Autism is common in individuals with fragile X syndrome and it is often difficult to diagnose. We compared the diagnostic classifications of two measures for autism diagnosis, the ADOS and the ADI-R, in addition to the DSM-IV-TR in 63 males with FXS. Overall, 30% of the subjects met criteria for Autistic Disorder and 30% met criteria for PDD-NOS. The classifications on the ADOS and DSM-IV-TR were most similar, whereas the ADI-R classified subjects as autistic much more frequently. We further investigated the relationship of both FMRP and FMR1 mRNA to symptoms of autism in this cohort and found that there was no significant relationship between the measures of autism and molecular features, including FMRP, FMR1 mRNA, and CGG repeat number.

Until recently, individuals with premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene were believed to be psychologically unaffected. However, the recent documentation of abnormal elevation of FMR1 mRNA, discovery of fragile X-associated tremor/ataxia syndrome (FXTAS), and reports of psychiatric disorders in children and adults with the premutation have suggested a pathogenic gene-brain-behavior mechanism. In a large collaborative study, 68 men and 144 women with the FMR1 premutation completed a psychological symptoms checklist and FMR1 genetic testing, including determination of CGG repeat size, percentage of FMR1 protein (FMRP)-positive lymphocytes, and FMR1 mRNA levels. Relative to published norms, men and women with FXTAS symptoms reported higher levels of several types of psychological symptoms. In addition, men and women with the premutation and no overt evidence of FXTAS reported higher levels of obsessive-compulsive symptoms. Elevated FMR1 mRNA, but not CGG repeat size or reduced FMRP (as measured by immunocytochemistry), was significantly associated with increased psychological symptoms, predominantly obsessive-compulsive symptoms and psychoticism, in premutation men with and without FXTAS symptoms. There was no relationship between CGG repeat size, FMR1 mRNA or FMRP and psychological symptoms in premutation women unless the sample was restricted to those with skewed X-activation ratio toward >50% active premutation alleles. The results of this study support the hypothesis that FMR1 function is associated with psychological difficulties in individuals with the premutation, and provide evidence concordant with an RNA toxic gain-of-function model in a neuropsychiatric phenotype.

BackgroundCurrently, chromosomal microarrays (CMA) are recommended as first-tier test in the investigation of developmental disorders to examine copy number variations. The modern platforms also include probes for single nucleotide polymorphisms (SNPs) that detect homozygous regions in the genome, such as long contiguous stretches of homozygosity (LCSH) also named runs of homozygosity (ROH). LCHS are chromosomal segments resulting from complete or segmental chromosomal homozygosity, which may be indicative of uniparental disomy (UPD), consanguinity, as well as replicative DNA repair events, however also are common findings in normal populations. Knowing common LCSH of a population, which probably represent ancestral haplotypes of low-recombination regions in the genome, facilitates the interpretation of LCSH found in patients, allowing to prioritize those with possible clinical significance. However, population records of ancestral haplotype derived LCSH by SNP arrays are still scarce, particularly for countries such as Brazil where even for the clinic, microarrays that include SNPs are difficult to request due to their high cost.MethodsIn this study, we evaluate the frequencies and implications of LCSH detected by Affymetrix CytoScan® HD or 750 K platforms in 430 patients with neurodevelopmental disorders in southern Brazil. LCSH were analyzed in the context of pathogenic significance and also explored to identify ancestral haplotype derived LCSH. The criteria for considering a region as LCSH was homozygosis ≥3 Mbp on an autosome.ResultsIn 95% of the patients, at least one LCSH was detected, a total of 1478 LCSH in 407 patients. In 2.6%, the findings were suggestive of UPD. For about 8.5% LCSH suggest offspring from first to fifth grade, more likely to have a clinical impact. Considering recurrent LCSH found at a frequency of 5% or more, we outline 11 regions as potentially representing ancestral haplotypes in our population. The region most involved with homozygosity was 16p11.2p11.1 (49%), followed by 1q21.2q21.3 (21%), 11p11.2p11.12 (19%), 3p21.31p21.2 (16%), 15q15 1q33p32.3 (12%), 2q11.1q12.1 (9%), 1p33p32.3 (6%), 20q11.21q11.23 (6%), 10q22.1q23.31 (5%), 6p22.2p22 (5%), and 7q11.22q11.23 (5%).ConclusionsIn this work, we show the importance and usefulness of interpreting LCSH in the results of CMA wich incorporate SNPs.

