Recurrent Chromosome 16p13.1 Duplications Are a Risk Factor for Aortic Dissections

Chromosomal deletions or reciprocal duplications of the 16p13.1 region have been implicated in a variety of neuropsychiatric disorders such as autism, schizophrenia, epilepsies, and attention-deficit hyperactivity disorder (ADHD). In this study, we investigated the association of recurrent genomic copy number variants (CNVs) with thoracic aortic aneurysms and dissections (TAAD). By using SNP arrays to screen and comparative genomic hybridization microarrays to validate, we identified 16p13.1 duplications in 8 out of 765 patients of European descent with adult-onset TAAD compared with 4 of 4,569 controls matched for ethnicity (P = 5.0×10−5, OR = 12.2). The findings were replicated in an independent cohort of 467 patients of European descent with TAAD (P = 0.005, OR = 14.7). Patients with 16p13.1 duplications were more likely to harbor a second rare CNV (P = 0.012) and to present with aortic dissections (P = 0.010) than patients without duplications. Duplications of 16p13.1 were identified in 2 of 130 patients with familial TAAD, but the duplications did not segregate with TAAD in the families. MYH11, a gene known to predispose to TAAD, lies in the duplicated region of 16p13.1, and increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. These data suggest chromosome 16p13.1 duplications confer a risk for TAAD in addition to the established risk for neuropsychiatric disorders. It also indicates that recurrent CNVs may predispose to disorders involving more than one organ system, an observation critical to the understanding of the role of recurrent CNVs in human disease and a finding that may be common to other recurrent CNVs involving multiple genes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Genetic heterogeneity of the β-globin gene in various geographic populations of Yunnan in southwestern China.

The aim of this study was to investigate the geographic distribution of β-globin gene mutations in different ethnic groups in Yunnan province.From 2004 to 2014, 1,441 subjects with hemoglobin disorders, identified by PCR-reverse dot blot and DNA sequencing, were studied according to ethnicity and geographic origin. Haplotypes were examined among 41 unrelated thalassemia chromosomes.Eighteen β-thalassemia mutations and seven hemoglobin variants were identified for 1,616 alleles in 22 different ethnic groups from all 16 prefecture-level divisions of Yunnan. The prevalence of β-thalassemia was heterogeneous and regionally specific. CD 41-42 (-TCTT) was the most prevalent mutation in the populations of northeastern Yunnan. CD 17 (A>T) was the most common mutation in the populations of southeastern Yunnan, especially for the Zhuang minority, whereas Hb E (CD 26, G>A) was the most prevalent mutation in populations of southwestern Yunnan, especially for the Dai minority. Among the seven types of haplotypes identified, CD 17 (A>T) was mainly linked to haplotype VII (+ - - - - - +) and IVS-II-654 (C>T) was only linked to haplotype I (+ - - - - + +).Our data underline the heterogeneity of β-globin gene mutations in Yunnan. This distribution of β-globin mutations in the geographic regions and ethnic populations provided a detailed ethnic basis and evolutionary view of humans in southern China, which will be beneficial for genetic counseling and prevention strategies

Epidemiology characteristics of human coronaviruses in patients with respiratory infection symptoms and phylogenetic analysis of HCoV-OC43 during 2010-2015 in Guangzhou.

