Effects of gene dosage and development on subcortical nuclei volumes in individuals with 22q11.2 copy number variations.

The 22q11.2 locus contains genes critical for brain development. Reciprocal Copy Number Variations (CNVs) at this locus impact risk for neurodevelopmental and psychiatric disorders. Both 22q11.2 deletions (22qDel) and duplications (22qDup) are associated with autism, but 22qDel uniquely elevates schizophrenia risk. Understanding brain phenotypes associated with these highly penetrant CNVs can provide insights into genetic pathways underlying neuropsychiatric disorders. Human neuroimaging and animal models indicate subcortical brain alterations in 22qDel, yet little is known about developmental differences across specific nuclei between reciprocal 22q11.2 CNV carriers and typically developing (TD) controls. We conducted a longitudinal MRI study in a total of 385 scans from 22qDel (n = 96, scans = 191, 53.1% female), 22qDup (n = 37, scans = 64, 45.9% female), and TD controls (n = 80, scans = 130, 51.2% female), across a wide age range (5.5-49.5 years). Volumes of the thalamus, hippocampus, amygdala, and anatomical subregions were estimated using FreeSurfer, and the linear effects of 22q11.2 gene dosage and non-linear effects of age were characterized with generalized additive mixed models (GAMMs). Positive gene dosage effects (volume increasing with copy number) were observed for total intracranial and whole hippocampus volumes, but not whole thalamus or amygdala volumes. Several amygdala subregions exhibited similar positive effects, with bi-directional effects found across thalamic nuclei. Distinct age-related trajectories were observed across the three groups. Notably, both 22qDel and 22qDup carriers exhibited flattened development of hippocampal CA2/3 subfields relative to TD controls. This study provides novel insights into the impact of 22q11.2 CNVs on subcortical brain structures and their developmental trajectories.

An Endocrinological Perspective on 22q11.2 Deletion Syndrome: A Single-center Experience

Objective: 22q11.2 deletion syndrome (22q11.2 DS) is the most common chromosomal microdeletion disorder. Associated problems in 22q11.2 DS may include cardiac abnormalities, immune dysfunction, facial dysmorphism, with endocrine, genitourinary and gastrointestinal problems, and developmental delay. The aim of this study was to evaluate and present all endocrinological findings of patients with 22q11.2 DS from a single center. Methods: All participants had confirmed 22q11.2 DS by fluorescence in situ hybridization with hypoparathyroidism. Data were retrieved by retrospective review of patient records. Results: A total of 17 patients were reviewed. On physical examination, all patients had similar dysmorphic features. The median age at diagnosis was 45 days (1 day-13 years). Most cases (64.7%, 11/17) were diagnosed with hypoparathyroidism incidentally after routine tests. At the time of diagnosis, mean calcium was 7.04±0.80 mg/dL, phosphorus was 6.2±1.1 mg/dL, and median parathyroid hormone (PTH) was 11.5 (3.7-47.6) ng/L. Transient hypoparathyroidism was detected in five cases (29.4%). There was no significant difference between patients with permanent or transient hypoparathyroidism regarding gender, age at diagnosis, calcium, phosphorus, and PTH levels. However, vitamin D levels were significantly lower in the transient group (p=0.036). During follow-up, short stature, obesity, and type 2 diabetes mellitus were absent. Thyroid autoantibodies were detected in two patients with normal thyroid function tests. Despite there being no pathological short stature, final stature was shorter than the general population (mean height standard deviation score: -0.94±0.83). Conclusion: Hypocalcemia may be detected during acute illness in some cases where hypocalcemia appears at later ages. There was no significant difference between permanent and transient hypoparathyroidism cases in terms of PTH level. Recognition of the more specific facial findings is important to trigger investigation of genetic variants, additional anomalies, and for follow-up.

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.

Favorable effects of omega-3 polyunsaturated fatty acids in attentional control and conversion rate to psychosis in 22q11.2 deletion syndrome.

