Remote assessment of the Penn computerised neurocognitive battery in individuals with 22q11.2 deletion syndrome.

BACKGROUND: Neurocognitive functioning is an integral phenotype of 22q11.2 deletion syndrome relating to severity of psychopathology and outcomes. A neurocognitive battery that could be administered remotely to assess multiple cognitive domains would be especially beneficial to research on rare genetic variants, where in-person assessment can be unavailable or burdensome. The current study compares in-person and remote assessments of the Penn computerised neurocognitive battery (CNB). METHODS: Participants (mean age = 17.82, SD = 6.94 years; 48% female) completed the CNB either in-person at a laboratory (n = 222) or remotely (n = 162). RESULTS: Results show that accuracy of CNB performance was equivalent across the two testing locations, while slight differences in speed were detected in 3 of the 11 tasks. CONCLUSIONS: These findings suggest that the CNB can be used in remote settings to assess multiple neurocognitive domains.

A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium.

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole-genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders.

Emergent, remitted and persistent psychosis-spectrum symptoms in 22q11.2 deletion syndrome.

Individuals with 22q11.2 deletion syndrome (22q11DS) are at markedly elevated risk for schizophrenia-related disorders. Stability, emergence, remission and persistence of psychosis-spectrum symptoms were investigated longitudinally. Demographic, clinical and cognitive predictors of psychosis were assessed. Prospective follow-up over 2.8 years was undertaken in 75 individuals with 22q11DS aged 8-35 years. Mood, anxiety, attention-deficit hyperactivity disorders and psychosis-spectrum symptoms were assessed with the Kiddie-Schedule for Affective Disorders and Schizophrenia and Scale of Prodromal Symptoms (SOPS). Four domains of cognition were evaluated with the Penn Computerized Neurocognitive Battery (executive functioning, memory, complex cognition and social cognition). Psychotic disorder or clinically significant SOPS-positive ratings were consistently absent in 35%, emergent in 13%, remitted in 22% and persistent in 31% of participants. Negative symptoms and functional impairment were found to be predictive of the emergence of positive psychosis-spectrum symptoms and to reflect ongoing deficits after remission of positive symptoms. Dysphoric mood and anxiety were predictive of emergent and persistent-positive psychosis-spectrum symptoms. Lower baseline global cognition and greater global cognitive decline were predictive of psychosis-spectrum outcomes but no particular cognitive domain stood out as being significantly more discriminating than others. Our findings suggest that negative symptoms, functioning and dysphoric mood are important predictors of psychosis risk in this population.

Incidental radiologic findings in the 22q11.2 deletion syndrome.

BACKGROUND AND PURPOSE: The 22q11.2 deletion syndrome is a common genetic microdeletion syndrome that results in cognitive delays and an increased risk of several psychiatric disorders, particularly schizophrenia. The current study investigates the prevalence of incidental neuroradiologic findings within this population and their relationships with psychiatric conditions. MATERIALS AND METHODS: Brain MR imaging from 58 individuals with 22q11.2 deletion syndrome was reviewed by board-certified radiologists by using standard clinical procedures. Intracranial incidental findings were classified into 8 categories and compared with a large typically developing cohort. RESULTS: The rate of incidental findings was significantly higher (P < .0001) in 22q11.2 deletion syndrome compared with typically developing individuals, driven by a high prevalence of cavum septum pellucidum (19.0%) and white matter abnormalities (10.3%). Both of these findings were associated with psychosis in 22q11.2 deletion syndrome. CONCLUSIONS: Cavum septum pellucidum and white matter hyperintensities are significantly more prevalent in patients with the 22q11.2 deletion syndrome and may represent biomarkers for psychosis.

Neurocognitive development in 22q11.2 deletion syndrome: comparison with youth having developmental delay and medical comorbidities.

