Neuroanatomical Correlates of Cognitive Dysfunction in 22q11.2 Deletion Syndrome.

22q11.2 Deletion Syndrome (22q11.2DS), the most common chromosomal microdeletion, presents as a heterogeneous phenotype characterized by an array of anatomical, behavioral, and cognitive abnormalities. Individuals with 22q11.2DS exhibit extensive cognitive deficits, both in overall intellectual capacity and focal challenges in executive functioning, attentional control, perceptual abilities, motor skills, verbal processing, as well as socioemotional operations. Heterogeneity is an intrinsic factor of the deletion's clinical manifestation in these cognitive domains. Structural imaging has identified significant changes in volume, thickness, and surface area. These alterations are closely linked and display region-specific variations with an overall increase in abnormalities following a rostral-caudal gradient. Despite the extensive literature developing around the neurocognitive and neuroanatomical profiles associated with 22q11.2DS, comparatively little research has addressed specific structure-function relationships between aberrant morphological features and deficient cognitive processes. The current review attempts to categorize these limited findings alongside comparisons to populations with phenotypic and structural similarities in order to answer to what degree structural findings can explain the characteristic neurocognitive deficits seen in individuals with 22q11.2DS. In integrating findings from structural neuroimaging and cognitive assessments, this review seeks to characterize structural changes associated with the broad neurocognitive challenges faced by individuals with 22q11.2DS.

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.

De novo start-loss variant in HIRA in patient with DiGeorge-like syndrome.

A case of a newborn with tetralogy of Fallot, corpus callosum hypoplasia, and phenotypic features similar to DiGeorge syndrome. Chromosomal microarray analysis did not reveal any alterations. Whole exome sequencing and Sanger sequencing identified a de novo variant in the HIRA gene resulting in the loss of the start codon.

Mitochondrial proteins encoded by the 22q11.2 neurodevelopmental locus regulate neural stem and progenitor cell proliferation.

Microdeletion of a 3Mb region encompassing 45 protein-coding genes at chromosome 22q11.2 (22q11.2DS) predisposes individuals to multiple neurodevelopmental disorders and is one of the greatest genetic risk factors for schizophrenia. Defective mitochondrial function has been hypothesized to contribute to 22q11.2DS pathogenesis; however, which of the six mitochondrial genes contribute to neurodevelopmental phenotypes and their underlying mechanisms remain unresolved. To systematically test 22q11.2DS genes for functional roles in neurodevelopment and behavior, we generated genetic mutants for each of the 37 conserved zebrafish orthologs and performed high throughput behavioral phenotyping using seven behavioral assays. Through this unbiased approach, we identified five single-gene mutants with partially overlapping behavioral phenotypes. Two of these genes, mrpl40 and prodha, encode for mitochondrial proteins and, similar to what we observed in mrpl40 and prodha mutants, pharmacologic inhibition of mitochondrial function during development results in microcephaly. Single mutant analysis shows that both mrpl40 and prodha mutants display aberrant neural stem and progenitor cell proliferation, with each gene regulating distinct cell populations. Finally, double mutants for both mrpl40 and prodha display aggravated behavioral phenotypes and neural stem and progenitor cell analysis reveals a previously unrecognized partially redundant role for mrpl40 and prodha in regulating radial glia-like cell proliferation. Combined, our results demonstrate a critical role for mitochondrial function in neural stem and progenitor cell populations in the developing vertebrate brain and provide compelling evidence that mitochondrial dysfunction during neurodevelopment is linked to brain volume and behavioral phenotypes observed in models of 22q11.2DS.

The mitochondria in schizophrenia with 22q11.2 deletion syndrome: From pathogenesis to therapeutic promise of targeted natural drugs.

Schizophrenia is a complex multi-factor neurological disorder that caused an array of severe indelible consequences to the individuals and society. Additionally, anti-schizophrenic drugs are unsuitable for treating negative symptoms and have more significant side effects and drug resistance. For better treatment and prevention, we consider exploring the pathogenesis of schizophrenia from other perspectives. A growing body of evidence of 22q11.2 deletion syndrome (22q11DS) suggested that the occurrence and progression of schizophrenia are related to mitochondrial dysfunction. So combing through the literature of 22q11DS published from 2000 to 2023, this paper reviews the mechanism of schizophrenia based on mitochondrial dysfunction, and it focuses on the natural drugs targeting mitochondria to enhance mitochondrial function, which are potential to improve the current treatment of schizophrenia.

