Clinical utility of the at-risk for psychosis state beyond transition: A multidimensional network analysis.

To be relevant to healthcare systems, the clinical high risk for psychosis (CHR-P) concept should denote a specific (i.e., unique) clinical population and provide useful information to guide the choice of intervention. The current study applied network analyses to examine the clinical specificities of CHR-P youths compared to general help-seekers and non-CHR-P youth. 146 CHR-P (mean age = 14.32 years) and 103 non-CHR-P (mean age = 12.58 years) help-seeking youth were recruited from a neuropsychiatric unit and assessed using the Structured Interview for Psychosis-Risk Syndromes, Children's Depression Inventory, Multidimensional Anxiety Scale for Children, Global Functioning: Social, Global Functioning: Role, and Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale. The first network structure comprised the entire help-seeking sample (i.e., help-seekers network), the second only CHR-P patients (i.e., CHR-P network), and the third only non-CHR-P patients (i.e., non-CHR-P network). In the help-seekers network, each variable presented at least one edge. In the CHR-P network, two isolated "archipelagos of symptoms" were identified: (a) a subgraph including functioning, anxiety, depressive, negative, disorganization, and general symptoms; and (b) a subgraph including positive symptoms and the intelligence quotient. In the non-CHR-P network, positive symptoms were negatively connected to functioning, disorganization, and negative symptoms. Positive symptoms were less connected in the CHR-P network, indicating a need for specific interventions alongside those treating comorbid disorders. The findings suggest specific clinical characteristics of CHR-P youth to guide the development of tailored interventions, thereby supporting the clinical utility of the CHR-P concept.

Hand Washing: When Ritual Behavior Protects! Covid-19 Experience in Children and Adolescents with (and without) Obsessive-Compulsive Disorder.

No abstract present.

Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.

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.

Developmental Psychopathology in the COVID-19 period. COVID-19 Pandemic Impact on Children and Adolescents' Mental Health.

Over the past year, the novel coronavirus (COVID-19) pandemic has forced many world countries, including Italy, to take strict restrictive measures as lockdown and social distancing. Children and adolescents exposed to the COVID-19 pandemic and social distancing would appear to be at greater risk of developing psychiatric disorders. In the last year, the Child and Adolescence Neuropsychiatry service at the Children's Hospital Bambino Gesù in Rome has recorded a significant increase in cases of mood disorders, self-injurious behaviors and suicidal ideation. These data underlined the need to define tailor-made intervention strategies for children and adolescents during this time of social and health emergency.

Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects.

The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p = .002), verbal IQ was decreased by 8.17 points (p = .0002) and performance IQ was decreased by 4.03 points (p = .028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.

Bridging the gap between different measures of the reading speed deficit in developmental dyslexia.

The study assessed how decoding and pronunciation times contribute to total reading time in reading aloud and how these measures change in the presence of developmental dyslexia. Vocal reaction times (RTs), pronunciation times, and total reading times were measured while 25 children with dyslexia and 43 age-matched typically developing readers read singly presented words and non-words that varied for length. Group differences were large for vocal RTs; children with dyslexia were increasingly slower as a function of condition difficulty (over-additivity effect); lexicality and length influenced RTs even when over-additivity was controlled for by z-score transformation. The group differences were also large for vocal total reading times, but the effect of over-additivity was smaller than that of vocal RTs and no selective influence of lexicality and length was detected. Pronunciation times showed very small individual differences and no over-additivity effect; children with dyslexia were more sensitive to the effect of lexicality and length than controls. To assess the contribution of the cognitive and sensory-motor compartments in determining group differences, we applied the difference engine model. As for RTs, the relationship between means and standard deviations closely supported the prediction of a general cognitive delay in the slow group, with no group difference in the sensory-motor compartment. The variance in total reading times was predicted by combining the model results for RTs with the linear relationship between pronunciation times and task difficulty. The results help clarify the internal structure of reading times, a measure largely used in clinical testing to assess reading rate.

Similarities and differences between eating disorders and obsessive-compulsive disorder in childhood and adolescence: a systematic review.