The 22q11.2 deletion syndrome (22q11DS) presents with medical and neuropsychiatric manifestations including neurocognitive deficits. Quantitative neurobehavioral measures linked to brain circuitry can help elucidate genetic mechanisms contributing to deficits. To establish the neurocognitive profile and neurocognitive 'growth charts', we compared cross-sectionally 137 individuals with 22q11DS ages 8-21 to 439 demographically matched non-deleted individuals with developmental delay (DD) and medical comorbidities and 443 typically developing (TD) participants. We administered a computerized neurocognitive battery that measures performance accuracy and speed in executive, episodic memory, complex cognition, social cognition and sensorimotor domains. The accuracy performance profile of 22q11DS showed greater impairment than DD, who were impaired relative to TD. Deficits in 22q11DS were most pronounced for face memory and social cognition, followed by complex cognition. Performance speed was similar for 22q11DS and DD, but 22q11DS individuals were differentially slower in face memory and emotion identification. The growth chart, comparing neurocognitive age based on performance relative to chronological age, indicated that 22q11DS participants lagged behind both groups from the earliest age assessed. The lag ranged from less than 1 year to over 3 years depending on chronological age and neurocognitive domain. The greatest developmental lag across the age range was for social cognition and complex cognition, with the smallest for episodic memory and sensorimotor speed, where lags were similar to DD. The results suggest that 22q11.2 microdeletion confers specific vulnerability that may underlie brain circuitry associated with deficits in several neuropsychiatric disorders, and therefore help identify potential targets and developmental epochs optimal for intervention.

Psychiatric disorders in 22q11.2 deletion syndrome are prevalent but undertreated.

BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11DS) is a common genetic disorder with high rates of psychosis and other psychopathologies, but few studies discuss treatment. Our aim was to characterize the prevalence and treatment of major psychiatric illnesses in a well-characterized sample of individuals with 22q11DS. METHOD: This was a cross-sectional study of 112 individuals aged 8 to 45 years with a confirmed diagnosis of 22q11DS. Each participant was administered a modified Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) and the Structured Interview for Prodromal Syndromes (SIPS). Phenotypes assessed were threshold and subthreshold psychosis, depression, mania, generalized and separation anxiety, obsessions/compulsions, inattention/hyperactivity and substance use. Histories of mental health care and current psychotropic treatment were obtained. RESULTS: Psychopathology was common, with 79% of individuals meeting diagnostic criteria for a disorder at the time of assessment. Diagnoses of psychosis were made in 11% of cases, attenuated positive symptom syndrome (APS) in 21%, and 47% experienced significant subthreshold symptoms. Peak occurrence of psychosis risk was during adolescence (62% of those aged 12-17 years). Criteria for a mood disorder were met by 14%, for anxiety disorder 34% and for attention deficit hyperactivity disorder (ADHD) 31%. Mental health care had been received by 63% of individuals in their lifetime, but only 40% continued therapy and 39% used psychotropics. Antipsychotics were used by 42% of participants with psychosis and none of the participants with APS. Half of those at risk for psychosis were receiving no mental health care. CONCLUSIONS: Psychopathology is common in 22q11DS but is not adequately treated or clinically followed. Particular attention should be paid to subthreshold psychotic symptoms, especially in adolescents.

More Clinical Overlap between 22q11.2 Deletion Syndrome and CHARGE Syndrome than Often Anticipated.

CHARGE (coloboma, heart defects, atresia of choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) and 22q11.2 deletion syndromes are variable, congenital malformation syndromes that show considerable phenotypic overlap. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. We described 2 patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and searched the literature for more cases. In addition, we screened our cohort of CHD7 mutation carriers (n = 802) for typical 22q11.2 deletion features and studied CHD7 in 20 patients with phenotypically 22q11.2 deletion syndrome but without haploinsufficiency of TBX1. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. We strongly recommend performing CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency and conversely, performing a genome-wide array in CHARGE syndrome patients without a CHD7 mutation.

A double hit implicates DIAPH3 as an autism risk gene.

Recent studies have shown that more than 10% of autism cases are caused by de novo structural genomic rearrangements. Given that some heritable copy number variants (CNVs) have been observed in patients as well as in healthy controls, to date little attention has been paid to the potential function of these non-de novo CNVs in causing autism. A normally intelligent patient with autism, with non-affected parents, was identified with a maternally inherited 10 Mb deletion at 13q21.2. Sequencing of the genes within the deletion identified a paternally inherited nonsynonymous amino-acid substitution at position 614 of diaphanous homolog 3 (DIAPH3) (proline to threonine; Pro614Thr). This variant, present in a highly conserved domain, was not found in 328 healthy subjects. Experiments showed a transient expression of Diaph3 in the developing murine cerebral cortex, indicating it has a function in brain development. Transfection of Pro614Thr in murine fibroblasts showed a significant reduction in the number of induced filopodia in comparison to the wild-type gene. DIAPH3 is involved in cell migration, axon guidance and neuritogenesis, and is suggested to function downstream of SHANK3. Our findings strongly suggest DIAPH3 as a novel autism susceptibility gene. Moreover, this report of a 'double-hit' compound heterozygote for a large, maternally inherited, genomic deletion and a paternally inherited rare missense mutation shows that not only de novo genomic variants in patients should be taken seriously in further study but that inherited CNVs may also provide valuable information.

