Impact of next generation sequencing on diagnostics in a genetic skin disease clinic

Abstract

Individuals with inherited skin diseases often pose one of the most difficult diagnostic challenges in dermatology. The hunt for the underlying molecular pathology may involve candidate gene screening or linkage analysis, which is usually determined by the initial history, the physical findings and laboratory tests. Recent technical advances in DNA sequencing, however, are shifting the diagnostic paradigm. Notably, next-generation sequencing allows a more comprehensive approach to diagnosing inherited diseases, with potential savings of both time and money. In the setting of a paediatric dermatology genetics clinic in Kuwait, we therefore performed whole-exome sequencing on seven individuals without a priori detailed knowledge of the patients' disorders: from these sequencing data, we diagnosed X-linked hypohidrotic ectodermal dysplasia (two cases), acrodermatitis enteropathica, recessive erythropoietic protoporphyria (two siblings) and localized recessive dystrophic epidermolysis bullosa (two siblings). All these groups of disorders are clinically and genetically heterogeneous, but the sequencing data proved inherently useful in improving patient care and avoiding unnecessary investigations. Our observations highlight the value of whole-exome sequencing, in combination with robust bioinformatics analysis, in determining the precise molecular pathology and clinical diagnosis in patients with genetic skin disorders, notably at an early stage in the clinical evaluation of these often complex disorders and thereby support a new paradigm for future diagnostics.

Whole‐exome sequencing for diagnosis of hereditary ichthyosis

“…Next‐generation sequencing (NGS) technologies applying whole‐exome sequencing (WES) enables sequencing all protein‐coding DNA regions in one run. Preliminary reports indicate a high diagnostic yield applying NGS in the molecular investigation of various genodermatoses in the clinic . In 2013, Oslo University Hospital implemented WES with analysis of ichthyosis‐related genes as a routine diagnostic test for patients suffering from inherited ichthyosis.…”

Dermatopathology – the link between ancillary techniques and clinical lesions

“…It can be performed on the entire genome, which includes noncoding areas of the DNA (introns), coding areas of the DNA (exons) and mitochondrial DNA, or limited to coding areas of the genome. The former is referred to as whole‐genome sequencing (WGS), whereas the latter is referred to as whole‐exome sequencing (WES) . The exome involves roughly 1.5% of the human genome, encompassing most exons of about 20,000 human genes; WES is therefore less labour‐intensive than WGS .…”

Update on autosomal recessive congenital ichthyosis: mRNA analysis using hair samples is a powerful tool for genetic diagnosis

“…Takeichi et al [46] have recently demonstrated the impact of next-generation sequencing technologies on clinical genetics in the dermatology field. Indeed, next-generation sequencing can reveal two autosomal recessive disorders in a single family.…”