Omega-3-polyunsaturated-fatty-acids were suggested against cognitive dysfunctions and conversion to psychosis. However, a recent multicenter trial found no effect in reducing conversion rates in individuals at risk of developing schizophrenia. Patients' genetic heterogeneity and the timing of treatment might influence omega-3 efficacy. Here, we addressed the impact of omega-3 early treatment in both mice and human subjects with a 22q11.2 genetic hemi-deletion (22q11DS), characterized by cognitive dysfunctions and high penetrance of schizophrenia. We first tested the behavioural and cognitive consequences of adolescent exposure to normal or omega-3-enriched diets in wild-type and 22q11DS (LgDel/+) mice. We then contrasted mouse data with those gathered from sixty-two patients with 22q11DS exposed to a normal diet or supplemented with omega-3 during pre-adolescence/adolescence. Adolescent omega-3 exposure had no effects in wild-type mice. However, this treatment ameliorated distractibility deficits revealed in LgDel/+ mice by the Five Choice Serial Reaction Time Task (5CSRTT). The omega-3 improvement in LgDel/+ mice was selective, as no other generalized cognitive and non-cognitive effects were evident. Similarly, omega-3-exposed 22q11DS patients showed long-lasting improvements on distractibility as revealed by the continuous performance test (CPT). Moreover, omega-3-exposed 22q11DS patients showed less risk of developing an Ultra High Risk status and lower conversion rate to psychosis. Our convergent mouse-human findings represent a first analysis on the effects of omega-3 early treatment in 22q11DS. The beneficial effects in attentional control and transition to psychosis could support the early use of omega-3 supplementation in the 22q11DS population.

Glutamatergic function in a genetic high-risk group for psychosis: A proton magnetic resonance spectroscopy study in individuals with 22q11.2 deletion.

Glutamatergic dysregulation is one of the leading theories regarding the pathoaetiolopy of schizophrenia. Meta-analysis of magnetic resonance spectroscopy studies in schizophrenia shows increased levels of glutamate and glutamine (Glx) in the medial frontal cortex and basal ganglia in clinical high-risk groups for psychosis and increased glutamine levels in the thalamus, but it is unclear if this is also the case in people at genetic high risk for psychosis. The aim of this study was to investigate glutamatergic function in the anterior cingulate cortex, striatum and thalamus in carriers of a genetic variant (22q11.2 deletion) associated with a high risk for psychosis. 53 volunteers (23 22q11.2 deletion carriers and 30 controls) underwent proton magnetic resonance spectroscopy imaging and neuropsychological assessments for prodromal psychotic symptoms, schizotypy, anxiety, depression and FSIQ. We did not find any difference between groups in Glx in the anterior cingulate cortex, striatum or thalamus (Glx: t(50)=-1.26, p = 0.21; U = 251, z = -0.7, p = 0.49; U = 316, z= -0.26, p = 0.79, respectively). No correlation was detected between Glx levels in any region and symptomatology or FSIQ. Our findings indicate that glutamatergic function is not altered in people at genetic high risk of psychosis due to the 22q11.2 deletion, which could suggest that this is not the mechanism underlying psychosis risk in 22q11.2 deletion carriers.

A typical 22q11.2 deletion syndrome and pseudohypoparathyroidism: A CARE compliant case report.

RATIONALE: It is rare to find 22q11.2 deletion syndrome with pseudohypoparathyroidism in children. Furthermore, the phenotypic spectrum of this disorder varies widely. PATIENT CONCERNS: A patient was diagnosed with pseudohypoparathyroidism at age 14 years because of convulsions, hypocalcemia, hyperphosphatemia, normal parathyroid hormone levels, and basal ganglia calcifications. Thereafter, the child presented with symptoms of nephrotic syndrome; subsequently, he was diagnosed with nephrotic syndrome at the local hospital. DIAGNOSIS: At our hospital, multiplex ligation-dependent probe amplification confirmed that the patient had 22q11.2 deletion syndrome. INTERVENTIONS: The patient continued to be treated with calcium supplements. OUTCOMES: Seizure activity and proteinuria ceased. LESSONS: Signs of this syndrome include delayed speech development due to velofacial dysfunction, recurrent croup attacks during early childhood due to latent hypocalcemia, and mild dysmorphic features. The findings of this patient indicated that 22q11.2 deletion syndrome may include a wide spectrum of clinical findings and that this diagnosis needs to be considered for all patients presenting with hypocalcemia, regardless of age.

