Molecular diagnostics with conventional Sanger sequencing for ichthyosis vulgaris (IV) has been hampered by the notoriously difficult to analyse filaggrin (FLG) gene, caused by its homologous and polymorphic repeated units. By implementation of single molecule molecular inversion probes (smMIPs) and next generation sequencing (NGS), an alternative screening strategy for analysis of the entire coding region of the FLG gene becomes feasible. Genetic analysis of the whole gene instead of screening for only population-specific mutations, would improve diagnostic yield by scrutinizing also for rare family-specific mutations. The smMIP-NGS strategy is easy to implement, affordable and since exclusion of NGS-duplicate-reads is possible, mutation-percentages can be related and assigned to polymorphic duplicated filaggrin-repeat-unit 8 and 10. In a cohort of previously screened Dutch patients (N=70) for only the  population-specific mutations, retrospectively the whole FLG gene was analysed. Since all known mutations result in premature protein termination, focus of attention was on identifying nonsense and small insertion or deletion mutations. In several (8/70) of the screened patients additional novel truncating mutations were identified, elucidating their previously unexplained (more severe) clinical presentations.
This study emphasises the need for screening the entire FLG gene for mutations, to improve the diagnostic yield in IV and identify hidden variants in the homologous repeated units of the gene. Herein, the smMIP-NGS method proves to be a reliable straightforward strategy to boost clinical diagnostics for IV.

Improving diagnostic yield for filaggrin; hidden mutations in the Dutch population