Background: The developmental age, comprising childhood and adolescence, constitutes an extremely important phase of neurodevelopment during which various psychiatric disorders can emerge. Obsessive-Compulsive Disorder (OCD) and Eating Disorders (ED) often manifest during this critical developmental period sharing similarities but also differences in psychopathology, neurobiology, and etiopathogenesis. The aim of this study is to focus on clinical, genetic and neurobiological similarities and differences in OCD and ED. Methods: This study is based on a PubMed/MEDLINE and Cochrane Central Register for Controlled Trial (CENTRAL). The research adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: The aforementioned search yielded an initial collection of 335 articles, published from 1968 to September 2023. Through the application of inclusion and exclusion criteria, a total of 324 articles were excluded, culminating in a final selection of 10 articles. Conclusions: Our findings showed both differences and similarities between OCD and ED. Obsessive-compulsive (OC) symptoms are more prevalent in ED characterized by a binge/purge profile than in those with a restrictive profile during developmental age. OC symptomatology appears to be a common dimension in both OCD and ED. When presents, OC symptomatology, exhibits transversal characteristic alterations in the anterior cingulate cortex and poorer cognitive flexibility. These correlations could be highlighted by genetic overlaps between disorders. A comprehensive definition, integrating psychopathological and neurobiological aspects could significantly aid treatment selection and thereby influence the prognosis of these patients.

School refusal behavior in children and adolescents: a five-year narrative review of clinical significance and psychopathological profiles.

The aim of the study was to explore the clinical significance of school refusal behavior, its negative impact on psychological well-being of children and adolescents and its relationship with the most common psychopathological conditions during childhood and adolescence (e.g. neurodevelopmental disorders, psychiatric disorders). School refusal behavior refers to a distressing condition experienced by children and adolescents that compromise regular school attendance and determine negative consequences on mental health and adaptive functioning. A narrative review of the literature published between January 2019 and March 2023 was conducted. Ten studies (n = 10) were included from a literature search of the electronic databases PubMed, CINAHL, PsycInfo, MedLine, and Cochrane Library. The results indicate that school refusal is highly present in neurodevelopmental disorders such as autism and attention-deficit/hyperactivity disorder due to the presence of behavioral problems and deficits in communication skills. As for psychiatric disorders, school refusal appears to be highly common in anxiety disorders, depressive disorders, and somatic symptoms. We also found that school refusal behavior may be associated with various emotional and behavioral conditions that act as risk factors. Especially, but are not limited to, it may be associated with a diminished self-concept, exposure to cyberbullying, specific affective profiles and excessive technology usage. Our results indicate that school refusal is a condition with many clinical facets. It can be attributed to both vulnerability factors, both temperamental and relational, and to various psychopathological conditions that differ significantly from each other, such as neurodevelopmental disorders and psychiatric disorders. Recognizing these aspects can improve the implementation of patient-tailored therapeutic interventions that are consequently more likely to produce effective outcomes. The therapeutic intervention should facilitate the recognition of cognitive biases regarding school as a threatening environment, while regulating negative emotions associated with school attendance. Additionally, therapeutic intervention programs linked to social skill training and problem-solving training, conducted directly within the school setting, can enhance children's abilities to cope with academic performance and social relationships, ultimately preventing school refusal.

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.

Service users perspectives on psychosis-risk terminology: An Italian study on labeling terms preferences and stigma.

AIMS: The current range of labeling terms-at-risk mental state (ARMS), ultra-high risk for psychosis (UHR), and attenuated psychotic syndrome (APS)-used to refer to the psychosis-risk concept is varied, and their acceptability and potential stigma are not well understood. By involving Italian youth with lived experience of mental ill-health, we aimed to generate new labeling terms for psychosis-risk, and to evaluate literacy, attitudes, and preferences regarding these and the existing terms. Additionally, we investigated opinions of disclosure of the at-risk concept in clinical practice. METHODS: Through a dual-moderator focus group, novel diagnostic terms were coined for the at-risk concept: psychosis proneness (PP), change of personal reality (CPR), and hints of subjectivity dysregulation (HSD). A specifically designed questionnaire was then completed by 47 help-seeking youths, 60 relatives, and 61 clinicians to test newly generated and already established at-risk terms. RESULTS: Literacy on already established terms was significantly lower among youth (mean= 42 %) and relatives (mean= 38 %). ARMS was the preferred and least stigmatizing term among young people and clinicians. UHR was considered the most stigmatizing label. Among newly generated terms, CPR was the least stigmatizing and most informative. Disclosure of at-risk terminology was generally preferred after establishing a trusting clinician-patient relationship. CONCLUSIONS: Findings support ARMS as a useful and acceptable term in clinical practice with young people, while UHR is associated with the highest stigma. CPR is promising and should be tested in cross-cultural studies. In Italy, there is an urgent need for improving literacy on prevention in mental health.

Developmental dyslexia in a regular orthography: can the reading profile be reduced to strategic control?