Atypical microdeletion in 22q11 deletion syndrome reveals new candidate causative genes: A case report and literature review.

RATIONALE: 22q11 deletion syndrome, the most common chromosomal microdeletion disease, is caused by megabase-sized deletions on chromosome 22q11.2. It is characterized by a wide spectrum of congenital anomalies in velopharyngeal and facial, cardiac, genitourinary, vertebroskeletal, respiratory, digestive, and central nervous systems. Phenotype-genotype studies have revealed several causative genes that regulate the development of the third and fourth pharyngeal arches in human. However, the exact pathogenesis of this syndrome remains unknown. Herein, we report a case of 22q11 deletion syndrome with an atypical microdeletion of 125 kb. PATIENT CONCERNS: A 15-year-old Chinese girl presented with symptoms of facial dysmorphia, cardiac defects, velopharyngeal insufficiency, splenomegaly, immunodeficiency, and thrombocytopenia. DIAGNOSES: Microarray analysis revealed a 22q11.23 deletion of 125 kb (chromosome 22: 24276973-24402263), suggesting the diagnosis of 22q11 deletion syndrome. The haploinsufficient genes included GSTT2B, GSTT2, DDTL, DDT, GSTTP1, LOC391322, GSTT1, and GSTTP2. INTERVENTIONS: The patient was administrated glucocorticoids and calcium supplements. OUTCOMES: No epistaxis or petechiae episode occurred during the follow-up; her platelet count ranged between 60 × 10 and 80 × 10/L. LESSONS: Although none of the previous reported causative genes were affected in the patient, her clinical manifestations were typical of 22q11 deletion syndrome, apart from her progressive splenomegaly. This case indicated 8 new candidate pathogenic genes for 22q11 deletion syndrome. Given that the loss of these genes was sufficient to induce 22q11DS defects, whether these genes directly influence the pathogenesis of 22q11DS or through interactions with known hotspot mutations is worthy of research.

Thalamic miR-338-3p mediates auditory thalamocortical disruption and its late onset in models of 22q11.2 microdeletion.

Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset.

Towards a safety net for management of 22q11.2 deletion syndrome: guidelines for our times.

UNLABELLED: The commonest autosomal deletion, 22q11.2 deletion syndrome (22q11DS) is a multisystem disorder varying greatly in severity and age of identification between affected individuals. Holistic care is best served by a multidisciplinary team, with an anticipatory approach. Priorities tend to change with age, from feeding difficulties, infections and surgery of congenital abnormalities particularly of the heart and velopharynx in infancy and early childhood to longer-term communication, learning, behavioural and mental health difficulties best served by evaluation at intervals to consider and initiate management. Regular monitoring of growth, endocrine status, haematological and immune function to enable early intervention helps in maintaining health. CONCLUSION: Guidelines to best practice management of 22q11DS based on a literature review and consensus have been developed by a national group of professionals with consideration of the limitations of available medical and educational resources.

DiGeorge syndrome/velocardiofacial syndrome: the chromosome 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion (CH22qD) syndrome is also known as DiGeorge syndrome or velocardiofacial syndrome. This deletion syndrome is extremely common with nearly one in 4000 children being affected. Recent advances and a holistic approach to patients have improved the care and well-being of these patients. This review will summarize advances in understanding the health needs and immune system of patients with CH22qD syndrome. Patients will most often need interventions directed at maximizing function for many organ systems but can ultimately have a high level of functioning.

Lower prepulse inhibition in children with the 22q11 deletion syndrome.

