A Case for Thalamic Mechanisms of Schizophrenia: Perspective From Modeling 22q11.2 Deletion Syndrome

Schizophrenia is a severe, chronic psychiatric disorder that devastates the lives of millions of people worldwide. The disease is characterized by a constellation of symptoms, ranging from cognitive deficits, to social withdrawal, to hallucinations. Despite decades of research, our understanding of the neurobiology of the disease, specifically the neural circuits underlying schizophrenia symptoms, is still in the early stages. Consequently, the development of therapies continues to be stagnant, and overall prognosis is poor. The main obstacle to improving the treatment of schizophrenia is its multicausal, polygenic etiology, which is difficult to model. Clinical observations and the emergence of preclinical models of rare but well-defined genomic lesions that confer substantial risk of schizophrenia (e.g., 22q11.2 microdeletion) have highlighted the role of the thalamus in the disease. Here we review the literature on the molecular, cellular, and circuitry findings in schizophrenia and discuss the leading theories in the field, which point to abnormalities within the thalamus as potential pathogenic mechanisms of schizophrenia. We posit that synaptic dysfunction and oscillatory abnormalities in neural circuits involving projections from and within the thalamus, with a focus on the thalamocortical circuits, may underlie the psychotic (and possibly other) symptoms of schizophrenia.

Aberrant right subclavian artery: embryology, prenatal diagnosis and clinical significance

Introduction The right subclavian artery normally arises as the first vessel from the brachiocephalic trunk. An aberrant right subclavian artery (ARSA) arises directly from the aortic arch and crosses behind the trachea towards the right arm. This variant occurs in approximately 1–2% of the population; however, the frequency increases in individuals with chromosomal abnormalities such as trisomy 21 and 22q11.2 microdeletion. Prenatal identification of ARSA therefore has a role in screening for such conditions. Methods Databases were searched for studies reporting the prenatal ultrasound evaluation of ARSA and its frequency in normal fetuses and in those with chromosomal abnormalities. Results A total of 23 studies were evaluated. Feasibility for the ultrasound evaluation of ARSA was 85–95%. The sonographic detection of ARSA is best in the three-vessel trachea view; however, sagittal and coronal imaging of the aortic arch may be useful. ARSA in isolation was not found to be associated with chromosomal abnormalities. The prevalence of ARSA in chromosomally abnormal fetuses was up to 24-fold higher than in normal fetuses, but the majority of chromosomally abnormal fetuses with ARSA had additional abnormal ultrasound findings, particularly cardiac abnormalities. Conclusions The prenatal detection of ARSA is a clinically useful prenatal marker for chromosomal abnormalities. In isolation, it is unlikely to be associated with pathogenic genetic variants. The ultrasound diagnosis of ARSA should prompt meticulous assessment of associated abnormalities. Invasive diagnostic testing should be offered to patients with non-isolated ARSA or in the presence of non-reassuring screening results or other risk factors.

Total Anomalous Pulmonary Venous Connection in Mother and Son with a Central 22q11.2 Microdeletion

In this clinical report, we describe a male infant and his mother, who had similar congenital heart defects. They were both diagnosed neonatally with total anomalous pulmonary venous connection (TAPVC) in combination with other heart defects. Neither of the two had any other organ malformations or dysmorphic facial features. SNP-array identified a central 22q11.2 microdeletion in the male infant and his mother as well as in the maternal grandmother and maternal aunt. The mother and the maternal aunt additionally harbored a 15q11.2 BP1-BP2 microdeletion. The maternal grandmother was unaffected by heart disease. However, heart computed tomography scan of the maternal aunt revealed a quadricuspid aortic valve. Additionally, the maternal grandmother and the maternal aunt both had significant learning disabilities. Rarely, TAPVC has been described in patients with the common 22q11.2 microdeletions. However, to the best of our knowledge, TAPVC has not previously been reported in patients with this small central 22q11.2 microdeletion. Haploinsufficiency of TBX1 was originally thought to be the main cause of the 22q11.2 microdeletion syndrome phenotype, but TBX1 is not included in the atypical central 22q11.2 microdeletion. Previous reports have suggested an association between TAPVC and the 15q11.2 BP1-BP2 microdeletion. Our report does not support this association as the maternal aunt, who harbors both microdeletions, is unaffected by TAPVC, and the male infant affected by TAPVC does not harbor the 15q11.2 BP1-BP2 microdeletion. Our findings support that genes located in the central 22q11.2 region are important for heart development and that haploinsufficiency of these genes plays a crucial role in the development of the rare heart defect TAPVC.

