RESUMO
Specific language impairment (SLI) is an unexpected deficit in the acquisition of language skills and affects between 5 and 8% of pre-school children. Despite its prevalence and high heritability, our understanding of the aetiology of this disorder is only emerging. In this paper, we apply genome-wide techniques to investigate an isolated Chilean population who exhibit an increased frequency of SLI. Loss of heterozygosity (LOH) mapping and parametric and non-parametric linkage analyses indicate that complex genetic factors are likely to underlie susceptibility to SLI in this population. Across all analyses performed, the most consistently implicated locus was on chromosome 7q. This locus achieved highly significant linkage under all three non-parametric models (max NPL = 6.73, P = 4.0 × 10(-11)). In addition, it yielded a HLOD of 1.24 in the recessive parametric linkage analyses and contained a segment that was homozygous in two affected individuals. Further, investigation of this region identified a two-SNP haplotype that occurs at an increased frequency in language-impaired individuals (P = 0.008). We hypothesise that the linkage regions identified here, in particular that on chromosome 7, may contain variants that underlie the high prevalence of SLI observed in this isolated population and may be of relevance to other populations affected by language impairments.
Assuntos
Cromossomos Humanos Par 7/genética , Predisposição Genética para Doença , Transtornos do Desenvolvimento da Linguagem/genética , Perda de Heterozigosidade , Criança , Pré-Escolar , Chile , Mapeamento Cromossômico , Cromossomos Humanos Par 7/química , Feminino , Efeito Fundador , Ligação Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Modelos Genéticos , Linhagem , FenótipoRESUMO
BACKGROUND: Choreoacanthocytosis (CHAC) (Online Mendelian Inheritance in Man accession No. 200150) is a hereditary neurodegenerative syndrome characterized by movement disorders, cognitive decline, myopathy, behavioral changes, and acanthocytosis and is caused by mutations in the VPS13A gene. OBJECTIVE: To describe the cases of 2 Mexican women with clinical and molecular characteristics compatible with CHAC. DESIGN: Case reports. Patients Choreoacanthocytosis was identified in 2 Mexican mestizo sisters with healthy consanguineous parents. Clinical manifestations began at different ages. RESULTS: The onset of signs and symptoms of CHAC in the proband was at age 32 years and was characterized by balancing problems followed by chorea, compulsive lip and tongue biting with buccolingual self-mutilation, dysarthria, dysphagia, and weight loss. The first clinical manifestations in the proband's sister occurred at age 45 years and included multiple motor and verbal tics, with coprolalia, followed by lip and tongue biting, self-mutilation, and chorea. The clinical findings in both sisters were remarkable for acanthocytosis that developed late, when neurologic changes were already evident. Mutation screening of the VPS13A gene revealed homozygosity for the frameshift mutation c.3556_3557dupAC in exon 33. Currently, the proband's sister, in whom neurologic defects developed 13 years after onset of CHAC in the proband, is the least affected. CONCLUSIONS: The same mutation of the VPS13A gene can be expressed differently in the same family. This observation confirms the notion that there is considerable heterogeneity in the clinical manifestation of CHAC.