A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome.

Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis of our current psychiatric diagnostic classification system with the recognition of an identifiable, highly penetrant genetic risk factor in an increasing proportion of patients with ASD or SSD? Second, what can be learned from studies of individuals with ASD or SSD who share a common genetic basis? And third, what accounts for the observed variable penetrance and pleiotropy of neuropsychiatric phenotypes in individuals with the same pathogenic variant? In this review, we focus on findings of clinical and preclinical studies of the 22q11.2 deletion syndrome (22q11DS). This particular variant is not only one of the most common among the increasing list of known rare pathogenic variants, but also one that benefits from a relatively long research history. Consequently, 22q11DS is an appealing model as it allows us to: (1) elucidate specific genotype-phenotype associations, (2) prospectively study behaviorally defined classifications, such as ASD or SSD, in the context of a known, well-characterized genetic basis, and (3) elucidate mechanisms underpinning variable penetrance and pleiotropy, phenomena with far-reaching ramifications for research and clinical practice. We discuss how findings from animal and in vitro studies relate to observations in human studies and can help elucidate factors, including genetic, environmental, and stochastic, that impact the expression of neuropsychiatric phenotypes in 22q11DS, and how this may inform mechanisms underlying neurodevelopmental expression in the general population. We conclude with research priorities for the field, which may pave the way for novel therapeutics.

Thymic hypoplasia induced by copy number variations contributed to explaining sudden infant death based on forensic autopsies.

Thymic hypoplasia is a primary cellular immunodeficiency that causes susceptibility to serious infections leading to sudden death in infants. Some genetic disorders in humans could result in the evident permanent hypoplasia or occasional aplasia of the thymus at birth. However, determining the genetic etiology of thymic hypoplasia is challenging for the sudden infant death due to primary cellular immunodeficiency. In this study, in order to find the fundamental reasons for sudden death of infants with thymic hypoplasia, 5 infants with suspected thymic hypoplasia and 10 control infants were assessed, and the immunohistochemistry and DNA analysis were used to investigate whether the infants with thymic hypoplasia had DiGeorge syndrome (DGS) with copy number variations (CNVs) in 22q11.2 and other chromosomes. The results showed that the weight of the thymus was significantly lower than the normal except the case 4, and that all the infants had hypocalcemia and a significant decrease or even absence of the markers CD1a, CD2, CD3, CD4 and CD8, which are related to T-cell maturation. In addition, multiplex ligation-dependent probe amplification (MLPA) analysis showed that these infants carried CNVs in 22q11.2 and other associated chromosomes with deletion and duplication of 25 genes. The results of thymus weight, histopathology, molecular pathology and MLPA analysis suggested that DGS predominantly with thymic hypoplasia induced by CNVs caused the sudden death of these infants under various infections or other unexplained reasons, which may provide new insights into the diagnosis of sudden infant death and could help the parents of deceased infants to attach more importance of genetic screening and thymus ultrasound to reduce the postnatal mortality of the infant, and demonstrates the value of genetic diagnosis in the forensic pathology.

Prenatal phenotype of 22q11 micro-duplications: A systematic review and report on 12 new cases.

The 22q11 region is prone to generating recurring Copy Number Variations (CNVs) as a result of the large numbers of Low Copy Repeats (LCRs). Typical duplications encompass the LCR-A-to-D region but atypical duplications of various sizes have also been reported. These duplications are responsible for highly variable phenotypes with incomplete penetrance and expressivity, which is challenging for adequate genetic counselling, especially in the prenatal period. To better delineate prenatal phenotypes associated with these CNVs, we report here a clinical and molecular description of twelve cases (9 foetuses and 3 deceased new-borns babies) carrying recurrent 22q11 duplications (diagnosed via aCGH), along with a review of the existing literature. 22q11 duplications were inherited from an apparently healthy parent in almost 60% of the cases. Other CNVs were diagnosed for 8% of the cases. Increased nuchal translucency and cardiac anomalies (CHD) were the most prominent phenotypes observed, along with mild renal and skeletal anomalies. Duplications encompassing the LCR-C-to-D region (and the CRKL gene) seemed more likely to generate CHDs and renal malformations. Cleft lip/palate were observed in foetuses with duplications encompassing the LCR-A-to-B region or the SPECC1L gene, as previously suggested. However, genotype-phenotype correlations remain difficult to ascertain. Second-hit point variants, epigenetic or environmental variations could play a role in the phenotypic variability of 22q11 duplications, but remain a challenge for assessment in the short period of pregnancy.

