Spread of X-chromosome inactivation into autosomal regions in patients with unbalanced X-autosome translocations and its phenotypic effects.

Patients with unbalanced X-autosome translocations are rare and usually present a skewed X-chromosome inactivation (XCI) pattern, with the derivative chromosome being preferentially inactivated, and with a possible spread of XCI into the autosomal regions attached to it, which can inactivate autosomal genes and affect the patients' phenotype. We describe three patients carrying different unbalanced X-autosome translocations, confirmed by G-banding karyotype and array techniques. We analyzed their XCI pattern and inactivation spread into autosomal regions, through HUMARA, ZDHHC15 gene assay and the novel 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, and identified an extremely skewed XCI pattern toward the derivative chromosomes for all the patients, and a variable pattern of late-replication on the autosomal regions of the derivative chromosomes. All patients showed phenotypical overlap with patients presenting deletions of the autosomal late-replicating regions, suggesting that the inactivation of autosomal segments may be responsible for their phenotype. Our data highlight the importance of the XCI spread into autosomal regions for establishing the clinical picture in patients carrying unbalanced X-autosome translocations, and the incorporation of EdU as a novel and precise tool to evaluate the inactivation status in such patients.

Rubinstein-Taybi syndrome in diverse populations.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.

Non-mosaic partial duplication 12p in a patient with dysmorphic characteristics and developmental delay.

Duplication of the short arm of chromosome 12 is a rare chromosomal abnormality that may arise de novo or result from malsegregation of a balanced parental translocation. This study comprises the clinical description, cytogenetic and cytogenomic analyses and genotype-phenotype correlation in a patient with facial dysmorphism, developmental delay and intellectual impairment caused by non-mosaic partial duplication and a paracentric inversion 12p. The patient's GTG-banded karyotype was 46,XX,invdup(12)(pter → p13.32::p11.1 → p13.31::p13.31 → qter). A genetic gain of approximately 28 Mb was detected in the chromosomal region arr[GRCh37]12p13.31-p11.1(6914072_34756209)x3. The chromosomal alteration seen in our patient is described as "pure" partial duplication 12p. In most cases, duplication 12p phenotype is characterized by dysmorphic features, multiple congenital anomalies and intellectual disability. A small number of cases in literature have described genes associated with neurodevelopmental disease, such as ING4, CHD4, MFAP5, GRIN2B, SOX5, SCN8A and PIANP. In our patient the duplication 12p was de novo. This study should contribute to the genotype-phenotype correlation in partial duplication 12p cases.

Schilbach-Rott syndrome associated with 9q22.32q22.33 duplication, involving the PTCH1 gene.

Schilbach-Rott syndrome (SRS, OMIM%164220) is a disorder of unknown aetiology that is characterised by hypotelorism, epichantal folds, cleft palate, dysmorphic face, hypospadia in males and mild mental retardation in some patients. To date, 5 families and 17 patients have exhibited this phenotype, and recurrence in two of these families suggests an autosomal dominant inheritance. SRS overlaps with a mild form of holoprosencephaly (HPE), but array-CGH analysis and sequencing of some HPE-related genes (SEPT9, SHH and TWIST) did not reveal any variants in at least one family. Herein, we investigated by array-CGH analysis a 11-year-old female patient and her father, both exhibiting the typical SRS phenotype, disclosing in the daughter-father couple the same microduplication of chromosome 9q22.32q22.33 [arr[hg19]9q22.32(98,049,611_98,049,636)x3,9q22.33 (99,301,483_99,301,508)x3], involving eight genes, including PTCH1. The duplication segregated with the disease, since it was not found in the healthy paternal grandparents of the proband. The gain-of-function variants of the PTCH1 gene are responsible for a mild form of HPE. This is the first genetic variant found in SRS. This finding reinforces the hypothesis that SRS belongs to the HPE clinical spectrum and suggests to perform array-CGH in patients with SRS phenotype and, if negative, to consider a potential benefit from sequencing of HPE-related genes.

Cornelia de Lange syndrome in diverse populations.

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.

Incorporation of 5-ethynyl-2'-deoxyuridine (EdU) as a novel strategy for identification of the skewed X inactivation pattern in balanced and unbalanced X-rearrangements.

