Array genotyping as diagnostic approach in medical genetics

Abstract

Genotyping arrays are by far the most widely used genetic tests but are not generally utilized for diagnostic purposes in a medical context. In the present study, we examined the diagnostic value of a standard genotyping array (Illumina Global Screening Array) for a range of indications. Applications included standalone testing for specific variants (32 variants in 10 genes), first-tier array variant screening for monogenic conditions (10 different autosomal recessive metabolic diseases), and diagnostic workup for specific conditions caused by variants in multiple genes (suspected familial breast and ovarian cancer, and hypercholesterolemia). Our analyses showed a high analytical sensitivity and specificity of array-based analyses for validated and non-validated variants, and identified pitfalls that require attention. Ethical-legal assessment highlighted the need for a software solution that allows for individual indication-based consent and the reliable exclusion of non-consented results. Cost/time assessment revealed excellent performance of diagnostic array analyses, depending on indication, proband data, and array design. We have implemented some analyses in our diagnostic portfolio, but array optimization is required for the implementation of other indications.

Filling the gap: Genetic risk assessment in hypercholesterolemia using LDL‐C and LPA genetic scores

“…The studied cohort was extracted from the database of the Austrian FH Register and is well characterized regarding demographic, biochemical, lifestyle and genetic data (Supplementary Tables S1–S3). The global screening array provided a cost‐effective and widely available tool and could be used in large screening efforts 26 . Confirmed by sequencing, 109 of 234 HC individuals in our study carried a (likely) pathogenic variant in one of four known disease‐causing FH genes: LDLR , APOB , PCSK9 and LDLRAP1 .…”

“…The global screening array provided a cost-effective and widely available tool and could be used in large screening efforts. 26 Confirmed by sequencing, 109 of 234 HC individuals in our study carried a (likely) pathogenic variant in one of four known disease-causing FH genes: LDLR, APOB, PCSK9 and LDLRAP1. Nine variants were novel and have been registered in ClinVar (www.ncbi.nlm.nih.gov/clinvar/variation/1341570).…”

“…LDL-C was considered elevated at ≥190 mg/dL, and the Lp(a) cut-off was set at ≥50 mg/dL as previously described. 17 After genotyping with standard methods 26 quality control was performed before imputation. Principal component analysis using LASER Server 27 was done to estimate the genetic ancestry of all 1.020 individuals and matched to population samples.…”