Plasma cells are essentially absent in the luminal gastrointestinal tract of patients with "complete" 22q11.2 deletion syndrome (DiGeorge syndrome).

Gastrointestinal symptoms are commonly reported in patients with 22q11.2 deletion syndrome or DiGeorge syndrome (DGS) in addition to the dominant cardiac manifestations and immunodeficiency. But literature providing specific morphologic details of the gastrointestinal tract pathology is very limited. Here, we provide the first comprehensive morphologic description of the luminal gastrointestinal tract changes in patients with DGS. Cytogenetically confirmed DGS patients were identified, clinical and laboratory data were reviewed to determine the severity of immunodeficiency, and patients were stratified into mildly immunocompromised, that is, partial DiGeorge anomaly or severely immunosuppressed, that is, complete DiGeorge anomaly groups. Gastrointestinal tract biopsies from these patients were retrospectively reviewed and compared with those from controls without the history of DGS. Patients with immunosuppressed DGS showed a near complete absence of plasma cells in the stomach, duodenum, and colon lamina propria by hematoxylin and eosin evaluation. Immunohistochemistry for CD138 used to highlight plasma cells confirmed this finding. The notable absence of plasma cells adds to the existing knowledge of the pathophysiology underlying DGS and expands the differential diagnostic considerations for this finding, which has been previously described in common variable immunodeficiency. It also provides a useful morphologic marker observable by the readily accessible light microscopy. Second, patients with DGS showed a mild increase in epithelial cell apoptosis in their colon. This finding is significant because of its overlap with morphologic features of gastrointestinal graft versus host disease as thymus transplantation is being used as a treatment option for patients with complete DGS.

Central 22q11.2 deletion (LCR22 B-D) in a fetus with severe fetal growth restriction and a mother with severe systemic lupus erythematosus: Further evidence of CRKL haploinsufficiency in the pathogenesis of 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2 DS, MIM #188400) is the most common chromosomal microdeletion with an incidence of 1 in 4000 live births. 22q11.2 DS patients present with varying penetrance and a broad phenotypic spectrum including dysmorphic features, congenital heart defects, hypoplastic thymus and T-cell deficiency, and hypocalcemia. The typical deletion spans 3 Mb between 4 large blocks of repetitive DNA, known as low copy repeats (LCRs), on chromosome 22 (LCR22) A and D. This deletion is found in ~85% of 22q11.2 DS patients, while only 4-5% have central LCR22B-D (1.5 Mb) and LCR22C-D (0.7 Mb) deletions. We report on a prenatally diagnosed, inherited case of central LCR22B-D 22q11.2 DS, born to a 22-year-old female with multiple autoimmune disorders. These include Sjogren's-syndrome-related antigen A (SSA+) severe systemic lupus erythematosus (SLE) with cutaneous and discoid components and seronegative antiphospholipid syndrome. Amniocentesis was performed due to fetal growth restriction (FGR). FISH with TUPLE1 (HIRA) probe was normal; however, chromosomal microarray identified a ~737 kb heterozygous loss between LCR22B-D. Subsequently, the same deletion was identified in the mother, which included CRKL and 19 other genes but excluded HIRA and TBX1, the typical candidate genes for 22q11.2DS pathogenesis. This case explores how loss of CRKL may contribute to immune dysregulation, as seen in the multiple severe autoimmune phenotypes of the mother, and FGR. Our experience confirms the importance of thorough workup in individuals with reduced penetrance of 22q11.2 DS features or atypical clinical presentations.

Second instance of co-occurring 22q11.2 deletion syndrome and Williams syndrome.