X-chromosome inactivation occurs randomly in normal female cells. However, the inactivation can be skewed in patients with alterations in X-chromosome. In balanced X-autosome translocations, normal X is preferentially inactivated, while in unbalanced X alterations, the aberrant X is usually inactivated. Here, we present a novel strategy to verify the skewed X inactivation pattern through the incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into cells, in 11 patients: five carriers of balanced X-autosome translocations and six of unbalanced X-chromosome alterations. Since EdU is a labeled nucleoside analog of thymidine, its incorporation during DNA synthesis can reveal late replication regions and the inactive X-chromosome. All EdU findings were validated by the human androgen receptor gene (HUMARA) assay. The late replication regions were easily and quickly visualized in all cells, where inactive Xs are marked with strong green fluorescence. It was observed that the normal X-chromosome was preferentially inactivated in patients with balanced X-autosome translocations; while the aberrant X-chromosome was inactivated in most cells from patients with unbalanced alterations. By performing the fluorescence-based EdU assay, the differences between the active and inactive X-chromosomes are more easily recognizable than by classic cytogenetic methods. Furthermore, EdU incorporation allows the observation of the late replication regions in autosomal segments present in X derivatives from X-autosome translocations. Therefore, EdU assay permits an accurate and efficient cytogenetic evaluation of the X inactivation pattern with a low-cost, easy to perform and highly reproducible technique.

Mucolipidosis types II and III and non-syndromic stuttering are associated with different variants in the same genes.

Homozygous mutations in GNPTAB and GNPTG are classically associated with mucolipidosis II (ML II) alpha/beta and mucolipidosis III (ML III) alpha/beta/gamma, which are rare lysosomal storage disorders characterized by multiple pathologies. Recently, variants in GNPTAB, GNPTG, and the functionally related NAGPA gene have been associated with non-syndromic persistent stuttering. In a worldwide sample of 1013 unrelated individuals with non-syndromic persistent stuttering we found 164 individuals who carried a rare non-synonymous coding variant in one of these three genes. We compared the frequency of these variants with those in population-matched controls and genomic databases, and their location with those reported in mucolipidosis. Stuttering subjects displayed an excess of non-synonymous coding variants compared to controls and individuals in the 1000 Genomes and Exome Sequencing Project databases. We identified a total of 81 different variants in our stuttering cases. Virtually all of these were missense substitutions, only one of which has been previously reported in mucolipidosis, a disease frequently associated with complete loss-of-function mutations. We hypothesize that rare non-synonymous coding variants in GNPTAB, GNPTG, and NAGPA may account for as much as 16% of persistent stuttering cases, and that variants in GNPTAB and GNPTG are at different sites and may in general, cause less severe effects on protein function than those in ML II alpha/beta and ML III alpha/beta/gamma.

Gagueira desenvolvimental persistente familial: disfluências e prevalência / Familial persistent developmental stuttering: disfluencies and prevalence

Resumo:OBJETIVO:caracterizar e comparar a frequência das disfluências da fala de adultos com gagueira desenvolvimental persistente familial do sexo masculino e feminino, a severidade do distúrbio e determinar a prevalência familial e a razão entre gêneros da gagueira nos familiares dos probandos.MÉTODOS:participaram 30 adultos com gagueira (18 a 53 anos), divididos em dois grupos, sendo 20 do sexo masculino e 10 do sexo feminino. Os procedimentos realizados foram: história clínica e familial, avaliação da fluência e Instrumento de Severidade da Gagueira.RESULTADOS:as porcentagens de disfluências típicas da gagueira (p=0,352), de outras disfluências (p=0,947) e do total das disfluências (p=0,522) foram semelhantes entre os grupos masculino e feminino. A média de disfluências típicas da gagueira foi 5,23% e de outras disfluências 5,50%. O subtipo leve foi manifestado pela maioria dos participantes (83,3%). Os familiares do gênero masculino apresentaram maior risco de apresentar gagueira (p<0,001). Do total de 1002 familiares, 85 apresentaram gagueira. No total de familiares afetados (n=85), 53 eram do sexo masculino e 32 do feminino.CONCLUSÃO:não houve diferenças entre os grupos masculino e feminino nas medidas analisadas. Quanto à frequência das disfluências, aproximadamente metade do total das disfluências foi caracterizada como disfluências típicas da gagueira. O subtipo de gagueira desenvolvimental persistente familial foi caracterizado principalmente por um distúrbio classificado quanto à severidade como leve. O risco dos familiares dos probandos afetados foi de 8,5%. A gagueira afetou mais pessoas do gênero masculino em relação ao feminino, numa proporção de 3,72:1.

