Targeted Next Generation Sequencing as a tool for large-scale early diagnosis of inborn errors of metabolism in Ghana
Inborn Errors of Metabolism (IEM) is a group of complex heterogeneous diseases caused by a deficiency or decreased activity of a single enzyme or its cofactor in a pathway of intermediary metabolism due to deleterious mutations in a single gene. The defective gene is often responsible for encoding either the enzyme itself or the cofactor needed for optimal enzyme activity. Children born with IEM have a defective metabolic pathway which increases their risk of death in early life or neurological damage with resultant poor quality of life. For most IEM, early diagnosis and proper treatment can greatly enhance both survival and quality of life of affected children. IEM causing mutations are many, however, certain specific mutations are often more prevalent in specific populations than others and their frequencies are higher in areas where intra-ethnic marriages are more encouraged than inter-ethnic marriages. In developed countries, such population-level significant IEM-causing mutations have been identified and constituted into genotyping panels for routine screening of children in newborn screening programs (NSPs) which are used alongside more traditional biochemical screening. This allows early detection of IEM and for early intervention measures to be initiated. In Ghana, there have been few published case reports on IEM mainly from the Korle Bu Teaching Hospital, the premier referral hospital in the country and there is a high probability that several IEM cases are undetected and unreported across the many hospitals in Ghana due to lack of reliable and affordable diagnostic tools. This study aims to identify IEM associated mutations in the Ghanaian population by employing a multi-locus gene capture approach using molecular inversion probes (MIPs) followed by parallel deep sequencing on the Illumina MiSeq. The identified IEM associated mutations will subsequently be used to develop a reliable, affordable and high-throughput diagnostic tool that can potentially be adopted for routine IEM-NSP in Ghana.
The goal of this study is to provide a reliable, high-throughput, rapid and low-cost tool for early diagnosis of IEM in the Ghanaian population.
- To identify the frequencies of specific IEM associated mutations in the Ghanaian population using the Molecular Inversion Probes (MIP) technique
- To develop the MIP technique as a low-cost method for the identification of IEM-associated mutations in Ghanaian populations and
- To define a panel of specific IEM associated mutations in Ghana that can be adopted in an IEM-specific NSP for new-borns.
Procurement of molecular inversion probes