Development and validation of next generation sequencing based 35-gene hereditary cancer panel.

BACKGROUND: Understanding the genetic basis of cancer risk is a major international endeavor. The emergence of next-generation sequencing (NGS) in late 2000's has further accelerated the discovery of many cancer susceptibility genes. The use of targeted NGS-based multigene testing panels to provide comprehensive analysis of cancer susceptible genes has proven to be a viable option, with the accurate and robust detection of a wide range of clinically relevant variants in the targeted genes being crucial. METHODS: We have developed and validated a targeted NGS-based test for hereditary cancer risk assessment using Illumina's NGS platform by analyzing the protein-coding regions of 35 hereditary cancer genes with a bioinformatics pipeline that utilizes standard practices in the field. This 35-gene hereditary cancer panel is designed to identify germline cancer-causing mutations for 8 different cancers: breast, ovarian, prostate, uterine, colorectal, pancreatic, stomach cancers and melanoma. The panel was validated using well-characterized DNA specimens [NIGMS Human Genetic Cell Repository], where DNA had been extracted using blood of individuals whose genetic variants had been previously characterized by the 1000 Genome Project and the Coriell Catalog. RESULTS: The 35-gene hereditary cancer panel shows high sensitivity (99.9%) and specificity (100%) across 4820 variants including single nucleotide variants (SNVs) and small insertions and deletions (indel; up to 25 bp). The reproducibility and repeatability are 99.8 and 100%, respectively. CONCLUSIONS: The use of targeted NGS-based multigene testing panels to provide comprehensive analysis of cancer susceptible genes has been considered a viable option. In the present study, we developed and validated a 35-gene panel for testing 8 common cancers using next-generation sequencing (NGS). The performance of our hereditary cancer panel is assessed across a board range of variants in the 35 genes to support clinical use.

CYP2D6 allele frequencies, copy number variants, and tandems in the population of Hong Kong.

BACKGROUND: CYP2D6 plays a crucial role in drug metabolism of several drugs. It is known to be highly polymorphic with enzymatic activity ranging from poor to ultrarapid metabolic rates. While the frequencies of CYP2D6 alleles are generally known in different Asian populations, data on frequencies of the copy number variations (CNV) and tandems in CYP2D6 in which they occur are less well studied in these populations. METHODS: A cohort of 800 consecutive, unrelated individuals were referred to Prenetics Limited (Prenetics) iGenes test by physicians in Hong Kong as part of their care with informed consent. These clinical samples were deidentified prior to further analysis. Genotyping and copy number determination of CYP2D6 were performed using target specific TaqMan® SNP genotyping and copy number assays. The phenotypes of CYP2D6 were predicted based on its genotypes and is dependent on the biallelic expression of alleles. RESULTS: Among the Asian group (n = 735, 92%), the observed frequency of CYP2D6*36-*10 tandems was 34.1%. We also identified duplication of CYP2D6 alleles in 86 (11.7%) individuals of the study cohort. The frequency of all CYP2D6 duplicated alleles was 154 (10.5%) while only 28 (1.9%) of the duplications were of functional alleles (ie CYP2D6*1 and CYP2D6*2). CONCLUSION: The present study provides a comprehensive analysis on the occurrences of CNV and tandems of the CYP2D6 gene in the Hong Kong population. The results contribute to the overall knowledge of pharmacogenomics and may accelerate the implementation of precision medicine in Asia.

Relationship between aberrant brain connectivity and clinical features in Angelman Syndrome: a new method using tract based spatial statistics of DTI color-coded orientation maps.