In languages with regular orthographies, the identification of different forms of reading impairment (such as surface or phonological dyslexia) has proved elusive. Alternatively, it has been proposed that different patterns of errors depend upon strategic choices on the part of the reader. The present study aimed to test this strategic interpretation by evaluating the effectiveness of instructions to read quickly (or accurately) in modifying the reading rate and types of errors of dyslexic children. Further, drawing on an error classification based on the contrast between sounding-out behaviour and word substitution, we examined the types of reading error that best characterize the deficit in a language with regular orthography (Italian). Thirty children with dyslexia and 30 chronologically age-matched controls read aloud passages and word lists with instructions to emphasize either rate or accuracy. When asked to read quickly, children with dyslexia increased their reading rate (although less than skilled children). However, the type of instructions had little influence on reading errors. Therefore, the results did not support the view that strategic control has an important role in modulating the types of reading errors made by children with dyslexia. For word lists, sounding-out behaviour, errors in stress assignment, and form-related nonwords were useful to correctly identifying children with dyslexia. For text passages, sounding-out behaviour and form-related errors were the best predictors of group membership. Thus, specific types of errors are a fundamental component of the reading deficit in children who speak a language with regular orthography over and above their reading slowness.

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.

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.

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.

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.

Has Anything Changed in the Frequency of Emergency Department Visits and the Profile of the Adolescent Seeking Emergency Mental Care during the COVID-19 Pandemic?

We described changes caused by the COVID-19 pandemic in the frequency of Emergency Department (ED) visits for mental health disorders (MHDs) in adolescents on a wider temporal range-that is, not just "the waves" of the pandemic-and characterized the profile of the adolescent seeking emergency psychiatric care. We conducted a retrospective longitudinal study by analyzing ED visits for MHDs from 10 March 2019 to 10 March 2021. A total of 1407 ED visits for MHDs were registered: 702 in the pre-COVID-19 and 707 in the COVID-19 period. The cumulative incidence of ED visits for MHDs was 1.22% in the pre-COVID-19 period and 1.77% in the COVID-19 period, with a statistically significant difference (p < 0.001). The principal characteristics of the adolescent with MHDs during the pandemic period: the odds of comorbidities decreased by 26% (p = 0.02), and the odds of transfer from other hospitals decreased by 71% (p < 0.001), while the odds of the ED presentation as first psychiatric episode were twice greater (p < 0.001). The risk of hospitalization increased by 54% (p = 0.001). Regarding psychopathology, the likelihood of attempted suicide increased by 74% during the pandemic (p = 0.02). The rate of mood and eating disorders grew significantly during the COVID-19 pandemic period (p = 0.005 and p = 0.031, respectively). Monitoring ED visits for MHDs and understanding changes in the profile of adolescents presenting to ED helps to reinforce the role of ED in identifying special clinical needs for these vulnerable patients in case of a future public health crisis.

Dopaminergic signalling and behavioural alterations by Comt-Dtnbp1 genetic interaction and their clinical relevance.

BACKGROUND AND PURPOSE: Cognitive and motor functions are modulated by dopaminergic signalling, which is shaped by several genetic factors. The biological effects of single genetic variants might differ depending on epistatic interactions that can be functionally multi-directional and non-linear. EXPERIMENTAL APPROACH: We performed behavioural and neurochemical assessments in genetically modified mice and behavioural assessments and genetic screening in human patients with 22q11.2 deletion syndrome (22q11.2DS). KEY RESULTS: Here, we confirm a genetic interaction between the Comt (catechol-O-methyltransferase, human orthologue: COMT) and Dtnbp1 (dystrobrevin binding protein 1, alias dysbindin, human orthologue: DTNBP1) genes that modulate cortical and striatal dopaminergic signalling in a manner not predictable by the effects of each single gene. In mice, Comt-by-Dtnbp1 concomitant reduction leads to a hypoactive mesocortical and a hyperactive mesostriatal dopamine pathway, associated with specific cognitive abnormalities. Like mice, in subjects with the 22q11.2DS (characterized by COMT hemideletion and dopamine alterations), COMT-by-DTNBP1 concomitant reduction was associated with analogous cognitive disturbances. We then developed an easy and inexpensive colourimetric kit for the genetic screening of common COMT and DTNBP1 functional genetic variants for clinical application. CONCLUSIONS AND IMPLICATIONS: These findings illustrate an epistatic interaction of two dopamine-related genes and their functional effects, supporting the need to address genetic interaction mechanisms at the base of complex behavioural traits.

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.