The constitutional t(11;22): implications for a novel mechanism responsible for gross chromosomal rearrangements.

The constitutional t(11;22)(q23;q11) is the most common recurrent non-Robertsonian translocation in humans. The breakpoint sequences of both chromosomes are characterized by several hundred base pairs of palindromic AT-rich repeats (PATRRs). Similar PATRRs have also been identified at the breakpoints of other nonrecurrent translocations, suggesting that PATRR-mediated chromosomal translocation represents one of the universal pathways for gross chromosomal rearrangement in the human genome. We propose that PATRRs have the potential to form cruciform structures through intrastrand-base pairing in single-stranded DNA, creating a source of genomic instability and leading to translocations. Indeed, de novo examples of the t(11;22) are detected at a high frequency in sperm from normal healthy males. This review synthesizes recent data illustrating a novel paradigm for an apparent spermatogenesis-specific translocation mechanism. This observation has important implications pertaining to the predominantly paternal origin of de novo gross chromosomal rearrangements in humans.

Detailed analysis of 22q11.2 with a high density MLPA probe set.

The presence of chromosome-specific low-copy repeats (LCRs) predisposes chromosome 22 to deletions and duplications. The current diagnostic procedure for detecting aberrations at 22q11.2 is chromosomal analysis coupled with fluorescence in situ hybridization (FISH) or PCR-based multiplex ligation dependent probe amplification (MLPA). However, there are copy number variations (CNVs) in 22q11.2 that are only detected by high-resolution platforms such as array comparative genomic hybridization (aCGH). We report on development of a high-definition MLPA (MLPA-HD) 22q11 kit that detects copy number changes at 37 loci on the long arm of chromosome 22. These include the 3-Mb region commonly deleted in DiGeorge/velocardiofacial syndrome (DGS/VCFS), the cat eye syndrome (CES) region, and more distal regions in 22q11 that have recently been shown to be deleted. We have used this MLPA-HD probe set to analyze 363 previously well-characterized samples with a variety of different rearrangements at 22q11 and demonstrate that it can detect copy number alterations with high sensitivity and specificity. In addition to detection of the common recurrent deletions associated with DGS/VCFS, variant and novel chromosome 22 aberrations have been detected. These include duplications within as well as deletions distal to this region. Further, the MLPA-HD detects deletion endpoint differences between patients with the common 3-Mb deletion. The MLPA-HD kit is proposed as a cost effective alternative to the currently available detection methods for individuals with features of the 22q11 aberrations. In patients with the relevant phenotypic characteristics, this MLPA-HD probe set could replace FISH for the clinical diagnosis of 22q11.2 deletions and duplications.

MLPA: a rapid, reliable, and sensitive method for detection and analysis of abnormalities of 22q.

In this study, essential test characteristics of the recently described multiplex ligation-dependent probe amplification (MLPA) method are presented, using chromosome 22 as a model. This novel method allows the relative quantification of approximately 40-45 different target DNA sequences in a single reaction. For the purpose of this study, MLPA was performed in a blinded manner on a training set containing over 50 samples, including typical 22q11.2 deletions, various atypical deletions, duplications (trisomy and tetrasomy), and unbalanced translocations. All samples in the training set have been previously characterized by fluorescence in situ hybridization (FISH) with cosmid or BAC clones and/or cytogenetic studies. MLPA findings were consistent with cytogenetic and FISH studies, no rearrangement went undetected and repeated tests gave consistent results. At a relative change in comparative signal strength of 30% or more, sensitivity and specificity values were 0.95 and 0.99, respectively. Given that MLPA is likely to be used as an initial screening method, a higher sensitivity, at the cost of a lower specificity, was deemed more appropriate. A receiver operator characteristic (ROC) curve analysis was performed to calculate the most optimal threshold range, with associated sensitivity and specificity values of 0.99 and 0.97, respectively. Finally, performance of each individual probe was analyzed, providing further useful information for the interpretation of MLPA results. In conclusion, MLPA has proven to be a highly sensitive and accurate tool for detecting copy number changes in the 22q11.2 region, making it a fast and economic alternative to currently used methods. The current study provides valuable and detailed information on the characteristics of this novel method.

Array based CGH and FISH fail to confirm duplication of 8p22-p23.1 in association with Kabuki syndrome.