Abstract:PURPOSE:to characterize and to compare the frequency of speech disfluency in adults with familial persistent developmental stuttering in males and females, the stuttering severity and then to determinate the familial prevalence and the sexual ratio of stuttering among the families members of the probands.METHODS:participants were 30 adults who stutter (ages between 18 and 53 years old), divided in two groups: one with 20 males, and the other with 10 females. Data were gathered by clinical and familial history, fluency assessment and Stuttering Severity Instrument.RESULTS:the percentages of stuttering-like disfluencies (SLD) (p=0.352), of other disfluencies (OD) (p=0.947) and of total disfluencies (TD) (p=0.522) were similar between the males and females. The participants showed a mean of 5.23% of SLD and 5.5% of OD. The mild subgroup was the prevalent among the participants (83.3%). The male families' members showed greater risk to stutter when compared to the females (p<0.001). The results of 1002 families' members showed 85 familiars with stuttering, which 53 were male and 32 female.CONCLUSIONS:there were no differences between the males and females concerning to the analyzed measures. Regarding the frequency of disfluencies the results show that around a half of total disfluencies was characterized as SLD. The subgroup of familial persistent developmental stuttering was characterized mainly as mild. The risk among relatives of affected probands was 8.5%.The familial prevalence data showed that risk that a person have to manifest stuttering when there is some familial affected was 8.5%.The sexual ratio showed stuttering affecting mainly males than females, and was 3.72:1.

X-linked intellectual disability related genes disrupted by balanced X-autosome translocations.

Detailed molecular characterization of chromosomal rearrangements involving X-chromosome has been a key strategy in identifying X-linked intellectual disability-causing genes. We fine-mapped the breakpoints in four women with balanced X-autosome translocations and variable phenotypes, in order to investigate the corresponding genetic contribution to intellectual disability. We addressed the impact of the gene interruptions in transcription and discussed the consequences of their functional impairment in neurodevelopment. Three patients presented with cognitive impairment, reinforcing the association between the disrupted genes (TSPAN7-MRX58, KIAA2022-MRX98, and IL1RAPL1-MRX21/34) and intellectual disability. While gene expression analysis showed absence of TSPAN7 and KIAA2022 expression in the patients, the unexpected expression of IL1RAPL1 suggested a fusion transcript ZNF611-IL1RAPL1 under the control of the ZNF611 promoter, gene disrupted at the autosomal breakpoint. The X-chromosomal breakpoint definition in the fourth patient, a woman with normal intellectual abilities, revealed disruption of the ZDHHC15 gene (MRX91). The expression assays did not detect ZDHHC15 gene expression in the patient, thus questioning its involvement in intellectual disability. Revealing the disruption of an X-linked intellectual disability-related gene in patients with balanced X-autosome translocation is a useful tool for a better characterization of critical genes in neurodevelopment. © 2015 Wiley Periodicals, Inc.

Clinical and molecular heterogeneity in brazilian patients with sotos syndrome.

Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macrocephaly, distinctive facial features and variable degree of intellectual disability. Haploinsufficiency of the NSD1 gene at 5q35.3, arising from 5q35 microdeletions, point mutations, and partial gene deletions, accounts for a majority of patients with SoS. Recently, mutations and possible pathogenetic rare CNVs, both affecting a few candidate genes for overgrowth, have been reported in patients with Sotos-like overgrowth features. To estimate the frequency of NSD1 defects in the Brazilian SoS population and possibly reveal other genes implicated in the etiopathogenesis of this syndrome, we collected a cohort of 21 Brazilian patients, who fulfilled the diagnostic criteria for SoS, and analyzed the NSD1 and PTEN genes by means of multiplex ligation-dependent probe amplification and mutational screening analyses. We identified a classical NSD1 microdeletion, a novel missense mutation (p.C1593W), and 2 previously reported truncating mutations: p.R1984X and p.V1760Gfs*2. In addition, we identified a novel de novo PTEN gene mutation (p.D312Rfs*2) in a patient with a less severe presentation of SoS phenotype, which did not include pre- and postnatal overgrowth. For the first time, our study implies PTEN in the pathogenesis of SoS and further emphasizes the existence of ethno-geographical differences in NSD1 molecular alterations between patients with SoS from Europe/North America (70-93%) and those from South America (10-19%).

Linguagem narrativa e fluência na síndrome de down: uma revisão / Narrative language and fluency in down syndrome: a review

A síndrome de Down é uma condição na qual os indivíduos apresentam comprometimento intelectual e alterações de linguagem oral. A disfluência de fala está presente tanto durante a conversa espontânea como em produções orais de narrativas direcionadas. Este estudo teve como principal objetivo revisar a literatura sobre a disfluência e a narrativa em indivíduos com a síndrome de Down, publicada entre 2002 e 2012, em bases de dados eletrônicos. Foram encontrados 17 artigos e selecionados oito, de acordo com os critérios de inclusão e exclusão. Destes, dois discorriam especificamente sobre a disfluência na síndrome de Down, e seis sobre a narrativa nesta população. A deficiência intelectual é parte do fenótipo dos indivíduos com SD e, em decorrência do comprometimento intelectual, prejuízos na aquisição e no desenvolvimento da linguagem. Estudos específicos, principalmente sobre a fluência/disfluência; e, sobre o desempenho na tarefa da narrativa, ainda são escassos e inconclusivos. A disfluência não aparece na maioria das descrições do fenótipo de linguagem dos indivíduos com esta condição, que mereceria, estudos clínicos adicionais.

Down’s syndrome is a condition in which individuals have intellectual impairment and oral language disorders. Speech disfluency is present during both spontaneous conversations as in productions of directed oral narratives. This study aimed to review the published literature between 2002 and 2012 in eletronic databases on disfluency and narrative in individuals with Down syndrome. There were 17 articles and eight were selected according to the criteria of inclusion and exclusion. Two of these articles specifically discoursed on dysfluency in Down’s syndrome and the other six on the narrative in this population. Intellectual disability is part of the phenotype of individuals with DS and, as a result of the intellectual impairment, losses occur on the acquisition and development of language. Specific studies about, mainly on fluency/disfluency, and the performance on a task of narrative and, are still scarce and inconclusive. Disfluency doesn’t appear in most descriptions of the language phenotype of individuals with this condition, which would deserve additional clinical studies.

A study of the role of the FOXP2 and CNTNAP2 genes in persistent developmental stuttering.

A number of speech disorders including stuttering have been shown to have important genetic contributions, as indicated by high heritability estimates from twin and other studies. We studied the potential contribution to stuttering from variants in the FOXP2 gene, which have previously been associated with developmental verbal dyspraxia, and from variants in the CNTNAP2 gene, which have been associated with specific language impairment (SLI). DNA sequence analysis of these two genes in a group of 602 unrelated cases, all with familial persistent developmental stuttering, revealed no excess of potentially deleterious coding sequence variants in the cases compared to a matched group of 487 well characterized neurologically normal controls. This was compared to the distribution of variants in the GNPTAB, GNPTG, and NAGPA genes which have previously been associated with persistent stuttering. Using an expanded subject data set, we again found that NAGPA showed significantly different mutation frequencies in North Americans of European descent (p=0.0091) and a significant difference existed in the mutation frequency of GNPTAB in Brazilians (p=0.00050). No significant differences in mutation frequency in the FOXP2 and CNTNAP2 genes were observed between cases and controls. To examine the pattern of expression of these five genes in the human brain, real time quantitative reverse transcription PCR was performed on RNA purified from 27 different human brain regions. The expression patterns of FOXP2 and CNTNAP2 were generally different from those of GNPTAB, GNPTG and NAPGA in terms of relatively lower expression in the cerebellum. This study provides an improved estimate of the contribution of mutations in GNPTAB, GNPTG and NAGPA to persistent stuttering, and suggests that variants in FOXP2 and CNTNAP2 are not involved in the genesis of familial persistent stuttering. This, together with the different brain expression patterns of GNPTAB, GNPTG, and NAGPA compared to that of FOXP2 and CNTNAP2, suggests that the genetic neuropathological origins of stuttering differ from those of verbal dyspraxia and SLI.

