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Revista Da Sociedade Brasileira De Fonoaudiologia, Dec 1, 2012

Molecular Syndromology, 2015

microdeletion, a novel missense mutation (p.C1593W), and 2 previously reported truncating mutatio... more 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%).

eLS, 2015

Stuttering is a common disorder that affects the flow of speech and is characterised by uncontrol... more Stuttering is a common disorder that affects the flow of speech and is characterised by uncontrollable repetitions, prolongations or interruptions in speech. The aetiology of developmental stuttering is still not well understood, however genetic studies over the past decade have made some important advances. Strong evidence for genetic factors in this disorder comes from twin and adoption studies, as well as from family studies that include measures of familial aggregation, segregation and genetic linkage analyses. However, Mendelian segregation of the disorder in families does not occur, and thus stuttering is a complex genetic disorder which poses a challenge for linkage and other genetic analyses. Nevertheless, genetic linkage studies have defined numerous loci-carrying genes that can cause persistent stuttering, and several causative genes have recently been identified. Application of massively parallel DNA (deoxyribonucleic acid) sequencing holds the promise of facilitating the identification of genes that cause stuttering and other speech and language disorders. Key Concepts Stuttering is a disorder of the flow of speech, in which the affected individuals know what they wish to say but are unable to say it owing to uncontrollable repetitions, prolongations or interruptions in their speech. Developmental stuttering typically arises at a characteristic time during the acquisition of speech in children, and approximately 75–80% children recover, sometimes with and sometimes without the aid of speech therapy. Twin studies provide strong evidence for the involvement of genetic factors in developmental stuttering. Stuttering is a complex genetic disorder in which Mendelian segregation does not occur. Genetic linkage studies in families have defined numerous loci for persistent stuttering, and several causative genes have recently been identified. Keywords: speech; developmental stuttering; genetic factors; heritability; twin and adoption studies; linkage analysis; genome-wide association analysis; GNPTAB; GNPTG; NAGPA

Journal of Human Genetics, Mar 10, 2011

Genetics and Molecular Research, 2014

Although twin, adoption, and family studies demonstrate that genetic factors are involved in the ... more Although twin, adoption, and family studies demonstrate that genetic factors are involved in the origins of stuttering, the mode of transmission of the disorder in families is not well defined and stuttering is considered a genetically complex trait. We performed a genomewide linkage scan in a group of 43 Brazilian families, each containing multiple cases of persistent developmental stuttering. Linkage analysis under a dominant model of inheritance generated significant evidence of linkage in two Brazilian families, with a combined maximum 2095

Journal of Human Genetics, Mar 1, 2011

Revista da Sociedade Brasileira de Fonoaudiologia, 2012

A gagueira é uma desordem da comunicação oral que tem uma característica multidimensional. A pred... more 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...

Neurobiology of Disease, 2014

A number of speech disorders including stuttering have been shown to have important genetic contr... more 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.

European journal of human genetics: EJHG

Homozygous mutations in GNPTAB and GNPTG are classically associated with mucolipidosis II (ML II)... more 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 al...

Molecular syndromology, 2015

Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macr... more 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.C1...