AIM: In order to relate brain structural abnormalities to clinical features of Angelman Syndrome (AS), we determined the locations of abnormal regional white matter architecture in AS children using a sensitive and objective whole brain approach to analyze diffusion tensor imaging (DTI) color-coded orientation maps. METHODS: Using tract based spatial statistics (TBSS) of DTI color-coded orientation maps, the fraction of fibers oriented in the anteroposterior (AP), mediolateral (ML) and superioinferior (SI) directions were determined in whole brain white matter of 7 children with AS (mean age: 70±25.78 months, 5 males) and 7 children with typical development (TD, mean age: 79.8±17.25 months, 4 males). TBSS of FA map was also performed for comparison. RESULTS: Children with AS had a significantly lower AP component than the TD group in 9 clusters (3 bilateral and 3 unilateral). Bilateral clusters were located in inferior fronto-occipital fasciculus, anterior thalamic radiation and arcuate fasciculus regions. Unilateral clusters involved left brainstem, left cingulum and right uncinate regions. Similarly, children with AS had significantly lower ML component than the TD group in 4 clusters (2 in corpus callosum and 2 unilateral clusters). Unilateral clusters were located in the left cingulum and left anterior thalamic radiation regions. SI component was lower in children with AS in two clusters compared to TD (corticospinal tract and corpus callosum). FA map clusters mostly corresponded with component clusters. INTERPRETATION: Children with AS have a global impairment of white matter integrity including AP, ML and SI components in whole brain suggesting a potential underlying error with axon guidance mechanisms during brain development possibly due to loss of UBE3A gene expression. Some of this aberrant connectivity can be related to the clinical features of AS.

Sensitive diffusion tensor imaging quantification method to identify language pathway abnormalities in children with developmental delay.

OBJECTIVE: To investigate whether abnormal regional white matter architecture in the perisylvian region could be used as an easy and sensitive quantitative method to demonstrate language pathway abnormalities in children with developmental delay (DD). STUDY DESIGN: We performed diffusion tensor imaging in 15 DD subjects (age, 61.1 ± 20.9 months) and 15 age-matched typically developing (TD) children (age, 68.4 ± 19.2 months). With diffusion tensor imaging color-coded orientation maps, we quantified the fraction of fibers in the perisylvian region that are oriented in anteroposterior (AP) and mediolateral (ML) directions, and their ratio (AP/ML) was calculated. RESULTS: The AP/ML ratio was more sensitive than tractography in characterizing perisylvian regional abnormalities in DD children. The AP/ML ratio of the left perisylvian region was significantly lower in DD children compared with TD children (P = .03). The ML component of bilateral perisylvian regions was significantly higher in DD children compared with TD children (P = .01 [left] and P = .004 [right]). No significant difference was found in the AP component in the two groups. A significant negative correlation of the left ML component with Vineland communication skills was observed (r = -0.657, P = .011). CONCLUSIONS: The AP/ML ratio appears to be a sensitive indicator of regional white matter architectural abnormalities in the perisylvian region of DD children.

Exome sequencing of a pedigree with Tourette syndrome or chronic tic disorder.

Ten members of a 3-generation pedigree with 7 showing Tourette syndrome/chronic tic phenotype (TS-CTD) were evaluated with whole exome sequencing. We identified 3 novel, nonsynonymous single nucleotide variants in the MRPL3, DNAJC13, and OFCC1 genes that segregated with chronic tic phenotype. These variants were not present in 100 control subjects or in dbSNP/1000 Genomes databases. A novel variant in the 5' untranslated region of the OFCC1 gene was found in 2 TS-CTD patients from a different pedigree. Further studies will clarify the importance of variants in MRPL3, DNAJC13, and OFCC1 genes in TS.

Alterations in frontal lobe tracts and corpus callosum in young children with autism spectrum disorder.

Major frontal lobe tracts and corpus callosum (CC) were investigated in 32 children with autism spectrum disorder (ASD, mean age: 5 years), 12 nonautistic developmentally impaired children (DI, mean age: 4.6 years), and 16 typically developing children (TD, mean age: 5.5 years) using diffusion tensor imaging tractography and tract-based spatial statistics. Various diffusion and geometric properties were calculated for uncinate fasciculus (UF), inferior fronto-occipital fasciculus (IFO), arcuate fasciculus (AF), cingulum (Cg), CC, and corticospinal tract. Fractional anisotropy was lower in the right UF, right Cg and CC in ASD and DI children; in right AF in ASD children; and in bilateral IFO in DI children, compared with TD children. Apparent diffusion coefficient was increased in right AF in both ASD and DI children. The ASD group showed shorter length of left UF and increased length, volume, and density of right UF; increased length and density of CC; and higher density of left Cg, compared with the TD group. Compared with DI group, ASD group had increased length, volume, and density of right UF; higher volume of left UF; and increased length of right AF and CC. Volume of bilateral UF and right AF and fiber density of left UF were positively associated with autistic features.