Folic Acid Fortification and Women's Folate Levels in Selected Communities in Brazil - A First Look.

BACKGROUND: Several countries have implemented mandatory folic acid fortification of wheat flour and selected grain products to increase the folate intake of reproductive-aged women. Brazil implemented a folic acid fortification program in 2004. No previous studies have examined folate differences among Brazilian women following the mandate. OBJECTIVE: We evaluate differences in serum and red blood cell (RBC) folate concentrations between two samples of women of childbearing age from selective communities in Brazil, one tested before (N = 116) and the other after the mandate (N = 240). METHODS: We compared the baseline folate levels of women enrolled in a prevention study shortly before the fortification mandate was implemented, to baseline levels of women from the same communities enrolled in the same study shortly after fortification began. The participants were women enrolled in a folate supplementation clinical trial, at a hospital specializing in treating craniofacial anomalies in the city of Bauru from January 29, 2004 to April 27, 2005. We only compared baseline folate levels before the women received oral cleft prevention program (OCPP) folic acid supplements. RESULTS: Women enrolled after the fortification mandate had higher means of serum folate (20.3 versus 11.2 nmol/L; p < 0.001) and RBC folate (368.3 versus 177.6 nmol/L; p < 0.001) than women enrolled before the mandate. Differences in folate levels between the two groups remained after adjusting for several co-variables. CONCLUSIONS: The results suggest that serum and RBC folate levels among women of childbearing age increased after implementing the folic acid fortification mandate in Brazil.

A rare non-Robertsonian translocation involving chromosomes 15 and 21.

CONTEXT: Robertsonian translocations (RT) are among the most common balanced structural rearrangements in humans and comprise complete chromatin fusion of the long arm of two acrocentric chromosomes. Nevertheless, non-Robertsonian translocation involving these chromosomes is a rare event. CASE REPORT: We report a de novo unbalanced translocation involving chromosomes 15 and 21. The newborn was the daughter of a 29-year-old mother and a 42-year-old father. The couple was non-consanguineous. Clinical findings led to the diagnosis of Down syndrome (DS) with severe congenital heart defects (persistent arterial duct, and complete atrioventricular septal defect), as well as low birth length and weight (< 5th and < 10th percentile, respectively, based on specific measurement curves for DS). Conventional cytogenetic analysis revealed the karyotype 46,XX,der(15)(15pter → 15q26.2::21q11.2 → 21 qter). The translocation was confirmed by means of fluorescence in situ hybridization. The parents had normal karyotypes. CONCLUSIONS: Differently from RT, in our case a rare event occurred involving the distal segment of 15q and the proximal segment of 21q. Only two reports of this translocation, involving chromosomes 15 and 21 but different breakpoints, have been described so far. The association between 21q duplication and 15q deletion makes it difficult to separate the effect of each chromosome, but might also be responsible for increasing the growth retardation, as detected in our case. Cytogenetic analysis on DS patients is mandatory not only to confirm the diagnosis, but also to assess the risk of recurrence at genetic counseling, as well as to evaluate the contribution of other chromosome aberrations in the final phenotype.

High dosage folic acid supplementation, oral cleft recurrence and fetal growth.

