Centro de Desenvolvimento da Criança
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- Genome-wide linkage analyses of quantitative and categorical autism subphenotypesPublication . Liu, XQ; Paterson, AD; Szatmari, P; Oliveira, G; Autism Genome Project ConsortiumBACKGROUND: The search for susceptibility genes in autism and autism spectrum disorders (ASD) has been hindered by the possible small effects of individual genes and by genetic (locus) heterogeneity. To overcome these obstacles, one method is to use autism-related subphenotypes instead of the categorical diagnosis of autism since they may be more directly related to the underlying susceptibility loci. Another strategy is to analyze subsets of families that meet certain clinical criteria to reduce genetic heterogeneity. METHODS: In this study, using 976 multiplex families from the Autism Genome Project consortium, we performed genome-wide linkage analyses on two quantitative subphenotypes, the total scores of the reciprocal social interaction domain and the restricted, repetitive, and stereotyped patterns of behavior domain from the Autism Diagnostic Interview-Revised. We also selected subsets of ASD families based on four binary subphenotypes, delayed onset of first words, delayed onset of first phrases, verbal status, and IQ > or = 70. RESULTS: When the ASD families with IQ > or = 70 were used, a logarithm of odds (LOD) score of 4.01 was obtained on chromosome 15q13.3-q14, which was previously linked to schizophrenia. We also obtained a LOD score of 3.40 on chromosome 11p15.4-p15.3 using the ASD families with delayed onset of first phrases. No significant evidence for linkage was obtained for the two quantitative traits. CONCLUSIONS: This study demonstrates that selection of informative subphenotypes to define a homogeneous set of ASD families could be very important in detecting the susceptibility loci in autism.
- A 3.2 Mb deletion on 18q12 in a patient with childhood autism and high-grade myopiaPublication . Gilling, M; Lauritsen, MB; Møller, M; Henriksen, KF; Vicente, A; Oliveira, G; Cintin, C; Eiberg, H; Andersen, PS; Mors, O; Rosenberg, T; Brøndum-Nielsen, K; Cotterill, RM; Lundsteen, C; Ropers, HH; Ullmann, R; Bache, I; Tümer, Z; Tommerup, NAutism spectrum disorders (ASDs) are a heterogeneous group of disorders with unknown aetiology. Even though ASDs are suggested to be among the most heritable complex disorders, only a few reproducible mutations leading to susceptibility for ASD have been identified. In an attempt to identify ASD susceptibility genes through chromosome rearrangements, we investigated a female patient with childhood autism and high-grade myopia, and an apparently balanced de novo translocation, t(5;18)(q34;q12.2). Further analyses revealed a 3.2 Mb deletion encompassing 17 genes at the 18q break point and an additional deletion of 1.27 Mb containing two genes on chromosome 4q35. Q-PCR analysis of 14 of the 17 genes deleted on chromosome 18 showed that 11 of these genes were expressed in the brain, suggesting that haploinsufficiency of one or more genes may have contributed to the childhood autism phenotype of the patient. Identification of multiple genetic changes in this patient with childhood autism agrees with the most frequently suggested genetic model of ASDs as complex, polygenic disorders.
- Molecular cytogenetic characterisation of a mosaic add(12)(p13.3) with an inv dup(3)(q26.31 --> qter) detected in an autistic boyPublication . Carreira, IM; Melo, JB; Rodrigues, C; Backx, L; Vermeesch, J; Weise, A; Kosyakova, N; Oliveira, G; Matoso, EBACKGROUND: Inverted duplications (inv dup) of a terminal chromosome region are a particular subset of rearrangements that often results in partial tetrasomy or partial trisomy when accompanied by a deleted chromosome. Associated mosaicism could be the consequence of a post-zygotic event or could result from the correction of a trisomic conception. Tetrasomies of distal segments of the chromosome 3q are rare genetic events and their phenotypic manifestations are diverse. To our knowledge, there are only 12 cases reported with partial 3q tetrasomy. Generally, individuals with this genomic imbalance present mild to severe developmental delay, facial dysmorphisms and skin pigmentary disorders. RESULTS: We present the results of the molecular cytogenetic characterization of an unbalanced mosaic karyotype consisting of mos 46,XY,add(12)(p13.3) [56]/46,XY [44] in a previously described 11 years old autistic boy, re-evaluated at adult age. The employment of fluorescence in situ hybridization (FISH) and multicolor banding (MCB) techniques identified the extra material on 12p to be derived from chromosome 3, defining the additional material on 12p as an inv dup(3)(qter --> q26.3::q26.3 --> qter). Subsequently, array-based comparative genomic hybridization (aCGH) confirmed the breakpoint at 3q26.31, defining the extra material with a length of 24.92 Mb to be between 174.37 and 199.29 Mb. CONCLUSION: This is the thirteenth reported case of inversion-duplication 3q, being the first one described as an inv dup translocated onto a non-homologous chromosome. The mosaic terminal inv dup(3q) observed could be the result of two proposed alternative mechanisms. The most striking feature of this case is the autistic behavior of the proband, a characteristic not shared by any other patient with tetrasomy for 3q26.31 --> 3qter. The present work further illustrates the advantages of the use of an integrative cytogenetic strategy, composed both by conventional and molecular techniques, on providing powerful information for an accurate diagnosis. This report also highlights a chromosome region potentially involved in autistic disorders.
