adolescents with Anorexia Nervosa: study protocol of a randomized, double blind, placebo-controlled trial.

BACKGROUND: Current psychological and pharmacological treatments for Anorexia Nervosa (AN) provide only moderate effective support, and there is an urgent need for research to improve therapies, especially in developing age. Non-invasive brain stimulation has suggested to have the potential to reducing AN symptomatology, via targeting brain alterations, such as hyperactivity of right prefrontal cortex (PFC). We suppose that transcranial direct current stimulation (tDCS) to the PFC may be effective in children and adolescents with AN. METHODS: We will conduct a randomized, double blind, add-on, placebo-controlled trial to investigate the efficacy of tDCS treatment on clinical improvement. We will also investigate brain mechanisms and biomarkers changes acting in AN after tDCS treatment. Eighty children or adolescent with AN (age range 10-18 years) will undergo treatment-as-usual including psychiatric, nutritional and psychological support, plus tDCS treatment (active or sham) to PFC (F3 anode/F4 cathode), for six weeks, delivered three times a week. Psychological, neurophysiological and physiological measures will be collected at baseline and at the end of treatment. Participants will be followed-up one, three, six months and one year after the end of treatment. Psychological measures will include parent- and self-report questionnaires on AN symptomatology and other psychopathological symptoms. Neurophysiological measures will include transcranial magnetic stimulation (TMS) with electroencephalography and paired pulse TMS and repetitive TMS to investigate changes in PFC connectivity, reactivity and plasticity after treatment. Physiological measures will include changes in the functioning of the endogenous stress response system, body mass index (BMI) and nutritional state. DISCUSSION: We expect that tDCS treatment to improve clinical outcome by reducing the symptoms of AN assessed as changes in Eating Disorder Risk composite score of the Eating Disorder Inventory-3. We also expect that at baseline there will be differences between the right and left hemisphere in some electrophysiological measures and that such differences will be reduced after tDCS treatment. Finally, we expect a reduction of endogenous stress response and an improvement in BMI and nutritional status after tDCS treatment. This project would provide scientific foundation for new treatment perspectives in AN in developmental age, as well as insight into brain mechanisms acting in AN and its recovery. Trial registration The study was registered at ClinicalTrials.gov (ID: NCT05674266) and ethical approval for the study was granted by the local research ethics committee (process number 763_OPBG_2014).

Autism spectrum disorder, very-early onset schizophrenia, and child disintegrative disorder: the challenge of diagnosis. A case-report study.

Background: Autism spectrum disorder (ASD) in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) contains several disorders previously present as distinct diagnoses in the DSM Revised Fourth Edition (DSM-IV-TR). These include child disintegrative disorder (CDD). The latter presents typical features, such as a late regression of developmental acquisitions. However, it also shows symptoms similar to ASD, and psychotic symptoms, such as very-early onset schizophrenia (VEOS), are described in the literature. Case report: In this case report we deepen the case of P., a child who presents a late regression, at 7 years old, associated with psychotic symptoms in the absence of organic alterations. The child was treated with antipsychotic drug therapy and cognitive behavioral therapy. P. was diagnosed with ASD with acute and late regression associated with psychotic symptoms. During the follow-up, there was a gradual improvement in the clinical conditions. Improvements were possible due to therapeutic intervention (pharmacological and psychotherapeutic) and/or the natural course of the disorder. Conclusion: The diagnostic difficulty of this case reflects a clinical complexity in which it is not easy to distinguish between neurodevelopmental and psychiatric aspects. Clinical cases such as that of P. emphasize the theme of the neurodevelopment continuum model in which neurodevelopmental and psychiatric disturbances can be considered within a pattern of pathological continuity.

Early and stable difficulties of everyday executive functions predict autism symptoms and emotional/behavioral problems in preschool age children with autism: a 2-year longitudinal study.

Introduction: Longitudinal studies of autistic children show that autism symptoms and emotional/behavioral problems vary and change over time. However, the factors that affect this variability remain far from certain and very little is known about what take place in the preschool period and the role of executive functions (EF). Methods: Here, we test the influence of stable difficulties in everyday executive functioning (EEF) during early childhood across 2 years on autistic symptoms and emotional and behavioral problems. Twenty-nine autistic children (24 males and 5 females) were assessed twice within the space of 2 years. At baseline (M = 29 months, SD =5.6 months), participants were assessed for EEF, cognitive development, autistic symptoms, and emotional/behavioral problems. At follow-up, we repeated the same assessment except for cognitive development. Results: The group with stable difficulties (across 2 years) in EEF during early childhood showed a worsening in the severity of autistic symptoms and emotional and behavioral problems compared with children without EEF difficulties (p < 0.05), and these effects cannot be attributable to cognitive development. Discussion: Our results suggest that early and stable EEF plays the role of a modifier by interacting with the core domains of autism, in particular with the social affect domain (SA CSS), influencing social cognition and exacerbating or lessening symptom expression and emotional behavioral problems. These short-term longitudinal and preliminary findings underscore the importance of EEF as necessary target for early intervention in children with autism.

Urgent psychiatric consultations for suicide attempt and suicidal ideation before and after the COVID-19 pandemic in an Italian pediatric emergency setting.

Introduction: Suicidal attempts (SAs) in youth have been increasing during the last decades. Methods: We studied consultations, SA, and suicidal ideation (SI) in a pediatric emergency department (ED). Results: From 1 January 2011 to 31 May 2022, 606,159 patients accessed the ED, 8,397 of who had a child psychiatry consultation (CPC). CPCs increased significantly by 11 times in the last decade (155 in 2011 vs. 1,824 in 2021, p < 0.001); CPCs for SA increased significantly by 33 times, from 6 in 2011 to 200 in 2021 (3.9% of total CPC vs. 11%, p < 0.001). While total CPCs increased constantly during the entire period (annual percent change (APC) of 21.7 from 2011 to 2021 in a 0 joinpoint model), CPCs for SA increased significantly from 2011 to 2016, were approximately stable from 2016 to 2020, and then had a peak in 2021 after the COVID-19 pandemic (APC from 2011 to 2016 of 64.1, APC of 1.2 from 2016 to 2020, and APC of 230 after 2020 in a 2-joinpoint model). Discussion: Total CPCs in ED as well as evaluation for SA and SI increased significantly during the last decade. CPCs for SA had an additional increase after the COVID-19 pandemic. This picture warrants timely and efficient improvements in emergency settings and mental health resources.

Phenomenological Considerations of the World of the Obsessive Patient.

Despite significant scientific advances in research on obsessive-compulsive disorder (OCD), the psychological and behavioral symptoms of this pathological condition remain hard to understand, until they seem paradoxical. The present work seeks to consider the significance and potential contribution of a phenomenological reading of OCD and how phenomenalism has influenced some cognitive models of this disorder. Transcendental phenomenology is a philosophical approach that attaches primary importance to intuitive experience and considers all phenomena intrinsically associated with the subject's inner world. Thus, the subject's intuition is considered the starting point for understanding their essential experience. This approach has had a profound influence on modern cognitive sciences. Among current cognitive models, post-rationalist cognitivism and cognitive neuropsychological psychotherapy seem most effective in capturing the world experiences of OCD patients. Both apply a phenomenological approach to identify these experiences, which are typically characterized by hyper-reflexivity, at the expense of 'natural evidence.' The models have found that OCD patients experience the world emotionally as a sterile set of rules, and this experience determines their suffering.

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.