OBJECTIVE: The 22q11 deletion syndrome is associated with a range of possible physical anomalies, probable ongoing learning disabilities, and a specific constellation of neuropsychological deficits, including impairments in selective and executive visual attention, working memory, and sensorimotor functioning. It has been estimated that 25% of the children with 22q11 deletion syndrome go on to develop schizophrenia in late adolescence or adulthood. This is of urgent concern. Specification of early brain network vulnerabilities may provide a basis for early intervention while indicating critical links between genes and severe psychiatric illness. Neuropsychological studies of children with 22q11 deletion syndrome have implicated an array of potentially aberrant brain pathways. This study was conducted to determine whether preattentive processing ("sensorimotor gating") deficits are present in this population. METHOD: The authors administered a test of prepulse inhibition to 25 children with 22q11 deletion syndrome and their 23 sibling comparison subjects, ages 6-13. It was predicted that the children with 22q11 deletion syndrome would have lower prepulse inhibition than the comparison subjects. RESULTS: Prepulse inhibition in the children with 22q11 deletion syndrome (26.06%) was significantly less than that of the sibling comparison subjects (46.41%). Secondary analyses suggested that this decrement did not reflect developmental delay, and lower prepulse inhibition was associated with particular subsyndromal symptoms in some children. CONCLUSIONS: Sensorimotor gating is lower in children with 22q11 deletion syndrome. These findings may indicate specific brain circuits that are anomalous in 22q11 deletion syndrome.

Isolation and characterization of a novel gene from the DiGeorge chromosomal region that encodes for a mediator subunit.

Hemizygous deletions on chromosome 22q11.2 result in developmental disorders referred to as DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS). We report the isolation of a novel gene, PCQAP (PC2 glutamine/Q-rich-associated protein), that maps to the DiGeorge typically deleted region and encodes a protein identified as a subunit of the large multiprotein complex PC2. PC2 belongs to the family of the human Mediator complexes, which exhibit coactivator function in RNA polymerase II transcription. Furthermore, we cloned the homologous mouse Pcqap cDNA. There is 83% amino acid identity between the human and the mouse predicted protein sequences, with 96% similarity at the amino- and carboxy-terminal ends. To assess the potential involvement of PCQAP in DGS/VCFS, its developmental expression pattern was analyzed. In situ hybridization of mouse embryos at different developmental stages revealed that Pcqap is ubiquitously expressed. However, higher expression was detected in the frontonasal region, pharyngeal arches, and limb buds. Moreover, analysis of subjects carrying a typical 22q11 deletion revealed that the human PCQAP gene was deleted in all patients. Many of the structures affected in DGS/VCFS evolve from Pcqap-expressing cells. Together with the observed haploinsufficiency of PCQAP in DGS/VCFS patients, this finding is consistent with a possible role for this novel Mediator subunit in the development of some of the structures affected in DGS/VCFS.

Congenital heart disease in mice deficient for the DiGeorge syndrome region.

The heterozygous chromosome deletion within the band 22q11 (del22q11) is an important cause of congenital cardiovascular defects. It is the genetic basis of DiGeorge syndrome and causes the most common deletion syndrome in humans. Because the deleted region is largely conserved in the mouse, we were able to engineer a chromosome deletion (Df1) spanning a segment of the murine region homologous to the human deleted region. Here we describe heterozygously deleted (Df1/+) mice with cardiovascular abnormalities of the same type as those associated with del22q11; we have traced the embryological origin of these abnormalities to defective development of the fourth pharyngeal arch arteries. Genetic complementation of the deletion using a chromosome duplicated for the Df1 DNA segment corrects the heart defects, indicating that they are caused by reduced dosage of genes located within Df1. The Df1/+ mouse model reveals the pathogenic basis of the most clinically severe aspect of DiGeorge syndrome and uncovers a new mechanism leading to aortic arch abnormalities. These mutants represent a mouse model of a human deletion syndrome generated by chromosome engineering.

Isolation of a zinc finger gene consistently deleted in DiGeorge syndrome.

DiGeorge syndrome is a human developmental disorder resulting in hypoplasia of the thymus and parathyroids, and conotruncal heart defects. We recently isolated four genes with zinc finger DNA binding motifs mapping to chromosome 22q11.2 DiGeorge critical region. We now report that one of them, ZNF74 gene, is hemizygously deleted in 23 out of 24 DiGeorge syndrome patients tested. ZNF74 mRNA transcripts are detected in human and mouse embryos but not in adult tissues. Sequence analysis of a corresponding cDNA reveals an an open reading frame encoding 12 zinc finger motifs of the Kruppel/TFIIIA type as well as N-terminal and C-terminal non-zinc finger domains. These results suggest that changes in the dosage of a putative transcription factor through ZNF74 hemizygous deletion may be critical for DiGeorge developmental anomalies.