- A genome-wide linkage and association scan reveals novel loci for autismPublication . Weiss, LA; Arking, DE; Daly, MJ; Chakravarti, A; Oliveira, G; Gene Discovery Project of Johns Hopkins & the Autism ConsortiumAlthough autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 x 10(-7)). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.
- A genome-wide scan for common alleles affecting risk for autismPublication . Anney, R; Klein, L; Pinto, D; Pegan, R; Magalhães, TR; Almeida, J; Oliveira, GAlthough autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
- Paralisia do plexo braquial no recém-nascido: experiência de dez anos numa Maternidade de Apoio Perinatal DiferenciadoPublication . Silva, S; Mimoso, G; Gonçalves, O; Araújo, H
- Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum DisordersPublication . Leblond, CS; Heinrich, J; Delorme, R; Proepper, C; Betancur, C; Huguet, G; Konyukh, M; Chaste, P; Oliveira, GAutism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
- CNVs leading to fusion transcripts in individuals with autism spectrum disorderPublication . Holt, R; Sykes, NH; Conceição, IC; Cazier, JB; Anney, RJ; Oliveira, G; Gallagher, L; Monaco, AP; Pagnamenta, ATThere is strong evidence that rare copy number variants (CNVs) have a role in susceptibility to autism spectrum disorders (ASDs). Much research has focused on how CNVs mediate a phenotypic effect by altering gene expression levels. We investigated an alternative mechanism whereby CNVs combine the 5' and 3' ends of two genes, creating a 'fusion gene'. Any resulting mRNA with an open reading frame could potentially alter the phenotype via a gain-of-function mechanism. We examined 2382 and 3096 rare CNVs from 996 individuals with ASD and 1287 controls, respectively, for potential to generate fusion transcripts. There was no increased burden in individuals with ASD; 122/996 cases harbored at least one rare CNV of this type, compared with 179/1287 controls (P=0.89). There was also no difference in the overall frequency distribution between cases and controls. We examined specific examples of such CNVs nominated by case-control analysis and a candidate approach. Accordingly, a duplication involving REEP1-POLR1A (found in 3/996 cases and 0/1287 controls) and a single occurrence CNV involving KIAA0319-TDP2 were tested. However, no fusion transcripts were detected by RT-PCR. Analysis of additional samples based on cell line availability resulted in validation of a MAPKAPK5-ACAD10 fusion transcript in two probands. However, this variant was present in controls at a similar rate and is unlikely to influence ASD susceptibility. In summary, although we find no evidence that fusion-gene generating CNVs lead to ASD susceptibility, discovery of a MAPKAPK5-ACAD10 transcript with an estimated frequency of ∼1/200 suggests that gain-of-function mechanisms should be considered in future CNVs studies.
- Síndromes de Deficiência Cerebral de CreatinaPublication . Malheiro, R; Diogo, L; Garcia, P; Fineza, I; Oliveira, GIntroduction: Creatine deficiency syndromes are a recently described group of diseases characterized by inborn errors of creatine metabolism. Clinical features include a spectrum of neurodevelopment disorders of diverse severity. They are characterized by low levels of cerebral creatine caused by different pathogenic mutations concerning the genes coding for creatine synthesis enzymes [arginine: glicyne amidinotransferase (AGAT, EC 2.1.4.1) and guanidinoacetate methyltansferase (GAMT, EC 2.1.1.2)], AGAT and GAMT, respectively, or its transporter (CT1 deficiency), SLC6A8. Enzymatic deficiencies are transmitted as autosomal recessive traits, whereas the transporter deficit is X-linked. Objectives: To characterize the clinical and laboratorial presentation, diagnosis and treatment of cerebral creatine deficiency patients, followed in Hospital Pediátrico Carmona da Mota. The awareness of these inborn errors of metabolism as neurological disorders, namely of neurodevelopment, among the medical community is a secondary aim of the present work. Methods and Material: Retrospective analysis of the clinical files of patients followed in our Hospital and diagnosed with cerebral creatine deficiency syndrome. Results: Twelve patients belonging to seven different families were diagnosed with creatine deficiency syndromes. Five presented GAMT deficiency and seven CT1 deficiency. Present ages are 2 to 38 years old. The most common clinical presentations were: global development delay in seven patients (two with epilepsy), and speech delay in two patients. Only one patient had communication and social interaction dysfunction. In all, global development delay in the range of intellectual delay was identified. The pathognomonic pattern of cerebral creatine deficiency in the brain image was demonstrated in eight patients. Pathogenic mutations in GAMT or SLC6A8 genes were identified in all cases. Conclusions: The suspicion of cerebral creatine depletion must be considered in all children presenting unexplained global psychomotor development delay. Pre-symptomatic therapy has shown promising results, especially in GAMT deficiency patients. The high rate of asymptomatic carriers of GAMT mutations in our population makes this disorder eligible to neonatal screening in Portugal.
- Pediatria do neurodesenvolvimento: levantamente nacional de recursos e necessidadesPublication . Oliveira, G; Duque, F; Duarte, C; Melo, F; Teles, L; Brito, F; Vale, MC; Guimarães, MJ; Gouveia, R