Evaluation of phenotypic abnormalities among patients with intellectual disability

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The development of more advanced genetic techniques like the SNP-­‐array and genome wide sequencing techniques contributed largely to the identifying of genetic causes of intellectual disability. Interpretation of the genetic variations found with these techniques, however, remains difficult. Multiple patients with the same phenotype and genotype are needed to decide about a variant’s pathogenicity. It is although difficult to determine how many patients are needed for a statistic significant conclusion. More information about the specificity of phenotypic features will greatly improve these considerations, as genetic variants in combination with rare features can be declared pathogenic when fewer patients are found than variants occurring in combination with common features. However, at the moment no comprehensive overview of the phenotype of patients with ID is available. This article provides an overview of the specificity of phenotypic features by an extensive evaluation of the phenotype of a large cohort of 7407 well-­‐defined patients with ID. From 1320 of these patients very detailed information was available, these patients formed a best-­‐ defined group used for the analyses, the other 6087 a well-­‐defined replication cohort An overview of the frequency of all Human Phenotype Ontology (HPO) features in these patients is presented. In addition we found 1534 combinations of positively associated features. These associations consisted of expected associations like Cleft lip (HP:0000204) and Cleft palate (HP:0000175) (P<0,001) but also unexpected associations like Short stature (HP:0004322) and Abnormality of the forebrain HP:0100547) (P<0,001). Most of these 1534 combinations were also associated in the replication-­‐cohort. We also proofed that half of the major anomalies registered by Eurocat occur more in patients with intellectual disability than in the normal population and that patients with more congenital anomalies have a higher chance of having facial dysmorphism.
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