Mortality Prediction of COVID-19 Patients at Intensive Care Unit Admission.

Background Coronavirus-2019 (COVID-19) patients admitted to the intensive care unit (ICU) have mortality rates between 30%-50%. Identifying patient factors associated with mortality can help identify critical patients early and treat them accordingly. Patients and methods In this retrospective study, the records of patients admitted to the COVID-19 ICU in a single tertiary care hospital from April 2020 to September 2020 were analysed. The clinical and laboratory parameters between patients who were discharged from the hospital (survival cohort) and those who died in the hospital (mortality cohort) were compared. A multivariate logistic regression model was constructed to identify parameters associated with mortality.  Results A total of 147 patients were included in the study. The age of the patients was 55 (45, 64), median (IQR), years. At admission, 23 (16%) patients were on mechanical ventilation and 73 (50%) were on non-invasive ventilation. Sixty patients (40%, 95% CI: 32.8 to 49.2%) had died. Patients who died had a higher Charlson comorbidity index (CCI): 3 (2, 4) vs. 2 (1, 3), p = 0.0019, and a higher admission sequential organ failure assessment (SOFA) score: 5 (4, 7) vs. 4 (3, 4), p < 0.001. Serum urea, serum creatinine, neutrophils on differential leukocyte count, neutrophil to lymphocyte ratio (N/L ratio), D-dimer, serum lactate dehydrogenase (LDH), and C-reactive protein were higher in the mortality cohort. The ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, platelet count, lymphocytes on differential leukocyte count, and absolute lymphocyte count was lower in the mortality cohort. The parameters and cut-off values used for the multivariate logistic regression model included CCI > 2, SOFA score > 4, D-dimer > 1346 ng/mL, LDH > 514 U/L and N/L ratio > 27. The final model had an area under the curve of 0.876 (95% CI: 0.812 to 0.925), p < 0.001 with an accuracy of 78%. All five parameters were found to be independently associated with mortality.  Conclusions CCI, SOFA score, D-dimer, LDH, and N/L ratio are independently associated with mortality. A model incorporating the combination of these clinical and laboratory parameters at admission can predict COVID-19 ICU mortality with good accuracy.

Diffusion tensor imaging of frontal lobe in autism spectrum disorder.

To investigate frontal lobe white matter in children with autism spectrum disorder (ASD), we performed diffusion tensor imaging (DTI) in 50 ASD children (mean age: 57.5 +/- 29.2 months, 43 males) and 16 typically developing children (mean age: 82.1 +/- 41.4 months, 11 males). The apparent diffusion coefficient (ADC) was significantly higher for whole frontal lobe (P = 0.011), long (P < 0.001) and short range (P = 0.0126) association fibers in ASD group. There was a trend toward statistical significance in the fractional anisotropy (FA) of whole frontal lobe fibers (P = 0.11). FA was significantly lower in ASD group for short range fibers (P = 0.0031) but not for long range fibers (P = not significant [NS]). There was no between-group difference in the number of frontal lobe fibers (short and long) (P = NS). The fiber length distribution was significantly more positively skewed in the normal population than in the ASD group (P < 0.001). The long range association fibers of frontal lobe were significantly longer in ASD group (P = 0.026 for both left and right hemispheres). Abnormal frontal FA and ADC may be due to white matter organization abnormalities in ASD. Lack of evidence for excessive short range connectivity in ASD in this study may need to be re-examined with future advances in DTI technology.

Absence of arcuate fasciculus in children with global developmental delay of unknown etiology: a diffusion tensor imaging study.