We present an 18-month-old male with Tetralogy of Fallot, retrognathia, short stature, global developmental delay, and dysmorphic features who was found to have dual diagnoses of both Williams syndrome and 22q11.2 deletion syndrome (22q11.2DS). To our knowledge, this is the second case of such a co-occurrence documented in the medical literature. Our patient presents with a blended physical phenotype of these two conditions and a behavioral phenotype that is distinct from what is typically observed in either disorder alone. We compare our patient's phenotype to the previously reported case and to the typical phenotypes for each individual condition. Additionally, we discuss why the occurrence of these two disorders together seems to be so rare, and the benefit of a genetics evaluation to an inpatient service team and the patient.

The point-of-care use of a facial phenotyping tool in the genetics clinic: Enhancing diagnosis and education with machine learning.

Computer-assisted pattern recognition platforms, such as Face2Gene® (F2G), can facilitate the diagnosis of children with rare genetic syndromes by comparing a patient's features to known genetic diagnoses. Our work designed, implemented, and evaluated an innovative model of care in clinical genetics in a heterogeneous and multicultural patient population that utilized this facial phenotyping software at the point-of-care. We assessed the performance of F2G by comparing the suggested diagnoses to the patient's confirmed molecular diagnosis. Providers' overall experiences with the technology and trainees' educational experiences were assessed with questionnaires. We achieved an overall diagnostic yield of 57%. This increased to 82% when cases diagnosed with syndromes not recognized by F2G were removed. The mean rank of a confirmed diagnosis in the top 10 was 2.3 (CI 1.5-3.2) and the mean gestalt score 37.6%. The most commonly suggested diagnoses were Noonan syndrome, mucopolysaccharidosis, and 22q11.2 deletion syndrome. Our qualitative assessment revealed that clinicians and trainees saw value using the tool in practice. Overall, this work helped to implement an innovative patient care delivery model in clinical genetics that utilizes a facial phenotyping tool at the point-of-care. Our data suggest that F2G has utility in the genetics clinic as a clinical decision support tool in diverse populations, with a majority of patients having their eventual diagnosis listed in the top 10 suggested syndromes based on a photograph alone. It shows promise for further integration into clinical care and medical education, and we advocate for its continued use, adoption and refinement along with transparent and accountable industrial partnerships.

A phenotypically diverse family with an atypical 22q11.2 deletion due to an unbalanced 18q23;22q11.2 translocation.

The 22q11.2 deletion syndrome (22q11.2 DS) is the most common deletion syndrome in humans. In most cases, it occurs de novo. A rare family of three with 22q11.2 deletion syndrome (22q11.2 DS) resulting from an unbalanced 18q;22q translocation is reported here. Their deletion region is atypical in that it includes only 26 of the 36 genes in the minimal critical 22q11.2 DS region but it involves the loss of the centromeric 22q region and the entire p arm. The deletion region overlaps with seven other rare atypical cases; common to all cases was the loss of a region including SEPT5-GP1BB proximally and most of ARVCF distally. Interrogation of the deleted 22q region proximal to the canonical 22q11.2 deletion region in the DECIPHER database showed seven cases with isolated or combined traits of 22q11.2 DS, including three with clefts. The phenotypes in the present family thus may result from the loss of a subset of genes in the critical region, or alternatively the loss of other genes or sequences in the proximal 22q deletion region, or interactive effects among these. Despite the identical deletion locus in the three affected family members, expression of the 22q11.2 DS traits differed substantially among them. These three related cases thus contribute to knowledge of 22q11.2 DS in that their unusual deletion locus co-occurred with the cardinal features of the syndrome while their identical deletions are associated with variable phenotypic expression.

Structural control energy of resting-state functional brain states reveals less cost-effective brain dynamics in psychosis vulnerability.