OBJECTIVES: To evaluate the effects of folic acid supplementation on isolated oral cleft recurrence and fetal growth. PATIENTS AND METHODS: The study included 2,508 women who were at-risk for oral cleft recurrence and randomized into two folic acid supplementation groups: 0.4 and 4 mg per day before pregnancy and throughout the first trimester. The infant outcome data were based on 234 live births. In addition to oral cleft recurrence, several secondary outcomes were compared between the two folic acid groups. Cleft recurrence rates were also compared to historic recurrence rates. RESULTS: The oral cleft recurrence rates were 2.9% and 2.5% in the 0.4 and 4 mg groups, respectively. The recurrence rates in the two folic acid groups both separately and combined were significantly different from the 6.3% historic recurrence rate post the folic acid fortification program for this population (p = 0.0009 when combining the two folic acid groups). The rate of cleft lip with palate recurrence was 2.9% in the 0.4 mg group and 0.8% in the 4 mg group. There were no elevated fetal growth complications in the 4 mg group compared to the 0.4 mg group. CONCLUSIONS: The study is the first double-blinded randomized clinical trial (RCT) to study the effect of high dosage folic acid supplementation on isolated oral cleft recurrence. The recurrence rates were similar between the two folic acid groups. However, the results are suggestive of a decrease in oral cleft recurrence compared to the historic recurrence rate. A RCT is still needed to identify the effect of folic acid on oral cleft recurrence given these suggestive results and the supportive results from previous interventional and observational studies, and the study offers suggestions for such future studies. The results also suggest that high dosage folic acid does not compromise fetal growth.

A rare non-Robertsonian translocation involving chromosomes 15 and 21 / Uma rara translocacao nao robertsoniana envolvendo os cromossomos 15 e 21

CONTEXT: Robertsonian translocations (RT) are among the most common balanced structural rearrangements in humans and comprise complete chromatin fusion of the long arm of two acrocentric chromosomes. Nevertheless, non-Robertsonian translocation involving these chromosomes is a rare event. CASE REPORT: We report a de novo unbalanced translocation involving chromosomes 15 and 21. The newborn was the daughter of a 29-year-old mother and a 42-year-old father. The couple was non-consanguineous. Clinical findings led to the diagnosis of Down syndrome (DS) with severe congenital heart defects (persistent arterial duct, and complete atrioventricular septal defect), as well as low birth length and weight (< 5th and < 10th percentile, respectively, based on specific measurement curves for DS). Conventional cytogenetic analysis revealed the karyotype 46,XX,der(15)(15pter→15q26.2::21q11.2→21qter). The translocation was confirmed by means of fluorescence in situ hybridization. The parents had normal karyotypes. CONCLUSIONS: Differently from RT, in our case a rare event occurred involving the distal segment of 15q and the proximal segment of 21q. Only two reports of this translocation, involving chromosomes 15 and 21 but different breakpoints, have been described so far. The association between 21q duplication and 15q deletion makes it difficult to separate the effect of each chromosome, but might also be responsible for increasing the growth retardation, as detected in our case. Cytogenetic analysis on DS patients is mandatory not only to confirm the diagnosis, but also to assess the risk of recurrence at genetic counseling, as well as to evaluate the contribution of other chromosome aberrations in the final phenotype. .

CONTEXTO: Translocações robertsonianas (TR) estão entre os rearranjos estruturais balanceados mais comuns em humanos e compreendem a fusão da cromatina completa do braço longo de dois cromossomos acrocêntricos. No entanto, são raras as translocações não Robertsonianas envolvendo esses cromossomos. RELATO DE CASO: Nós descrevemos uma translocação não balanceada de novo envolvendo os cromossomos 15 e 21. A recém-nascida era filha de uma mãe de 29 anos e de um pai de 42 anos, casal não consanguíneo. Os achados clínicos levaram ao diagnóstico de síndrome de Down (SD) com defeitos cardíacos congênitos graves (persistência do canal arterial e defeito do septo atrioventricular completo), além de baixos comprimento e peso ao nascimento (< 5o e < 10o percentil em curvas de medidas específicas para SD, respectivamente). A análise citogenética convencional revelou o cariótipo 46,XX,der(15)(15pter→15q26.2::21q11.2→21qter). A translocação foi confirmada por hibridação in situ fluorescente. Os pais apresentavam cariótipo normal. CONCLUSÕES: Diferentemente das TR, nesse caso ocorreu evento raro envolvendo o segmento distal de 15q e o proximal de 21q. Apenas dois relatos dessa translocação, envolvendo os cromossomos 15 e 21 e diferentes pontos de quebra, já foram descritos. A associação entre duplicação 21q e deleção 15q dificulta a distinção dos efeitos de cada cromossomo, mas poderia também ser responsável pelo acentuado retardo de crescimento. A análise citogenética é obrigatória em pacientes com SD não apenas para confirmar o diagnóstico, mas também para avaliar o risco de recorrência no aconselhamento genético, bem como avaliar a contrib...