OBJECTIVE: To investigate cortical association tracts using diffusion tensor imaging (DTI) in children with global developmental delay of unknown etiology. STUDY DESIGN: We performed DTI in 20 patients (age range: 18-83 months, mean: 45 +/- 16 months, 12 males) with a history of global developmental delay and 10 typically developing children (age range: 26-99 months, mean: 54 +/- 24 months, 5 males). DTI tractography was performed to isolate major cortical association tracts. RESULTS: In 9 out of 20 patients, arcuate fasciculus (AF) was absent bilaterally and in another 2 patients, it was absent in left hemisphere. In contrast, AF was present bilaterally in all typically developing children. Fractional Anisotropy (FA) of inferior longitudinal fasciculus (ILF) was asymmetric in the control group but not in the developmental delay group (P = .04). FA was significantly reduced in right ILF in developmentally delayed children compared with controls (P = .03). FA of other association tracts was not different between patients and controls (P = NS). The apparent diffusion coefficient (ADC) showed no asymmetry for these tracts in controls or developmentally delayed children (P = NS). CONCLUSIONS: DTI can be used to identify absence of AF and inadequate maturation of ILF in children with global developmental delay of unknown etiology.

Diffusion tensor analysis of temporal and extra-temporal lobe tracts in temporal lobe epilepsy.

OBJECTIVE: To determine whether the major temporal lobe white matter tracts in patients with temporal lobe epilepsy manifest abnormal water diffusion properties. METHODS: Diffusion tensor MRI measurements were obtained from tractography for uncinate, arcuate, inferior longitudinal fasciculi and corticospinal tract in 13 children with left temporal lobe epilepsy and normal conventional MRI, and the data were compared to measurements in 12 age-matched normal volunteers. The relationship between tensor parameters and duration of epilepsy was also determined. RESULTS: All four tracts in the affected left hemisphere showed lower mean anisotropy, planar and linear indices, but higher spherical index in patients versus controls. Diffusion changes in the left uncinate and arcuate fasciculus correlated significantly with duration of epilepsy. Arcuate fasciculus showed a reversal of the normal left-right asymmetry. Various diffusion abnormalities were also seen in the four tracts studied in the right hemisphere. CONCLUSION: Our findings indicate abnormal water diffusion in temporal lobe and extra-temporal lobe tracts with robust changes in the direction perpendicular to the axons. Diffusion abnormalities associated with duration of epilepsy suggest progressive changes in ipsilateral uncinate and arcuate fasciculus due to chronic seizure activity. Finally, our results in arcuate fasciculus are consistent with language reorganization to the contralateral right hemisphere.

Quantification of protein synthesis in the human brain using L-[1-11C]-leucine PET: incorporation of factors for large neutral amino acids in plasma and for amino acids recycled from tissue.

UNLABELLED: The rate of incorporation of exogenous amino acids into brain proteins is indicative of the protein synthesis rate (PSR). The objective of this study was to assess the effect of plasma concentrations of leucine and large neutral amino acids (LNAAs) on the unidirectional uptake rate constant (Kcplx) of l-[1-(11)C]-leucine in the brain and to estimate the amino acid pool recycled from tissue. METHODS: Twenty-seven healthy adult volunteers (11 men and 16 women; age range, 20-50 y) underwent dynamic l-[1-(11)C]-leucine PET with arterial blood sampling. Data were analyzed with a standard 2-tissue-compartment model yielding the unidirectional uptake rate of plasma leucine into tissue (Kcplx = K(1)k(3)/(k(2) + k(3))) and the fraction of leucine originating from exogenous sources (lambda = k(2)/(k(2) + k(3))). PSR in brain was calculated as PSR = [Kcplx/lambda] x leucine. RESULTS: The mean plasma concentration of the sum of all LNAAs was 13% higher in men (981 +/- 86 micromol/L) than in women (850 +/- 76 micromol/L, P = 0.012), whereas the plasma leucine concentration was found to be similar in both sexes (men, 64 +/- 20 micromol/L; women, 58 +/- 21 micromol/L, P = 0.57). The whole-brain value for lambda was determined to be 0.64 +/- 0.03 and did not show a sex difference (P = 0.66). Whole-brain Kcplx values were significantly higher in women (0.0162 +/- 0.0024) than in men (0.0121 +/- 0.0031, P = 0.011); however, after normalization of the Kcplx to a standard plasma concentration of the sum of all LNAAs (Kcplx'), the Kcplx' was similar between the sexes (P = 0.21), as was the PSR' (1.24 +/- 0.49 micromol/L/min in men; 1.29 +/- 0.62 micromol/L/min in women, P = 0.87). No relationship between plasma leucine and Kcplx (r = -0.13, P = 0.63) was observed. Finally, there was a significant correlation between the PSR and the Kcplx derived using Patlak graphical analysis (rho = 0.65, P < 0.001). CONCLUSION: We conclude that both the Kcplx macroparameter and the PSR are stable indices of brain protein synthesis and are appropriate measures for testing altered protein synthesis in neurologic disorders.