BACKGROUND: Kabuki (Niikawa-Kuroki) syndrome comprises a characteristic facial appearance, cleft palate, congenital heart disease, and developmental delay. Various cytogenetically visible chromosomal rearrangements have been reported in single cases, but the molecular genetic basis of the condition has not been established. A recent report described a duplication of 8p22-p23.1 in 13/13 patients. OBJECTIVE: To determine the frequency of an 8p duplication in a cohort of patients with Kabuki syndrome. METHODS: An 8p duplication was sought using two independent methods--array based comparative genomic hybridisation (aCGH) and fluorescence in situ hybridisation (FISH)--in 15 patients with a definitive clinical diagnosis of Kabuki syndrome. RESULTS: No evidence for a duplication of 8p was obtained by FISH or aCGH in any of the 15 patients. CONCLUSIONS: 8p22-p23.1 duplication may not be a common mechanism for Kabuki syndrome. Another genetic abnormality may be responsible for the aetiology in many patients.

Chromosome 22q11 deletion in patients with truncus arteriosus.

The association between truncus arteriosus and chromosome 22q11 deletion is well recognized, but the frequency of a chromosome 22q11 deletion has not been characterized in a large series of patients with truncus arteriosus, and little is known about cardiovascular morphologic features associated with a chromosome 22q11 deletion in this group of patients. We prospectively enrolled 50 consecutive patients with truncus arteriosus who were admitted to The Children's Hospital of Philadelphia between November 1991 and December 2001. Patients were studied for chromosome 22q11 deletion using fluorescence in situ hybridization. Correlations between anatomic features and chromosome 22q11 deletion were assessed. A chromosome 22q11 deletion was detected in 20 of the 50 patients (40%). Anatomic features that were significantly associated with a chromosome 22q11 deletion included a right-sided aortic arch, an abnormal aortic arch branching pattern, both abnormal sidedness and branching of the aortic arch, and the combined category of either abnormal sidedness or branching of the aortic arch. There was a trend toward the association of discontinuous pulmonary arteries with a chromosome 22q11 deletion. Interruption of the aortic arch and truncal valve morphology and function did not correlate significantly with the presence of a chromosome 22q11 deletion. In conclusion, a chromosome 22q11 deletion is common in patients with truncus arteriosus, and those with abnormal sidedness and/or branching of the aortic arch are significantly more likely to have a deletion. Clinically important anatomic variables, such as abnormalities of the truncal valve and interrupted aortic arch, were not associated with a chromosome 22q11 deletion in this series.

Long AT-rich palindromes and the constitutional t(11;22) breakpoint.

The constitutional t(11;22) is the most frequently occurring non-Robertsonian translocation in humans. The breakpoint (BP) of the t(11;22) has been identified within palindromic AT-rich repeats (PATRRs) on chromosomes 11 and 22, suggesting that hairpin/cruciform structures mediate double-strand breaks leading to the translocation. To further characterize the mechanism of the translocation, identification of the precise location of the translocation BP is essential. Thus, the PATRRs from normal chromosomes 11 have been analyzed in detail. The majority of individuals have a PATRR that is 445 bp in length with a nearly symmetrical structure. The shorter, previously reported 204 bp PATRR has been shown to be a rare polymorphism. There are several nucleotide differences between the proximal and distal arms of the 445 bp palindrome (cis-morphisms) that correspond to five polymorphic sites within the PATRR. Using these data, the junction fragments of 40 unrelated t(11;22) families have been examined to determine the position of their 11q23 BPs. Sequence analysis demonstrates that BPs are located at the center of the longer PATRR in 39 of 40 cases. The data suggest that the center of the palindrome is susceptible to double-strand breaks leading to translocations that sustain small symmetrical deletions at the BP junction. The sequence of the larger, chromosome 22 PATRR deduced from junction fragments has three cis-morphisms, and the derivative chromosomes sustain symmetric deletions at the center of 22q11 PATRR. In one unusual case, the BPs on both chromosomes appear to correspond to these cis-morphic sites, suggesting that double-strand breaks at mismatched regions caused this variant translocation. De novo t(11;22) BPs have been analyzed using translocations detected in sperm samples from normal males. cis-Morphisms reveal no exclusive utilization of a particular allele in meiosis to produce the translocation. Our data lend support to the hypothesis that palindrome-mediated double-strand breaks in meiosis cause illegitimate recombination between 11q23 and 22q11 resulting in this recurrent translocation.

