Candidate gene variant effects on language disorders in Robinson Crusoe Island.

Background: Robinson Crusoe Island is a geographically and socially isolated settlement located over 600 km west of the Port of Valparíso, Chile. An unusually high incidence (30%) of the Chilean equivalent of developmental language disorder (in Spanish, trastorno especifico de lenguaje (TEL)), has been reported in Islander children, with 90% of these affected children found to be direct descendants of a pair of original founder-brothers, therefore strongly suggesting a shared genetic basis. Aim: This study reports a comprehensive examination of 34 genes that have been previously directly implicated in language-related mechanisms. It utilises whole-genome sequencing to investigate potential underlying variants in seven TEL affected and 10 unaffected islanders. The aim was to identify the underlying genetic cause of the TEL phenotype under two inheritance model paradigms; Mendelian monogenic and complex susceptibility. Subjects and methods: A targeted candidate gene approach was used to look for rare, shared variants that may underlie the diagnosis of TEL in a Mendelian genetic model. This study tested whether an overall burden of rare variants is enriched in individuals affected by TEL or with Islanders related to the founder-brother lineage. It further examined if any variants segregate with affection status or with founder-brother-related status and, therefore, may increase risk of developing a language disorder as part of a complex model. Finally, gene-based tests were performed to evaluate relationships between combined variation across candidate genes and TEL affection status. Results: No single pathogenic rare variant segregated with either affection or founder-related status within the 34 candidate genes. Additionally, no evidence was found of an overall increased variant burden in TEL individuals compared to those with TLD. Gene-based analysis found no clear association between the combined effects of variants across the 34 genes and affection status or founder-brother-relatedness. Conclusion: The high prevalence of language disorders found on Robinson Crusoe Island is not caused by either a shared high-impact variant, or an increased burden of variants within candidate genes previously implicated in language disorders. We have comprehensively tested for 'low hanging fruit' in genes implicated in language disorders. Therefore, the underlying cause of TEL on Robinson Crusoe lies outside of these known language disorder genes, or within a complex susceptibility model.

Dental morphological markers as a proxy for ethnicity in Robinson Crusoe Islanders / Marcadores morfológicos dentarios en la estimación de la etnicidad poblacional de la Isla Robinson Crusoe

Chilean Robinson Crusoe Island is a semi-isolated location with unusually high rates of both consanguinity and language disorder. The current population of 633 inhabitants is descended almost exclusively from the colonization at the end of the 19th century, as there were few preceding immigrations to the island. This study investigates the genetic composition and degree of miscegenation within the island population, using dental morphological markers. The universe of island children was studied (n= 128, 3 to 15 years of age) using clinical exams, dental cast, and identification of each individual within a previously-constructed extensive genealogy for the island. The frequencies for Carabelli's cusp (61.7%), shovel-shaped incisor (9.4%), and sixth cusp (2.3%), along with the absence of seventh cusp, are consistent with a primarily Caucasian population. The estimated degree of miscegenation suggests an Amerindian component of 4.3%, which is consistent with the extensive known genealogies of the founders. Characterizing the genetic profile of Robinson Crusoe Island, a location with a remarkably high prevalence of language disorder, facilitates the comparison of the genetic variants underlying this pathology with those identified in European populations.

La isla chilena Robinson Crusoe es un semiaislado geográfico de alta consanguinidad. Su población actual de 633 habitantes proviene de la última colonización ocurrida a finales del siglo XIX y pocas migraciones posteriores, en quienes recientemente se ha descrito una alta incidencia de trastorno de lenguaje. Este estudio estimó el componente genético y grado de miscegenación de la población isleña usando marcadores morfológicos dentarios. Se estudió al universo de niños isleños (n= 128, 3 a 15 años de edad) con exámenes clínicos, modelos dentales y ubicación de cada individuo en genealogías extensas confeccionadas previamente. La frecuencia de Tubérculo de Carabelli fue 61,7%, Diente en Pala 9,4%, tubérculo sexto 2,3% y ausencia del rasgo tubérculo séptimo, lo que concuerda con una población eminentemente caucásica. El grado de miscegenación estima que el componente amerindio de esta población es de 4,3%, que también se evidencia al analizar las genealogías extensas originadas por los colonizadores. La descripción del perfil genético de esta población, donde se han reportado altas prevalencias de trastorno de lenguaje, permitirá comparar con las variantes genéticas subyacentes a esta patología descritas para poblaciones europeas.

Alta prevalencia de trastorno específico de lenguaje en isla Robinson Crusoe y probable efecto fundador / High prevalence of specific language impairment in Robinson Crusoe Island. A possible founder effect

Specific language impairment (SLI) occurs in 2 percent to 8 percent of preschool children. Major and candidate genes are probably involved. Genetic drift is a cause for the presence of high frequencies of deleterious alíeles of a specific disease and the founder effect is one of its forms. Robinson Crusoe Island has 633 inhabitants and its actual population began with 8 families that repopulated the island at the end ofXIXth century. Aim To assess the frequency of specific language impairment among children living in Robinson Crusoe Island. Material and methods: All 66 children aged between 3 and 9 years living in the island, were studied. Parents were interviewed and in children, non verbal intelligence, audiometric parameters, comprehension and expression of oral language were assessed. Extended genealogies were also performed. Results: Forty children had at least one parent that was descending of founder families. Among these, 35 percent had SLI. Eighth five percent of SLI affected children came from the same colonizer family. Conclusions: The prevalence of SLI in Robinson Crusoe Island is higher than that reponed in mainland Chile and abroad. This high prevalence, associated to a high frequency of consanguinity, supports the influence of genetic mechanisms in SLI transmission, based on a founder effect.