Simplified kinetic analysis of tumor 18F-FDG uptake: a dynamic approach.

UNLABELLED: Standardized uptake value (SUV) is often used to quantify (18)F-FDG tumor use. Although useful, SUV suffers from known quantitative inaccuracies. Simplified kinetic analysis (SKA) methods have been proposed to overcome the shortcomings of SUV. Most SKA methods rely on a single time point (SKA-S), not on tumor uptake rate. We describe a hybrid between Patlak analysis and existing SKA-S methods, using multiple time points (SKA-M) but reduced imaging time and without measurement of an input function. We compared SKA-M with a published SKA-S method and with Patlak analysis. METHODS: Twenty-seven dynamic (18)F-FDG scans were performed on 11 cancer patients. A population-based (18)F-FDG input function was generated from an independent patient population. SKA-M was calculated using this population input function and either a short, late, dynamic acquisition over the tumor (starting 25-35 min after injection and ending approximately 55 min after injection) or dynamic imaging 10 or 25 min to approximately 55 min after injection but using only every second or third time point, to permit a 2- or 3-field-of-view study. SKA-S was also calculated. Both SKA-M and SKA-S were compared with the gold standard, Patlak analysis. RESULTS: Both SKA-M (1 field of view) and SKA-S correlated well with Patlak slope (r > 0.99, P < 0.001, and r = 0.96, P < 0.001, respectively), as did multilevel SKA-M (r > 0.99 and P < 0.001 for both). Mean values of SKA-M (25-min start time) and SKA-S were statistically different from Patlak analysis (P < 0.001 and P < 0.04, respectively). One-level SKA-M differed from the Patlak influx constant by only -1.0% +/- 1.4%, whereas SKA-S differed by 15.1% +/- 3.9%. With 1-level SKA-M, only 2 of 27 studies differed from K(i) by more than 20%, whereas with SKA-S, 10 of 27 studies differed by more than 20% from K(i). CONCLUSION: Both SKA-M and SKA-S compared well with Patlak analysis. SKA-M (1 or multiple levels) had lower variability and bias than did SKA-S, compared with Patlak analysis. SKA-M may be preferred over SUV or SKA-S when a large unmetabolized (18)F-FDG fraction is expected and 1-3 fields of view are sufficient.

Infantile spasms are associated with abnormal copy number variations.

The authors tested the hypothesis that de novo copy number variations (CNVs) implicated in known genomic disorders ("pathogenic CNVs") are significant predisposing factors of infantile spasms. The authors performed a genome-wide analysis of single-nucleotide polymorphism genotyping microarray data to identify the role of de novo/known pathogenic large CNVs in 13 trios of children affected by infantile spasms. A rare, large (4.8 Mb) de novo duplication was detected in the 15q11-13 region of 1 patient. In addition, 3 known pathogenic CNVs (present in the patient as well as 1 of the parents) were detected in total. In 1 patient, a known pathogenic deletion was detected in the region of 2q32.3. Similarly, in 1 other patient, 2 known pathogenic deletions in the regions of 16p11.2 and Xp22.13 (containing CDKL5) were detected. These findings suggest that some specific pathogenic CNVs predispose to infantile spasms and may be associated with different phenotypes.

