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Access to Genetic Diagnostics for Genodermatoses: Who Should Get Tested? Why? Who Pays?

In this issue, Shagalov et al (1) report the results of a survey that examined obstacles to obtaining genetic testing for patients with genetic skin diseases. Respondents were pediatric dermatologists in the United States, the majority of whom were working in academic centers. They found that virtually all respondents encountered a situation in which they required genetic testing at some point; private insurance was the most common source of funding. Almost two-thirds of participants had made attempts to obtain funding from insurance companies and half of these participants were unsuccessful in more than 75% of their requests. The majority of their patients (87.4%) were unable to pay out of pocket for genetic testing, highlighting the financial barriers routinely encountered in theUnited States in performing genetic testing in patients with genodermatoses. The use of genetic testing in dermatology has been increasing over the last 2 decades, since the identification of several single-gene disorders, beginning with the STS gene in recessive X-linked ichthyosis (2). With the development of more sophisticated mapping techniques and international collaborative approaches such as the Human Genome Mapping Project (3), there has been a rapid increase in the rate of identification of causative genes in a myriad of singlegene disorders. Genetic testing offers many benefits to patients and their families. For many, a definitive genetic diagnosis is valuable and empowering, even if no new treatment results immediately or in the near future from this diagnosis (4). A definitive diagnosis enables the family to prepare psychologically, socially, and financially for their patient’s future needs. This is especially important for diseases for which the longterm sequelae are not obvious at birth. As an example, Chanarin–Dorfman syndrome is largely indistinguishable at birth from other autosomal recessive congenital ichthyoses but is associated with significant extracutaneous manifestations that may develop later in life. For others, genotype-driven treatments can improve care by identifying and targeting the assayed biologic pathways that the mutation affects (5). In the case of tuberous sclerosis, the identification of mammalian target of rapamycin (mTOR) mutations has led to use of the mTOR inhibitor sirolimus for the treatment of facial angiofibromas (6). Genetic testing usually (but not always) provides parents with a definitive pattern of inheritance and the likelihood of transmission of the disease (e.g., autosomal dominant or recessive, sex linked, mitochondrial or mosaic inheritance) and allows for effective genetic counseling. Shagalov et al (1) reported that 25% of participants in their survey cited prenatal diagnosis as a reason to obtain genetic testing. Historically, prenatal diagnoses for suspected genodermatoses were made using chorionic villous sampling or fetal skin biopsy (7).More modern and less invasive techniques allow diagnoses to be established using cellfree fetal DNA obtained from the maternal circulation (7,8), which will further increase the accessibility and utility of prenatal genetic testing. With advances in fertility treatment, preimplantation and DNA-based genetic diagnosis is now an option for families with severe genodermatoses. By identifying the causative gene, it may be possible to select embryos for implantation that do not carry the mutation. Several centers around the world now offer licensed therapies for a number of severe, fatal, life-limiting genodermatoses. Genetic techniques continue to evolve. Nextgeneration sequencing, such as whole-exome sequencing, allows gene identification to be performed on an individual basis in syndromes or diseases without a clear diagnosis in a more cost-effective manner (9). Diagnosis of epidermolysis bullosa, a severe and potentially lethal genodermatosis, is a time-consuming and costly process. It is diagnosed in the neonatal period by skin biopsy for electron microscopy, immunohistochemistry, and Sanger sequencing of candidate genes (10). Recently, whole-exome sequencing has been used to complement this and can increase mutation detection and improve diagnostic accuracy. Ultimately this may replace established diagnostic techniques for these severe genodermatoses. Genetic testing is not without weaknesses, and clinicians should remain cognizant that no test is perfect. The test may not identify all the possible causative gene mutations and therefore can have limited predictive value (11), making effective genetic counseling difficult. In addition, the genetic variation or mutation detected may not be pathogenic. Recently Manrai et al (12) reported on multiple patients of African or unspecified ancestry who received positive reports when tested for hypertrophic cardiomyopathy using sequencing results. The individuals tested were relatives of affected patients and those with ambiguous clinical presentations. Using publicly available exome data, these mutations were subsequently found to be significantly more common in black Americans