Date of Award

2014

Document Type

Open Access Thesis

Department

Genetic Counseling

First Advisor

Michael J Friez

Abstract

Intellectual disability (ID) refers to reduced cognitive function, apparent before the age of 18, that negatively affects a person's learning and adaptive capacity. Approximately 1-3% of the population is affected with ID, males more than females, and most in the mild-to-moderate range. ID creates financial, logistical and psychosocial challenges for affected persons and their families and caregivers. It is estimated that up to 50% of ID has a genetic cause. Molecular genetic diagnosis may help in obtaining services and has important implications for family members, but can be elusive. Genes causing ID are known to be over-represented on the X chromosome. Over 160 X-linked intellectual disability (XLID) syndromes and more than 100 XLID genes have been identified to date. Greenwood Genetic Center (GGC) offers a next-generation sequencing panel of approximately 90 XLID genes. The diagnostic potential offered by large gene panels is offset by the challenges of interpreting variants of uncertain significance (VUS). In this study, molecular and clinical data from 592 cases submitted for XLID panel testing were evaluated for patterns of phenotype and genotype, in order to further the understanding of XLID. We found a low pathogenic hit rate, a high VUS-only rate and a general absence of statistically significant phenotypic patterns. These results highlight the need for appropriate patient selection, full and accurate phenotype reporting and open sharing of information in order to interpret and learn from the results of genetic testing.

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