How the brain's white-matter anatomy constrains brain activity is an open question that might give insights into the mechanisms that underlie mental disorders such as schizophrenia. Chromosome 22q11.2 deletion syndrome (22q11DS) is a neurodevelopmental disorder with an extremely high risk for psychosis providing a test case to study developmental aspects of schizophrenia. In this study, we used principles from network control theory to probe the implications of aberrant structural connectivity for the brain's functional dynamics in 22q11DS. We retrieved brain states from resting-state functional magnetic resonance images of 78 patients with 22q11DS and 85 healthy controls. Then, we compared them in terms of persistence control energy; that is, the control energy that would be required to persist in each of these states based on individual structural connectivity and a dynamic model. Persistence control energy was altered in a broad pattern of brain states including both energetically more demanding and less demanding brain states in 22q11DS. Further, we found a negative relationship between persistence control energy and resting-state activation time, which suggests that the brain reduces energy by spending less time in energetically demanding brain states. In patients with 22q11DS, this behavior was less pronounced, suggesting a deficiency in the ability to reduce energy through brain activation. In summary, our results provide initial insights into the functional implications of altered structural connectivity in 22q11DS, which might improve our understanding of the mechanisms underlying the disease.

Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth.

The 22q11.2 deletion syndrome (22q11DS) is associated with a wide spectrum of cognitive and psychiatric symptoms. Despite the considerable work performed over the past 20 years, the genetic etiology of the neurodevelopmental phenotype remains speculative. Here, we report de novo heterozygous truncating variants in the HIRA (Histone cell cycle regulation defective, S. Cerevisiae, homolog of, A) gene associated with a neurodevelopmental disorder in two unrelated patients. HIRA is located within the commonly deleted region of the 22q11DS and encodes a histone chaperone that regulates neural progenitor proliferation and neurogenesis, and that belongs to the WD40 Repeat (WDR) protein family involved in brain development and neuronal connectivity. To address the specific impact of HIRA haploinsufficiency in the neurodevelopmental phenotype of 22q11DS, we combined Hira knock-down strategies in developing mouse primary hippocampal neurons, and the direct study of brains from heterozygous Hira+/- mice. Our in vitro analyses revealed that Hira gene is mostly expressed during neuritogenesis and early dendritogenesis stages in mouse total brain and in developing primary hippocampal neurons. Moreover, shRNA knock-down experiments showed that a twofold decrease of endogenous Hira expression level resulted in an impaired dendritic growth and branching in primary developing hippocampal neuronal cultures. In parallel, in vivo analyses demonstrated that Hira+/- mice displayed subtle neuroanatomical defects including a reduced size of the hippocampus, the fornix and the corpus callosum. Our results suggest that HIRA haploinsufficiency would likely contribute to the complex pathophysiology of the neurodevelopmental phenotype of 22q11DS by impairing key processes in neurogenesis and by causing neuroanatomical defects during cerebral development.

Abnormal Auditory Processing and Underlying Structural Changes in 22q11.2 Deletion Syndrome.

The 22q11.2 deletion syndrome (22q11.2 DS), one of the highest genetic risk for the development of schizophrenia, offers a unique opportunity to understand neurobiological and functional changes preceding the onset of the psychotic illness. Reduced auditory mismatch negativity response (MMN) has been proposed as a promising index of abnormal sensory processing and brain pathology in schizophrenia. However, the link between the MMN response and its underlying cerebral mechanisms in 22q11.2 DS remains unexamined. We measured auditory-evoked potentials to frequency deviant stimuli with high-density electroencephalogram and volumetric estimates of cortical and thalamic auditory areas with structural T1-weighted magnetic resonance imaging in a sample of 130 individuals, 70 with 22q11.2 DS and 60 age-matched typically developing (TD) individuals. Compared to TD group, the 22q11.2 deletion carriers reveal reduced MMN response and significant changes in topographical maps and decreased gray matter volumes of cortical and subcortical auditory areas, however, without any correlations between MMN alteration and structural changes. Furthermore, exploratory research on the presence of hallucinations (H+\H-) reveals no change in MMN response in 22q11.2DS (H+ and H-) as compared to TD individuals. Nonetheless, we observe bilateral volume reduction of the superior temporal gyrus and left medial geniculate in 22q11.2DSH+ as compared to 22q11.2DSH- and TD participants. These results suggest that the mismatch response might be a promising neurophysiological marker of functional changes within the auditory pathways that might underlie elevated risk for the development of psychotic symptoms.

Interaction of the craniofacial complex and velopharyngeal musculature on speech resonance in children with 22q11.2 deletion syndrome: An MRI analysis.