SCN2A mutation is associated with infantile spasms and bitemporal glucose hypometabolism.

BACKGROUND: Genetic mutations play a crucial role in the etiology of cryptogenic infantile spasms, but the cause is still unknown in a significant proportion of patients. Whole exome sequencing technology shows great promise in identifying genetic causes of infantile spasms. METHODS: In this study whole exome sequencing was performed with 2-deoxy-2-((18)F)fluoro-d-glucose positron emission tomography scan of an infant boy with infantile spasms. Exome sequencing was also performed in the parents to identify any de novo mutations. RESULTS: The positron emission tomography scan showed a pattern of bilateral symmetric temporal lobe glucose hypometabolism. A total of 8171 nonsynonymous variants were identified in the child. Despite the large number of nonsynonymous variants, there was only a single de novo missense mutation in SCN2A in the child (NCBI hg19 assembly, position: Chr2:166234116, K1422E). Subsequent Sanger sequencing confirmed the de novo status of this variant. This mutation has never been reported in 6500 individuals of the exome variant server database. Similarly, this variant is not reported in the Online Mendelian Inheritance in Man Database or the Human Gene Mutation Database. It has previously been shown that SCN2A mutations are associated with hippocampal hyperexcitability. Therefore, this study indicates that infantile spasms and bitemporal hypometabolism in this patient might have been caused by hippocampal hyperexcitability due to SCN2A mutation. CONCLUSIONS: The simultaneous presence of an SCN2A mutation and bitemporal hypometabolism in this patient with infantile spasms suggests a plausible hippocampal origin. However, additional mechanistic and clinical studies are required to validate this link.

Increased L-[1-11 C] leucine uptake in the leptomeningeal angioma of sturge-weber syndrome: a PET study.

BACKGROUND AND PURPOSE: We used L-[1-(11) C]leucine (LEU) positron emission tomography (PET) to measure amino acid uptake in children with Sturge-Weber syndrome (SWS), and to relate amino acid uptake measures with glucose metabolism. METHODS: LEU and 2-deoxy-2[(18) F]fluoro-D-glucose (FDG) PET were performed in 7 children (age: 5 months-13 years) with unilateral SWS. Asymmetries of LEU uptake in the posterior brain region, underlying the angioma and in frontal cortex, were measured and correlated with glucose hypometabolism. Kinetic analysis of LEU uptake was performed in 4 patients. RESULTS: Increased LEU standard uptake value (SUV, mean: 15.1%) was found in the angioma region in 6 patients, and smaller increases in LEU SUV (11.5%) were seen in frontal cortex in 4 of the 6 patients, despite normal glucose metabolism in frontal regions. High LEU SUV was due to both increased tracer transport (3/4 patients) and high protein synthesis rates (2/4). FDG SUV asymmetries in the angioma region were inversely related to LEU SUV asymmetries (r=-.83, P= .042). CONCLUSIONS: Increased amino acid uptake in the angioma region and also in less affected frontal regions may provide a marker of pathological mechanisms contributing to chronic brain damage in children with SWS.

Abnormal brain protein synthesis in language areas of children with pervasive developmental disorder: a L-[1-11C]-leucine PET study.

This study was performed to evaluate the cerebral protein synthesis rate of language brain regions in children with developmental delay with and without pervasive developmental disorder. The authors performed L-[1-(11)C]-leucine positron emission tomography (PET) on 8 developmental delay children with pervasive developmental disorder (mean age, 76.25 months) and 8 developmental delay children without pervasive developmental disorder (mean age, 77.63 months). They found a higher protein synthesis rate in developmental delay children with pervasive developmental disorder in the left posterior middle temporal region (P = .014). There was a significant correlation of the Gilliam Autism Rating Scale autism index score with the protein synthesis rate of the left posterior middle temporal region (r = .496, P = .05). In addition, significant asymmetric protein synthesis (right > left) was observed in developmental delay children without pervasive developmental disorder in the middle frontal and posterior middle temporal regions (P = .03 and P = .04, respectively). In conclusion, abnormal language area protein synthesis in developmentally delayed children may be related to pervasive symptoms.