Segmental duplications: an 'expanding' role in genomic instability and disease.

The knowledge that specific genetic diseases are caused by recurrent chromosomal aberrations has indicated that genomic instability might be directly related to the structure of the regions involved. The sequencing of the human genome has directed significant attention towards understanding the molecular basis of such recombination 'hot spots'. Segmental duplications have emerged as a significant factor in the aetiology of disorders that are caused by abnormal gene dosage. These observations bring us closer to understanding the mechanisms and consequences of genomic rearrangement.

Unexpectedly high rate of de novo constitutional t(11;22) translocations in sperm from normal males.

Junction fragments from the constitutional t(11;22)(q23;q11) translocation have previously been cloned and sequenced. Here we report a high incidence of translocation-specific PCR products in sperm DNA from normal individuals. Somatic DNA from these and other normal individuals or from people with chromosomal breakage syndromes do not yield PCR junction fragments, indicating that this translocation originates during meiosis.

The 22q11.2 deletion syndrome.

Estimates suggest that the 22q11.2 deletion occurs in approximately 1 in 4000 live births, making this disorder a significant health concern in the general population. The 22q11.2 deletion has been identified in the majority of patients with DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome, suggesting that they are phenotypic variants of the same disorder. The findings associated with the 22q11.2 deletion are extensive and highly variable from patient to patient. In this chapter, we discuss the features of this disorder, with an emphasis on the clinical findings and an approach to the evaluation of these patients. In addition, we present the current understanding at the molecular level, of the genomic mechanisms and genes that are likely to play a central role in causing this frequent genetic condition.

Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net!

PURPOSE: The chromosome 22q11.2 deletion has been identified in the majority of patients with DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome and in some patients with the autosomal dominant Opitz G/BBB syndrome and Cayler cardiofacial syndrome. In addition, 22q11.2 deletion studies are becoming part of a standardized diagnostic workup for some isolated defects such as conotruncal cardiac anomalies and velopharyngeal incompetence. However, there is little information available on the clinical findings of unselected patients. For example, those individuals identified during prenatal diagnosis, as part of a generalized screening protocol, or following the diagnosis in a relative. This information will be invaluable in defining the variability of the disorder and in observing long-term outcome in the absence of targeted remediations. This study allows one to examine the first unselected cohort of patients and serves to highlight the importance of deletion testing in parents of affected probands. METHODS: Thirty individuals with a 22q11.2 deletion were identified following the diagnosis in a relative. Nineteen were adults ascertained only following the diagnosis in their child, 10 were children identified following the diagnosis in their sibling, and one was a child diagnosed prenatally following the diagnosis in her parent. RESULTS: Sixty percent of patients had no visceral anomalies. In fact, only 6 of the 19 adults (32%) and 6 of the 11 children (55%) had major findings which would have brought them to medical attention. Deletion sizing demonstrated the same large 3-4 MB deletion in most families despite wide inter and intrafamilial variability and there was no difference in clinical findings based on the parent of origin. Thus, no genotype-phenotype correlations could be made. CONCLUSION: We report the first unselected cohort of patients with the 22q11.2 deletion identified through an affected relative. Analysis of this series of 30 patients, many with very mild manifestations of the deletion, allows one to examine the outcome in individuals who lacked specific remediations for this disorder. It emphasizes the importance of broadening the index of suspicion in order to provide appropriate recurrence risk counseling, cognitive remediation, and medical management. Further, it underscores the lack of familial concordance and the current lack of genotype-phenotype correlations in this disorder, and it raises the possibility that the deletion is more common than previously reported.

Evolutionarily conserved low copy repeats (LCRs) in 22q11 mediate deletions, duplications, translocations, and genomic instability: an update and literature review.

Several constitutional rearrangements, including deletions, duplications, and translocations, are associated with 22q11.2. These rearrangements give rise to a variety of genomic disorders, including DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes (DGS/VCFS/CAFS), cat eye syndrome (CES), and the supernumerary der(22)t(11;22) syndrome associated with the recurrent t(11;22). Chromosome 22-specific duplications or low copy repeats (LCRs) have been directly implicated in the chromosomal rearrangements associated with 22q11.2. Extensive sequence analysis of the different copies of 22q11 LCRs suggests a complex organization. Examination of their evolutionary origin suggests that the duplications in 22q11.2 may predate the divergence of New World monkeys 40 million years ago. Based on the current data, a number of models are proposed to explain the LCR-mediated constitutional rearrangements of 22q11.2.