The diagnosis of inherited metabolic diseases by microarray gene expression profiling

Total mRNA extracted from cultured fibroblast cell lines was hybridized to Affymetrix U133 Plus 2.0 arrays. Expression data was analyzed for the presence of a gene expression signature characteristic of an inherited metabolic disorder and for genes expressing significantly decreased levels of mRNA.No characteristic signatures were found. However, in 16% of cases, disease-associated nonsense and frameshift mutations generating premature termination codons resulted in significantly decreased mRNA expression of the defective gene. The microarray assay detected these changes with high sensitivity and specificity.In patients with a suspected familial metabolic disorder where initial screening tests have proven uninformative, microarray gene expression profiling may contribute significantly to the identification of the genetic defect, shortcutting the diagnostic cascade.At least 300 different IMDs have been described [1] and new disorders are being identified [2,3] due to increasing awareness and advances in identification techniques. The birth prevalence of IMDs in the West Midlands is estimated to be 1 in 784 live births, extrapolating to approximately 800 new cases per year in the UK as a whole [4]. The majority of patients (72%) are diagnosed by the age of 15 years, with only one-third diagnosed by the age of one year. Any hope of effective treatment rests on precise and early diagnosis [4,5]. The diagnosis of IMDs may be a long and tedious process. The first step relies on matching clinical presentation to a potentially defective metabolic pathway. These investigations may take several months to complete, and even after this time, it may not be possible to make a diagnosis. Indeed, our experience in the Purine Research Laboratory at Guy's and St Thomas' Hospitals shows that a definitive diagnosis is only made in about 1% of children investigated for a suspected purine or pyrimidine disorder, with one reason being the overlap in clinical presentation between unrelated