Suely Rodrigues dos Santos

Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith–Magenis syndrome

Smith–Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of ∼139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS.

Haplotype analysis of the CAG and CCG repeats in 21 Brazilian families with Huntington’s disease

We studied the allelic profile of CAG and CCG repeats in 61 Brazilian individuals in 21 independent families affected by Huntington’s disease (HD). Thirteen individuals had two normal alleles for HD, two had one mutable normal allele and no HD phenotype, and forty-six patients carried at least one expanded CAG repeat allele. Forty-five of these individuals had one expanded allele and one individual had one mutable normal allele (27 CAG repeats) and one expanded allele (48 CAG repeats). Eleven of these forty-five subjects had a mutant allele with reduced penetrance, and thirty-four patients had a mutant allele with complete penetrance. Inter- and intragenerational investigations of CAG repeats were also performed. We found a negative correlation between the number of CAG repeats and the age of disease onset (r=−0.84; P<0.001) and no correlation between the number of CCG repeats and the age of disease onset (r=0.06). We found 40 different haplotypes and the analysis showed that (CCG)10 was linked to a CAG normal allele in 19 haplotypes and to expanded alleles in two haplotypes. We found that (CCG)7 was linked to expanded CAG repeats in 40 haplotypes (95.24%) and (CCG)10 was linked to expanded CAG repeats in only two haplotypes (4.76%). Therefore, (CCG)7 was the most common allele in HD chromosomes in this Brazilian sample. It was also observed that there was a significant association of (CCG)7 with the expanded CAG alleles (χ2=6.97, P=0.0084). Worldwide, the most common CCG alleles have 7 or 10 repeats. In Western Europe, (CCG)7 is the most frequent allele, similarly to our findings.

Novel microduplications at Xp11.22 including HUWE1 : clinical and molecular insights into these genomic rearrangements associated with intellectual disability

Recently, we defined a minimal overlapping region for causal Xp11.22 copy number gains in males with intellectual disability (ID), and identified HECT, UBA and WWE domain-containing protein-1 (HUWE1) as the primary dosage-sensitive gene, whose overexpression leads to ID. In the present study, we used this minimal interval to search for HUWE1 copy number variations by quantitative polymerase chain reaction in a large cohort of Brazilian males with idiopathic ID. We detected two unrelated sporadic individuals with syndromic ID carrying unique overlapping duplications encompassing HUWE1. Breakpoint junction analysis showed a simple tandem duplication in the first patient, which has probably arisen by microhomology-mediated break-induced repair mechanism. In the second patient, the rearrangement is complex having an insertion of an intrachromosomal sequence at its junction. This kind of rearrangement has not been reported in Xp11.22 duplications and might have emerged by a replication- or recombination-based mechanism. Furthermore, the presence of infantile seizures in the second family suggests a potential role of increased KDM5C expression on epilepsy. Our findings highlight the importance of microduplications at Xp11.22 to ID, even in sporadic cases, and reveal new clinical and molecular insight into HUWE1 copy number gains.

A Study of a Geographical Cluster of Huntington's Disease in a Brazilian Town of Zona da Mata, Minas Gerais State

Background/Aims: Our aim was to investigate a geographical cluster of Huntingtons disease (HD) in Ervalia, a Brazilian town of Minas Gerais state (MG). Therefore, we calculated the minimum prevalence of HD in Ervalia, known to have many HD affected families. We also determined the genetic profile of the polymorphic CAG region of the HTT gene in 32 subjects of these affected families. Methods: A descriptive cross-sectional study was performed, starting in January 2011 until June 2013. Individuals who participated in the survey were all from Ervalia town, MG. Results: The minimum prevalence rate found was 7.2/10,000 people, higher than the worldwide prevalence. Conclusion: The minimum prevalence of HD in Ervalia was at least 10.3- to 14.4-fold greater than that of the world population, although it does not represent the overall prevalence of the disease in Brazil. Certainly an expanded survey in the country will lead to a lower prevalence estimate than Ervalias.

Absence of subtelomeric rearrangements in selected patients with mental retardation as assessed by multiprobe T FISH

BackgroundMental retardation (MR) is a heterogeneous condition that affects 2-3% of the general population and is a public health problem in developing countries. Chromosomal abnormalities are an important cause of MR and subtelomeric rearrangements (STR) have been reported in 4-35% of individuals with idiopathic MR or an unexplained developmental delay, depending on the screening tests and patient selection criteria used. Clinical checklists such as that suggested by de Vries et al. have been used to improve the predictive value of subtelomeric screening.FindingsFifteen patients (1–20 years old; five females and ten males) with moderate to severe MR from a genetics outpatient clinic of the Gaffrée and Guinle Teaching Hospital (HUGG) of the Federal University of Rio de Janeiro State (UNIRIO) were screened with Multiprobe T FISH after normal high resolution karyotyping. No subtelomeric rearrangements were detected even though the clinical score of the patients ranged from four to seven.ConclusionIn developing countries, FISH-based techniques such as Multiprobe T FISH are still expensive. Although Multiprobe T FISH is a good tool for detecting STR, in this study it did not detect STR in patients with unexplained MR/developmental delay even though these patients had a marked chromosomal imbalance. Our findings also show that clinical scores are not reliable predictors of STR.

Immunological Profile of Patients Presenting Down Syndrome andAlopecia Areata

Aim: This study was undertaken to contribute to knowledge of the immunological profile of Down syndrome and alopecia areata patients. Material and Methods: Observational, case series study, with comparison group. The following data were computed: gender, age, karyotype, previous disease and immunological profile: complete blood count, Blood Sedimentation Rate (BSR), cellular and humoral immunity and autoimmunity. Frequency, central trends and dispersion measurements for descriptive analysis. The nonparametric χ2 test and Fisher Exact test for exploratory analyses; significance level for p value < 0.05. Results: Eighty-three Down Syndrome (DS) patients were evaluated: 21 with Alopecia Areata (AA) and 62 without it. The average age of patients with AA was 13.3 years (SD ± 5.0) and of DS without AA was 12.2 (SD ± 5.3); 94.7% presented free trisomy. The predominant previous illness was hypothyroidism, which occurred only in DS patients with AA (3/21). Hemogram was normal in 40.9% and the most frequent alteration was an increase of hematocrit (22.9%). The BSR was elevated in 71.1%. About cellular immunity, the principal abnormality was the decrease in CD4. Immunoglobulin electrophoresis was normal in 100.0%; DS patients showed normal levels of IgA in 100.0% of cases, of IgM in 98.8% and IgG, in 85.5%. Complement C4 and C3 were decreased in 67.4% and in 9.6% of the patients, respectively. The majority of studied antibodies were non reagent, but the presence of antiperoxidase antibody was significant in DS patients with AA. Conclusion: There was no significant difference between the groups, related to their immunological profile, except for the presence of antiperoxidase antibody that maybe associated with the presence of hypothyroidism in DS patients with AA. Perhaps some of the findings are justified by the small sample; the authors suggest further studies with a larger sample and with HLA testing in order to understand the mechanism of AA in DS.