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.

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10–4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model.

The population of Robinson Crusoe Island is estimated at 633 inhabitants. The current population has a common origin from the first eight families who colonized the island at the end of the 19th century. The objective of this study was to determine the rates of consanguinity, the average coefficients of inbreeding, the types of consanguineous marriages and the inbreeding evolution between 1900 and 2000 on the island. All marriages registered on the island, from the last colonization until 2000 (417 in total), were included in the analysis. In addition, extended genealogies were obtained. The consanguinity rate was 14.9% and the average coefficient of inbreeding (α) 54.05 × 10(-4). The most frequent type of consanguineous marriages was between second cousins, followed by first cousins. The average value of the first/second cousin ratio was 1.11. The population of Robinson Crusoe Island has a high rate of inbreeding. The unique characteristic of the island - its small current population, originating from just a few families, with small rate of gene flow - could explain the observed high and increasing consanguinity.

Severe periodontitis is prevalent in Down syndrome (DS). This study aimed to identify genetic variations associated with periodontitis in individuals with DS. The study group was distributed into DS patients with periodontitis (n = 50) and DS patients with healthy periodontium (n = 36). All samples were genotyped with the “Axiom Spanish Biobank” array, which contains 757,836 markers. An association analysis at the individual marker level using logistic regression, as well as at the gene level applying the sequence kernel association test (SKAT) was performed. The most significant genes were included in a pathway analysis using the free DAVID software. C12orf74 (rs4315121, p = 9.85 × 10−05, OR = 8.84), LOC101930064 (rs4814890, p = 9.61 × 10−05, OR = 0.13), KBTBD12 (rs1549874, p = 8.27 × 10−05, OR = 0.08), PIWIL1 (rs11060842, p = 7.82 × 10−05, OR = 9.05) and C16orf82 (rs62030877, p = 8.92 × 10−05, OR = 0.14) showed a higher probability in the individual analysis. The analysis at the gene level highlighted PIWIL, MIR9-2, LHCGR, TPR and BCR. At the signaling pathway level, PI3K-Akt, long-term depression and FoxO achieved nominal significance (p = 1.3 × 10−02, p = 5.1 × 10−03, p = 1.2 × 10−02, respectively). In summary, various metabolic pathways are involved in the pathogenesis of periodontitis in DS, including PI3K-Akt, which regulates cell proliferation and inflammatory response.

Robinson Crusoe Island is a geographically and socially isolated settlement located over 600km west of the Port of Valparíso, Chile. An unusually high incidence (30%) of the Chilean equivalent of developmental language disorder (TEL) has been reported in Islander children, with 90% of these affected children found to be direct descendants of a pair of original founderbrothers, therefore strongly suggesting a shared genetic basis. Here we utilise whole-genome sequencing to investigate potential underlying variants in a panel of thirty-four genes known to play a role in language disorders, in seven TEL affected and ten unaffected islanders. We use this targeted approach to look for rare, shared variants that Here we report a comprehensive examination of genes directly implicated in languagerelated mechanisms to identify 'low hanging fruit' of causative monogenic Mendelian variants, and complex association model of increased susceptibility in developmental language disorder found on Robinson Crusoe Island.

María Angélica Fernández (5) , Hernán M. Palomino (6) RESUMEN Objetivo: el presente trabajo pretende evaluar el efecto de los aparatos ortodóncicos fi jos linguales en la articulación de los fones, en pacientes que hablen español chileno, y la adaptación a estos efectos dentro del primer mes de uso de los aparatos. Métodos: la muestra consistió en 13 pacientes que acudieron para instalación de aparato ortodóncico fi jo lingual. Se realizó un examen fonoarticulatorio en condiciones estandarizadas, en 5 momentos diferentes: previo a la instalación de los aparatos fi jos (E0), inmediatamente después de realizada esta (E1), a las 24 horas posteriores (E2), a los 7 días (E3) y un mes después de la instalación (E4). Se determinaron los fones afectados en los distintos momentos de examen respecto a la línea base dada por el examen previo, y se analizó su resolución. Resultados: se observaron cambios signifi cativos en el punto de articulación de los fones [d], [s] y [r]Los fones [d] y [s] mostraron una resolución favorable dentro del primer mes de uso de los aparatos. El fone vibrante múltiple [r] no mostró una recuperación de la alteración una vez cumplido un mes de uso de los aparatos ortodóncicos. Conclusiones: la instalación de aparato ortodóncico fi jo lingual produce modifi caciones en el punto de articulación de los fones consonánticos, las cuales tienden a mejorar dentro del primer mes de uso de los aparatos, con excepción del fone vibrante múltiple [r].

The study substantiates the existence of a familial form of speech and language disorder on Robinson Crusoe Island. Furthermore, we find that the familiarity is stable regardless of non-verbal IQ, supporting the recent movement to reduce the importance of non-verbal IQ criterion in DLD diagnoses.

Indigenous origin in Chile is an independent risk factor for precocious gonadarche and pubarche in boys but not in girls.