Human coronavirus (HCoV) is one of the most common causes of respiratory tract infection throughout the world. To investigate the epidemiological and genetic variation of HCoV in Guangzhou, south China, we collected totally 13048 throat and nasal swab specimens from adults and children with fever and acute upper respiratory infection symptoms in Gunazhou, south China between July 2010 and June 2015, and the epidemiological features of HCoV and its species were studied. Specimens were screened for HCoV by real-time RT-PCR, and 7 other common respiratory viruses were tested simultaneously by PCR or real-time PCR. HCoV was detected in 294 cases (2.25%) of the 13048 samples, with most of them inpatients (251 cases, 85.4% of HCoV positive cases) and young children not in nursery (53.06%, 156 out of 294 HCoV positive cases). Four HCoVs, as OC43, 229E, NL63 and HKU1 were detected prevalent during 2010-2015 in Guangzhou, and among the HCoV positive cases, 60.20% were OC43, 16.67% were 229E, 14.97% were NL63 and 7.82% were HKU1. The month distribution showed that totally HCoV was prevalent in winter, but differences existed in different species. The 5 year distribution of HCoV showed a peak-valley distribution trend, with the detection rate higher in 2011 and 2013 whereas lower in 2010, 2012 and 2014. The age distribution revealed that children (especially those 50 years) were both high risk groups to be infected by HCoV. Of the 294 HCoV positive patients, 34.69% (101 cases) were co-infected by other common respiratory viruses, and influenza virus was the most common co-infecting virus (30/101, 29.70%). Fifteen HCoV-OC43 positive samples of 2013-2014 were selected for S gene sequencing and phylogenetic analysis, and the results showed that the 15 strains could be divided into 2 clusters in the phylogenetic tree, 12 strains of which formed a separate cluster that was closer to genotype G found in Malaysia. It was revealed for the first time that genotype B and genotype G of HCoV-OC43 co-circulated and the newly defined genotype G was epidemic as a dominant genotype during 2013-2014 in Guanzhou, south China

Cognitive Function of Children and Adolescents with Attention Deficit Hyperactivity Disorder and Learning Difficulties: A Developmental Perspective

Background: The cognitive function of children with either attention deficit hyperactivity disorder (ADHD) or learning disabilities (LDs) is known to be impaired. However, little is known about the cognitive function of children with comorbid ADHD and LD. The present study aimed to explore the cognitive function of children and adolescents with ADHD and learning difficulties in comparison with children with ADHD and healthy controls in different age groups in a large Chinese sample. Methods: Totally, 1043 participants with ADHD and learning difficulties (the ADHD + learning difficulties group), 870 with pure ADHD (the pure ADHD group), and 496 healthy controls were recruited. To investigate the difference in cognitive impairment using a developmental approach, all participants were divided into three age groups (6–8, 9–11, and 12–14 years old). Measurements were the Chinese-Wechsler Intelligence Scale for Children, the Stroop Color-Word Test, the Trail-Making Test, and the Behavior Rating Inventory of Executive Function-Parents (BRIEF). Multivariate analysis of variance was used. Results: The results showed that after controlling for the effect of ADHD symptoms, the ADHD + learning difficulties group was still significantly worse than the pure ADHD group, which was, in turn, worse than the control group on full intelligence quotient (98.66 ± 13.87 vs. 105.17 ± 14.36 vs. 112.93 ± 13.87, P < 0.001). The same relationship was also evident for shift function (shifting time of the Trail-Making Test, 122.50 [62.00, 194.25] s vs. 122.00 [73.00, 201.50] s vs. 66.00 [45.00, 108.00] s, P< 0.001) and everyday life executive function (BRIEF total score, 145.71 ± 19.35 vs. 138.96 ± 18.00 vs. 122.71 ± 20.45, P < 0.001) after controlling for the effect of the severity of ADHD symptoms, intelligence quotient, age, and gender. As for the age groups, the differences among groups became nonsignificant in the 12–14 years old group for inhibition (meaning interference of the Stroop Color-Word Test, 18.00 [13.00, 25.00] s vs. 17.00 [15.00, 26.00] s vs. 17.00 [10.50, 20.00] s , P = 0.704) and shift function (shifting time of the Trail-Making Test, 62.00 [43.00, 97.00] s vs. 53.00 [38.00, 81.00] s vs. 101.00 [88.00, 114.00] s, P = 0.778). Conclusions: Children and adolescents with ADHD and learning difficulties have more severe cognitive impairment than pure ADHD patients even after controlling for the effect of ADHD symptoms. However, the differences in impairment in inhibition and shift function are no longer significant when these individuals were 12–14 years old

Atypicalities in the developmental trajectory of cortico-striatal functional connectivity in autism spectrum disorder