Características clínicas, comportamentais, cognitivas e comunicativa na síndrome Smith-Magenis / Clinical, cognitive, behavioral and communicative features of Smith-Magenis syndrome

TEMA: o objetivo deste estudo foi descrever os aspectos clínico, comportamental, cognitivo e comunicativo de indivíduos com o diagnóstico genético da Síndrome Smith-Magenis. PROCEDIMENTOS: participaram dois indivíduos do sexo masculino, de nove e 19 anos. Realizou-se a avaliação genética clínica e laboratorial (teste FISH, utilizando sonda para região 17p11.2). A avaliação psicológica constou da observação comportamental e aplicação da Escala Wechsler de Inteligência. A avaliação Fonoaudiológica foi realizada por meio de procedimentos formais e informais e avaliação auditiva periférica. RESULTADOS: a análise genética clínica evidenciou as características fenotípicas da síndrome Smith-Magenis, confirmada pela avaliação laboratorial. A avaliação psicológica evidenciou o fenótipo comportamental peculiar da síndrome Smith-Magenis e comprovou a deficiência intelectual de grau moderado nos dois indivíduos. A avaliação fonoaudiológica mostrou alterações no desempenho linguístico, com alterações nos níveis fonológico, semântico, sintático e pragmático e nas habilidades psicolinguísticas, interferindo nas habilidades comunicativas e de aprendizagem. A avaliação auditiva indicou audição periférica dentro de parâmetros de normalidade. CONCLUSÃO: a avaliação multidisciplinar favoreceu a descrição dos aspectos clínicos, comportamentais, cognitivos que pertencem ao fenótipo comportamental da síndrome Smith-Magenis e permitiu verificar que estes apresentam graves alterações da linguagem oral, das habilidades psicolinguísticas e do processamento das informações visuais e auditivas com reflexos marcantes no desenvolvimento das habilidades comunicativas e processos de aprendizagem.

BACKGROUND: this study aimed to describe the clinical, behavioral, cognitive and communicative features of subjects with Smith-Magenis Syndrome genetic diagnosis. PROCEDURES: the subjects were two males, 09 and 19 year old. We performed a clinical and laboratory genetic evaluation (FISH assay using probes for the region 17p11.2). The psychological evaluation consisted of behavioral observation and application of the Wechsler Intelligence Scale. Speech evaluation was performed by means of formal and informal procedures and peripheral hearing evaluation. RESULTS: the clinical genetic analysis showed the phenotypic characteristics of Smith-Magenis syndrome, confirmed by laboratory evaluation. The psychological evaluation revealed the peculiar phenotype behavioral of Smith-Magenis syndrome and confirmed the moderate intellectual disabilities in two subjects. Speech evaluation showed changes in language performance, with changes in phonological, semantic, syntactic and pragmatic levels and psycholinguistic skills, interfering with communication and learning skills. The hearing test showed peripheral hearing within normal parameters. CONCLUSION: the multidisciplinary approach made easier the description of clinical, behavioral, cognitive aspects, belonging to the behavioral phenotype of Smith-Magenis syndrome and showed that these changes have severe oral language alterations in skills and psycholinguistic processing of visual and auditory information with remarkable consequences on the development of communicative skills and learning processes.

