This poster (#2574T) will be presented at the ASHG Annual Meeting by Chris Tan, our genetic counselor, Thursday October 24: 11:30am-12:30pm. Stop by and learn more

Intellectual Disability (ID), with a prevalence estimated to be between 1-3% of the general population, is a lifelong disability typically presenting in infancy or early childhood.   It is estimated that mutations in the genes on the X chromosome may account for about 10% of all cases of ID, thus molecular investigations into the X chromosome in elucidating the etiology of an individual with ID have been routinely suggested. Due to the genetic and phenotypic heterogeneity of patients with non-syndromic ID, multi-gene testing, the concurrent analysis of multiple genetic loci, can be beneficial.  The utilization of high throughput, massively parallel sequencing, or next generation sequencing (NGS), has greatly improved the ability to simultaneously analyze multiple genetic loci, and X-linked ID (XLID) panels including analysis of a large panel of X-linked genes can be used for diagnosis.  

We performed next generation sequencing analysis of a total of 95 genes implicated in non-syndromic ID.  The 95 genes included 61 X-linked genes, 20 Autosomal Recessive genes and 14 Autosomal Dominant genes. Genes were selected based on a criterion of ‘non-syndromic ID’ although some syndromic genes were also included, as a range of mutations in a single gene can sometimes confer both syndromic and non-syndromic phenotypes.  As more genes are identified and implicated in non-syndromic ID, it seems appropriate to consider the inclusion of autosomal genes in multi-gene panel testing. To date, we have studied 38 patients and have identified pathogenic mutations in 5 out of the 38 patients, including two de-novo frameshift mutations in SYNGAP1 (c.1783del and c.2602del), one splicing mutation in TCF4 (c.991-2A>G), one missense mutation in MECP2 (c.397C>T) and one frameshift mutation in AP4B1 (c.311del).  Four out of the five genes in which mutations were identified are autosomal.  Phenotypic information was collected on four out of the five patients.  Both patients identified with the SYNGAP1 mutations were non-dysmorphic and were characterized as having global development delays.  The patients identified with the TCF4 and MECP2 mutations had clinical features that were possibly suggestive of a spectrum of monogenic conditions.

Our five mutation positive cases provide further evidence supporting the utility of including autosomal genes in multi-gene panel analysis of patients with intellectual disability and also highlight the utility of multi-gene sequencing panels to elucidate the etiology of phenotypically overlapping/genetically heterogeneous conditions.