Prevalence of associated extracardiac anomalies in prenatally diagnosed congenital heart diseases

Objective To investigate the prevalence of extracardiac anomalies (ECA) in prenatally diagnosed congenital heart diseases (CHD), and to provide more information for counseling of women with prenatally diagnosed fetal CHD. Methods This was a retrospective cohort study of 791 cases of fetal CHD diagnosed by prenatal ultrasound from January 2005 to April 2018. Associated ECAs included extracardiac structural malformation (ECM), chromosomal anomaly, and 22q11.2 microdeletion. CHD was classified into 10 groups according to a modified anatomic and clinical classification of congenital heart defects. Results The overall prevalence of ECA in our CHD cohort was 28.6% (226/791): ECM, 25.3%; chromosomal anomaly, 11.7%; and 22q11.2 microdeletion, 5.5%. For those with ECM, ventricular septal defect (VSD) had the highest prevalence (34.5%), followed by anomalies of atrioventricular junctions and valves (28.8%) and heterotaxy (26.9%). For those with chromosomal anomaly, anomalies of atrioventricular junctions and valves had the highest prevalence (37.5%), followed by anomalies of atria and interatrial communications (25.0%) and VSD (22.9%). 22q11.2 microdeletion was detected only in those with anomalies of extrapericardial arterial trunks (14.3%) or ventricular outflow tracts (6.4%). Conclusion ECM, chromosomal anomaly, and 22q11.2 microdeletion have different prevalence according to the type of CHD.

Genotypic and phenotypic variability of 22q11.2 microdeletions – an institutional experience

<abstract> <p>Patients with chromosome 22q11.2 deletion syndromes classically present with variable cardiac defects, parathyroid and thyroid gland hypoplasia, immunodeficiency and velopharyngeal insufficiency, developmental delay, intellectual disability, cognitive impairment, and psychiatric disorders. New technologies including chromosome microarray have identified smaller deletions in the 22q11.2 region. An increasing number of studies have reported patients presenting with various features harboring smaller 22q11.2 deletions, suggesting a need to better elucidate 22q11.2 deletions and their phenotypic contributions so that clinicians may better guide prognosis for families. We identified 16 pediatric patients at our institution harboring various 22q11.2 deletions detected by chromosomal microarray and report their clinical presentations. Findings include various neurodevelopmental delays with the most common one being attention deficit hyperactivity disorder (ADHD), one reported case of infant lethality, four cases of preterm birth, one case with dual diagnoses of 22q11.2 microdeletion and Down syndrome. We examined potential genotypic contributions of the deleted regions.</p> </abstract>

Interrupted aortic arch, type A: report of 3 cases

Three cases of interrupted aortic arch of type A (IAA, type A) identified on prenatal ultrasound examination are presented. IAA, type A was a component of 22q11.2 microdeletion syndrome, established by molecular analysis of the aborted fetus`s tissues in the first case and a part of trisomy 13 in the second one. In the third fetus with a normal karyotype, IAA, type A was diagnosed at 31 weeks of gestation and successful cardiac surgery was performed after birth. In a fetus with 22q11.2 microdeletion syndrome, IAA was combined with ascending aorta hypoplasia and ventricular septal defect. In fetuses with Patau syndrome and normal karyotype IAA type A was accompanied by an aortopulmonary window.