Chromosomal microarray (CMA) is now recommended as first tier for the evaluation in individuals with unexplained neurodevelopmental disorders (ND). However, in developing countries such as Brazil, classical cytogenetic tests are still the most used in clinical practice, as reflected by the scarcity of publications of microarray investigation in larger cohorts. This is a retrospective study which analyses the reading files of CMA and available clinical data from 420 patients from the south of Brazil, mostly children, with neurodevelopmental disorders requested by medical geneticists and neurologists for diagnostic purpose. Previous karyotyping was reported for 138 and includes 17 with abnormal results. The platforms used for CMA were CYTOSCAN 750K (75%) and CYTOSCAN HD (25%). The sex ratio of the patients was 1.625 males :1 female and the mean age was 9.5 years. A total of 96 pathogenic copy number variations (CNVs), 58 deletions and 38 duplications, were found in 18% of the patients and in all chromosomes, except chromosome 11. For 12% of the patients only variants of uncertain clinical significance were found. No clinically relevant CNV was found in 70%. The main referrals for chromosomal microarrays (CMA) were developmental delay (DD), intellectual disability (ID), facial dysmorphism and autism spectrum disorder (ASD). DD/ID were present in 80%, facial dysmorphism in 52% and ASD in 32%. Some phenotypes in this population could be predictive of a higher probability to carry a pathogenic CNV, as follows: dysmorphic facial features (p-value = < 0.0001, OR = 0.32), obesity (p-value = 0.006, OR = 0.20), short stature (p-value = 0.032, OR = 0.44), genitourinary anomalies (p-value = 0.032, OR = 0.63) and ASD (p-value = 0.039, OR = 1.94). The diagnostic rate for CMA in this study was 18%. We present the largest report of CMA data in a cohort with ND in Brazil. We characterize the rare CNVs found together with the main phenotypes presented by each patient, list phenotypes which could predict a higher diagnostic probability by CMA in patients with a neurodevelopmental disorder and show how CMA and classical karyotyping results are complementary.

Familial mental retardation: a review and practical classification

Background Intellectual Disability (ID) is characterized by significant limitations that affect intellectual functioning, adaptive behavior, and practical skills which directly interfere with interpersonal relationships and the environment. In Western countries, individuals with ID are overrepresented in the health system, often due to associated comorbidities, and its life-time cost places ID as one of the most expensive conditions of all diagnoses in the International Classification of Diseases. Most of the people affected (75%) live in low-income countries, suffer from malnutrition, lack health care, and do not have access to adequate treatment. The aim of this study was to obtain an estimate of the diagnostic status as well as the prevalence of familial ID among individuals with serious (moderate or severe) ID in a region of the State of Santa Catarina, investigating attendees of special education schools of the Florianópolis Macroregion. Methods This was a cross-sectional study conducted between August 2011 and August 2014, through a semi-structured screening questionnaire for the collection of relevant developmental, clinical, familial and educational data, applied in an interview to guardians of students of special education schools of the macroregion of Florianópolis. Results The participant special schools enrolled close to 1700 students during the study period and the questionnaire was applied to 849 (50.5%). The male to female ratio of the participants was 1.39:1. Clear etiologic explanations were relatively scarce (24%); most diagnoses referring only to the type and the degree of impairment and for the majority (61.4%) the cause was unknown. About half were sporadic cases within their families (considering three generations). For 44.2% at least one other case of an ID-related condition in the extended family was mentioned, with 293 (34.5%) representing potential familial cases. Conclusion Here we describe the epidemiological profile, the available diagnostics, etiology, family history and possible parental consanguinity of participants with ID of special education schools in the South of Brazil. The main results show the need for etiological diagnosis and uncover the relevance of potential hereditary cases in a population where consanguineous unions have a relatively low frequency (0,6%) and highlight the need for public health actions.

Familial mental retardation: a review and practical classification

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