There are limited MRI studies of craniofacial and velopharyngeal features in children with 22q11.2 deletion syndrome (22q11.2DS) and to date, none have explored the potential relationship between these features and the speech phenotype. The purpose of this study was to examine the relationship between craniofacial and related velopharyngeal structures in children with 22q11.2DS and to assess their correlation to resonance features using an unsedated MRI protocol. Fifteen children with 22q11.2DS and 15 age- and sex-matched controls with normal velopharyngeal anatomy (ages 4-12 years) successfully completed the study. Analysis of covariance was used to compare differences between the experimental (22q11.2DS) and control (children with normal anatomy) groups. Correlation analyses and regression models were also utilized. The 22q11.2DS group demonstrated significantly shorter nasion-to-sella, sella-to-basion, and basion-to-opisthion distances. The anterior cranial base angle was significantly more obtuse. The levator veli palatini (levator) muscle was significantly thinner and shorter, with an obtuse angle of origin in the 22q11.2DS group. Levator length was significantly correlated with the sella-to-basion measure and hypernasality was correlated with levator origin-to-origin distance. Preliminary results from this study indicate a significant association between hypernasality and levator origin-to-origin distance. Findings from the present study, provide an insight into the pathophysiology of velopharyngeal dysfunction related to this clinically complex population.

Epilepsy, neuropsychiatric phenotypes, neuroimaging findings, and genotype-neurophenotype correlation in 22q11.2 deletion syndrome.

OBJECTIVE: To describe the epilepsy, neuropsychiatric manifestations, and neuroimaging findings in a group of patients with 22q11.2 DS, and to correlate the size of the deleted genetic material with the severity of the phenotype. METHODS: We retrospectively analyzed the medical records of 28 patients (21 pediatric patients and 7 adults) with a genetically confirmed diagnosis of 22q11.2 DS. Clinical data (epilepsy, neurological exam, neuropsychological and developmental assessment, and psychiatric disorders), neuroimaging, and cytogenetic tests were analyzed RESULTS: Of the 28 patients with 22q11.2 DS, 6 (21.4%) had epileptic seizures, 2 had symptomatic hypocalcemic seizures, 4 (14.2%) had a psychiatric disorder, which comprised of attention deficit hyperactivity disorder, autism spectrum disorder, psychosis, and mood disorder, and 17 (60.7%) had developmental delay. All patients with epilepsy had a developmental delay. Twelve patients underwent a neuropsychology assessment. Intellectual levels ranged from moderate intellectual disability (7/12, 58%) to average (5/12, 41.6%). Of the 16 patients, 6 (37.5%) had a normal brain, while 10 (62.5%) had abnormal neuroimaging findings. No significant correlation was found between the size of the deleted genetic material and the severity of the phenotype. CONCLUSION: 22q11.2DS patients are at high risk to develop epilepsy, neuropsychiatric manifestations, and structural brain abnormalities. This indicates that this defined genetic locus is crucial for the development of the nervous system, and patients with 22q11.2 DS have genetic susceptibility to develop epilepsy.

Replacing defective thymus function.

PURPOSE OF REVIEW: Transplantation of cultured postnatal allogeneic thymus has been successful for treating athymia, mostly associated with complete DiGeorge syndrome, for more than 20 years. Advances in molecular genetics provide opportunities for widening the range of athymic conditions that can be treated while advances in cell culture and organ/tissue regeneration may offer the prospect of alternative preparations of thymic tissue. There are potential broader applications of this treatment outside congenital athymia. RECENT FINDINGS: At the same time as further characterization of the cultured thymus product in terms of thymic epithelial cells and lymphoid composition, preclinical studies have looked at de-novo generation of thymic epithelial cells from stem cells and explored scaffolds for delivering these as three-dimensional structures. In the era of newborn screening for T-cell lymphopaenia, a broadening range of defects leading to athymia is being recognized and new assays should allow differentiation of these from haematopoietic cell defects, pending their genetic/molecular characterization. Evidence suggests that the tolerogenic effect of transplanted thymus could be exploited to improve outcomes after solid organ transplantation. SUMMARY: Thymus transplantation, the accepted standard treatment for complete DiGeorge syndrome is also appropriate for other genetic defects leading to athymia. Improved strategies for generating thymus may lead to better outcomes and broader application of this treatment.