Arcuate fasciculus and speech in congenital bilateral perisylvian syndrome.

Standard magnetic resonance imaging can diagnose congenital bilateral perisylvian polymicrogyria, but is limited in explaining the heterogeneous clinical spectrum of the related congenital bilateral perisylvian syndrome, characterized by pseudobulbar dysfunction, developmental delay, and epilepsy. We analyzed arcuate fasciculi using diffusion tensor imaging, a major language tract in the perisylvian region interconnecting the Broca and Wernicke areas, and at high risk of becoming developmentally affected in this condition. Six patients with congenital bilateral perisylvian syndrome underwent diffusion tensor imaging and were evaluated. The arcuate fasciculus was manually isolated, using tractography. The tract was identified in three patients who had developed speech, and whose values for various diffusion parameters were similar to those in age-matched controls (patients/controls means: fractional anisotropy, 0.50/0.52; apparent diffusion coefficient, 0.0022/0.0022 mm(2)/second; P = ns for both). However, in three patients with severe impairment and no speech development, the arcuate fasciculus could not be identified by fiber-tracking. In this small series, the absence of arcuate fasciculi on diffusion tensor imaging correlated with a more severe phenotype, which cannot be appreciated via structural magnetic resonance imaging alone.

Abnormal language pathway in children with Angelman syndrome.

Angelman syndrome is a genetic disorder characterized by pervasive developmental disability with failure to develop speech. We examined the basis for severe language delay in patients with Angelman syndrome by diffusion tensor imaging. Magnetic resonance imaging/diffusion tensor imaging was performed in 7 children with genetically confirmed Angelman syndrome (age 70 ± 26 months, 5 boys) and 4 age-matched control children to investigate the microstructural integrity of arcuate fasciculus and other major association tracts. Six of 7 children with Angelman syndrome had unidentifiable left arcuate fasciculus, while all control children had identifiable arcuate fasciculus. The right arcuate fasciculus was absent in 6 of 7 children with Angelman syndrome and 1 of 4 control children. Diffusion tensor imaging color mapping suggested aberrant morphology of the arcuate fasciculus region. Other association tracts, including uncinate fasciculus, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and corticospinal tract, were identifiable but manifested decreased fractional anisotropy in children with Angelman syndrome. Increased apparent diffusion coefficient was seen in all tracts except uncinate fasciculus when compared to control children. Patients with Angelman syndrome have global impairment of white matter integrity in association tracts, particularly the arcuate fasciculus, which reveals severe morphologic changes. This finding could be the result of a potential problem with axon guidance during brain development, possibly due to loss of UBE3A gene expression.

Tourette syndrome is associated with recurrent exonic copy number variants.

BACKGROUND: Multiple rare copy number variants (CNVs) including genomic deletions and duplications play a prominent role in neurodevelopmental disorders such as mental retardation, autism, and schizophrenia, but have not been systematically studied in Tourette syndrome (TS). METHODS: We performed a genome-wide screening of single nucleotide polymorphism (SNP) genotyping microarray data to identify recurrent or de novo rare exonic CNVs in a case-control association study of patients with TS. RESULTS: We identified 5 exon-affecting rare CNVs that are either de novo or recurrent in 10 out of 111 patients with TS but were not found in 73 ethnically matched controls or in the entries of the Database of Genomic Variants (containing 21,178 CNVs at 6,558 loci). Three out of the 5 CNVs have been implicated previously by other studies in schizophrenia, autism, and attention-deficit hyperactivity disorder, suggesting that these CNVs produce a continuum of neuropsychiatric disturbances that manifest in different ways depending on other genetic, environmental, or stochastic factors. CONCLUSIONS: Rare, recurrent exonic copy number variants are associated in a subset of patients with Tourette syndrome.