Gagueira desenvolvimental persistente familial: perspectivas genéticas / Familial persistent developmental stuttering: genetic perspectives

A gagueira é uma desordem da comunicação oral que tem uma característica multidimensional. A predisposição biológica no desenvolvimento da gagueira ainda não é bem compreendida, mas contribuições genéticas para esta predisposição são reforçadas tanto por referências à agregação familial da gagueira, quanto à gagueira familial, que têm aparecido na literatura há mais de 70 anos. Assim, procuramos estabelecer uma revisão quanto aos prováveis fatores genéticos envolvidos com a manifestação da gagueira desenvolvimental persistente familial. A identificação de genes relacionados à gagueira, bem como de alterações em suas estruturas (por exemplo, mutações), contribuem significativamente para sua compreensão. O modelo exato de transmissão da herança genética para a gagueira ainda não está claramente definida e, provavelmente pode ser diferente entre diferentes famílias e populações. As análises genômicas demonstram, concomitantemente, a relevância dos componentes genéticos envolvidos e sua complexidade, sugerindo assim tratar-se de uma doença poligênica, na qual diversos genes de efeitos variados podem estar envolvidos com o aumento da susceptibilidade de ocorrência da gagueira. O clínico deverá estar alerta ao fato de que uma criança com histórico familial positivo para gagueira poderá ter uma forte tendência a desenvolver o distúrbio de forma crônica. É importante que o clínico esteja atento, de modo a fornecer às famílias orientações precisas sobre o distúrbio. As avaliações objetivas e os tratamentos controlados têm um papel muito importante para o domínio da evolução do distúrbio.

Stuttering is a disorder of oral communication that has a multidimensional character. The biological predisposition in the development of stuttering is still not well understood, but genetic contributions to this predisposition are enhanced by both references to the familial aggregation of stuttering and to familial stammering, which have appeared in the literature for over 70 years. Thus, we conducted a review as to the likely genetic factors involved in the manifestation of familial persistent developmental stuttering. The identification of genes related to stuttering, as well as alterations in their structures (e.g., mutations), contribute significantly to its understanding. The exact transmission pattern of genetic inheritance for stuttering is still not clearly defined and might probably be different among different families and populations. Genomic analysis have shown, concomitantly, the relevance of the genetic components involved and their complexity, thus suggesting that this is a polygenic disease in which several genes of different effects may be involved with the increased susceptibility of occurrence of stuttering. The clinician should be alert to the fact that a child with positive familial history for stuttering may have a strong tendency to develop the disorder chronically. It is important that the clinician is aware, in order to provide precise information about the disorder to the families. Objective evaluations and controlled treatments play an important role in the knowledge of the disorder's development.

Oral cleft prevention program (OCPP).

BACKGROUND: Oral clefts are one of the most common birth defects with significant medical, psychosocial, and economic ramifications. Oral clefts have a complex etiology with genetic and environmental risk factors. There are suggestive results for decreased risks of cleft occurrence and recurrence with folic acid supplements taken at preconception and during pregnancy with a stronger evidence for higher than lower doses in preventing recurrence. Yet previous studies have suffered from considerable design limitations particularly non-randomization into treatment. There is also well-documented effectiveness for folic acid in preventing neural tube defect occurrence at 0.4 mg and recurrence with 4 mg. Given the substantial burden of clefting on the individual and the family and the supportive data for the effectiveness of folic acid supplementation as well as its low cost, a randomized clinical trial of the effectiveness of high versus low dose folic acid for prevention of cleft recurrence is warranted. METHODS/DESIGN: This study will assess the effect of 4 mg and 0.4 mg doses of folic acid, taken on a daily basis during preconception and up to 3 months of pregnancy by women who are at risk of having a child with nonsyndromic cleft lip with/without palate (NSCL/P), on the recurrence of NSCL/P. The total sample will include about 6,000 women (that either have NSCL/P or that have at least one child with NSCL/P) randomly assigned to the 4 mg and the 0.4 mg folic acid study groups. The study will also compare the recurrence rates of NSCL/P in the total sample of subjects, as well as the two study groups (4 mg, 0.4 mg) to that of a historical control group. The study has been approved by IRBs (ethics committees) of all involved sites. Results will be disseminated through publications and presentations at scientific meetings. DISCUSSION: The costs related to oral clefts are high, including long term psychological and socio-economic effects. This study provides an opportunity for huge savings in not only money but the overall quality of life. This may help establish more specific clinical guidelines for oral cleft prevention so that the intervention can be better tailored for at-risk women. CLINICALTRIALS.GOV IDENTIFIER: NCT00397917.