The last decades of neuroimaging research has revealed atypical development of intrinsic functional connectivity within and between large-scale cortical networks in autism spectrum disorder, but much remains unknown about cortico-subcortical developmental connectivity atypicalities. This study examined cortico-striatal developmental intrinsic functional connectivity changes in autism spectrum disorder and explored how those changes may be correlated with autistic traits. We studied 49 individuals with autism spectrum disorder and 52 age-, sex-, and head motion-matched typically developing individuals (5-30 years old (14.0 +/- 5.6)) using resting-state functional magnetic resonance imaging. Age-related differences in striatal intrinsic functional connectivity were compared between the two groups by adopting functional network-based parcellations of the striatum as seeds. Relative to typically developing individuals, autism spectrum disorder individuals showed atypical developmental changes in intrinsic functional connectivities between almost all striatal networks and sensorimotor network/default network, with connectivity increasing with age in the autism spectrum disorder group and decreasing or constant in typically developing individuals. Age-related degree centrality and voxel-mirrored homotopic connectivity atypicalities in sensorimotor network/default network and voxel-mirrored homotopic connectivity disruptions in striatal regions were also observed in autism spectrum disorder. Significant correlations were found between cortico-striatal intrinsic functional connectivities and Autism Diagnostic Observation Schedule communication/repetitive and restricted-behavior subscores in autism spectrum disorder. Our results indicated that developmental atypicalities of cortico-striatal intrinsic functional connectivities might contribute to the neuropathology of autism spectrum disorder. Lay abstract Autism spectrum disorder has long been conceptualized as a disorder of "atypical development of functional brain connectivity (which refers to correlations in activity levels of distant brain regions)." However, most of the research has focused on the connectivity between cortical regions, and much remains unknown about the developmental changes of functional connectivity between subcortical and cortical areas in autism spectrum disorder. We used the technique of resting-state functional magnetic resonance imaging to explore the developmental characteristics of intrinsic functional connectivity (functional brain connectivity when people are asked not to do anything) between subcortical and cortical regions in individuals with and without autism spectrum disorder aged 6-30 years. We focused on one important subcortical structure called striatum, which has roles in motor, cognitive, and affective processes. We found that cortico-striatal intrinsic functional connectivities showed opposite developmental trajectories in autism spectrum disorder and typically developing individuals, with connectivity increasing with age in autism spectrum disorder and decreasing or constant in typically developing individuals. We also found significant negative behavioral correlations between those atypical cortico-striatal intrinsic functional connectivities and autistic symptoms, such as social-communication deficits, and restricted/repetitive behaviors and interests. Taken together, this work highlights that the atypical development of cortico-subcortical functional connectivity might be largely involved in the neuropathological mechanisms of autism spectrum disorder

Frequency-specific age-related changes in the amplitude of spontaneous fluctuations in autism

Background: Autism spectrum disorder is characterized by atypical developmental changes during brain maturation, but regional brain functional changes that occur with age and across different frequency bands are unknown. Therefore, the current study aimed to explore potential age and frequency band-related changes in the regional brain activities in autism. Methods: A total of 65 participants who met the DSM-IV criteria for autistic disorder and 55 typically developed (TD) participants (both age 6-30 years) were recruited in the current study. The two groups were matched in age (t=-1.314, P=0.191) and gender (chi(2) =2.760, P=0.097). The amplitude of low-frequency fluctuations (ALFF) was employed to explore the effect of development on spontaneous brain activity in individuals with autism and in TD participants across slow-5 (0.01-0.027 Hz), slow-4 (0.027-0.073 Hz), and slow-3 (0.073-0.1 Hz) frequency bands. The diagnosis-by-age interaction effect in the whole brain voxels in autism and TD groups was investigated. Results: Autism individuals showed significantly higher ALFF in the dorsal striatum in childhood (Caudate duster: t=3.626, P=0.001; Putamen cluster: t=2.839, P=0.007) and remarkably lower ALFF in the dorsal striatum in adulthood (Caudate cluster: t=-2.198, P=0.038; Putamen duster: t=-2.314, P=0.030) relative to TD, while no significant differences were observed in adolescence (all P>0.05). In addition, abnormal ALFF amplitudes were specific to the slow-4 (0.027-0.073 Hz) frequency band in the clusters above. Conclusions: The current study indicated abnormal development patterns in the spontaneous activity of the dorsal striatum in autism and highlighted the potential role of the slow-4 frequency band in the pathology of autism. Also, the potential brain mechanism of autism was revealed, suggesting that autism-related variations should be investigated in a specific frequency