Genodermatoses and 125 years of theBJD

Of all the topics the BJD has covered over the last 125 years, genetic skin diseases have certainly been an integral part of the journal. Over its existence, the BJD has published close to 2000 manuscripts on inherited skin conditions, encompassing a variety of known and unknown clinical entities and a spectrum of developmental, chromosomal or other inherited disorders with skin anomalies. Approximately 85% of these genetic skin disease manuscripts have made it to press within the last 25 years of BJD publishing, probably reflecting what has become technically possible in the modern era of molecular biological dissection of disease and functional genomics. Of course, many other dermatology journals have also published an increasing number of papers on genetic skin diseases in recent years, which raises the question of whether the BJD has managed to create a special home for genodermatology? The answer has to be a resounding yes! For clinical academics working in genetics, there has always been a professional tendency to try to publish new gene discoveries and first mutation reports in the highest impact genetics journals, perhaps offering accounts of the second or third mutations for a particular condition to journals like the BJD. Nevertheless, the recent surge in the impact factor of the BJD (currently 3·759) puts it on a par with genetics journals like the European Journal of Human Genetics,Heredity and Human Genetics, which therefore makes the BJD a very competitive journal to which to submit those primary genetic findings. However, the willingness of the BJD to publish the follow‐on papers for monogenic disorders still has considerable value, both to the readership and the journal, in furthering understanding of the molecular basis of inherited skin diseases and in helping to expand genotype–phenotype correlation. But the track record of the BJD has been so much more substantial than this, notably in showing the impact of genetics on common diseases that dermatologists see every day. For example, since mutational analysis of the FLG gene, encoding the skin barrier component filaggrin, became feasible in 2006,1 the BJD has published more than 60 articles on FLG mutations allied to diseases such as atopic, contact or irritant dermatitis, as well as hand eczema, skin infections, atopy and ichthyosis vulgaris.2 3 These reports include data from 12 different countries, demonstrating that for genetics, as for the rest of dermatology, the BJD is truly a global journal in which to publish. Although approximately 35% of all reports on monogenic skin diseases in the BJD have been case reports, including case series, several predominantly clinical papers published over the last 125 years have offered beautiful descriptive accounts of observations on genetic skin diseases that have withstood the test of time. Rereading these original papers in the BJD also demonstrates just how careful and detailed these clinical descriptions tended to be before analysis of genes became the focus of most modern‐day reports. The 1950s, for example, saw several landmark clinical reports of novel genodermatoses. Notably, two eponymous syndromes were described in back‐to‐back issues of the BJD in 1954. These are an autosomal dominant form of trauma‐induced skin fragility, which subsequently became known as Dowling–Meara epidermolysis bullosa simplex (OMIM 131760),4 and an autosomal recessive skin fragility and poikilodermatous disorder, which thereafter has been known as Kindler syndrome (OMIM 173650).5 Both of these genodermatoses have become established as distinct clinicopathological entities and, in modern times, when eponymous syndrome names have tended to be replaced by more descriptive or mechanistic disease titles, it is interesting to note that the latest classification of epidermolysis bullosa published in 2008 retained Dowling–Meara as one of the few eponymous types of epidermolysis bullosa simplex and inserted Kindler syndrome as a distinct fourth major category of epidermolysis bullosa.6 Other novel clinical descriptions of genetic skin diseases published in the BJD have also led to designation as eponymous syndromes, including a 1976 publication of an autosomal dominant form of ectodermal dysplasia, subsequently known as Hay–Wells syndrome (OMIM 106240),7 although this disorder has now been rebranded as ankyloblepharon–ectodermal defects–clefting syndrome, with perhaps synonymous overlap with another type of ectodermal dysplasia, Rapp–Hodgkin syndrome (OMIM 129400), first published in 1968.8 Aside from these historical focal points, one of the major attractions of the BJD and genetics has been that the journal has offered a home for detailed reviews, many of which have relevance to clinical practice, providing pointers to making accurate clinical diagnoses.9 The journal has also reported innovative laboratory tests, guidelines for treatment10 and interventions such as prenatal diagnosis that may benefit families at risk of recurrence of inherited skin diseases.11 Few journals can match the BJD for the clinical significance of its genetics publications. Nevertheless, more than 40% of the BJD publications on genetic skin diseases in the last 5 years have centred on mutation data, perhaps indicative of the current focus of laboratory work to investigate patients. Worthy as such publications may be, times are changing and the advent of next‐generation sequencing is definitely moving the emphasis from mutation detection to skin genetics with more clinical relevance.12 Once efficient clinical service platforms are established for next‐generation sequencing, automation with whole‐genome or whole‐exome sequencing and bioinformatics analyses will lead to faster identification of disease genes and mutations – such that finding the pathogenic mutations then becomes the starting point rather than taking pride of place in a report.13 There may then be a re‐emphasis on careful phenotyping and really understanding the biology of what underlies a patient's genetic skin disease, and why this presents as it does to dermatologists in the clinic. At that time, the forte of the BJD in reporting clinical aspects of genetics may come to even more prominence. Looking to the future, new data about gene regulation arising from projects such as the Encode Consortium (http://www.genome.gov/10005107) are likely to offer a plethora of genomic data that will require careful clinical correlation. The Encode project represents an ambitious attempt to find all the functional elements in the human genome.14 Established in 2003, the first data released in late 2012 were jaw dropping. Contrary to the popular belief that approximately 98·5% of human DNA is merely ‘junk’, the Encode data have shown that in fact approximately 60% of the genome is transcribed (but with no known function) and that approximately 20% of noncoding DNA is actually functional with a role in regulating expression of known coding genes – a function that has been called the ‘regulome’. Deciphering the specific relevance of these findings to particular diseases is now a focus of great activity. Given the relative ease of phenotyping skin disorders compared with some other diseased organs, dermatologists may be in an enviable position of being able to match new data from the genome to specific changes in patient skin, thereby creating a much more refined genotype–phenotype correlation that provides far greater insight into genetic skin diseases and how to improve clinical care of patients. The BJD is likely to have a clear and leading role to play in this ‘next‐generation regulome data’ publishing – and in making it relevant to both clinical dermatologists and their patients. One other area of emphasis of modern genetics research germane to the BJD has been translational medicine, promoting awareness of bench‐to‐bedside research; such work also includes clinical trials. Publication of clinical trials data in inherited skin diseases may not always be attractive to major general medical or genetics journals, perhaps because of the rare disease niche, and yet the BJD has shown, and continues to show, a willingness to publish appropriately performed randomized controlled clinical trials that take genetic skin disease from discovery to therapy.15 After all, genetics should be relevant to the readership of the BJD, and articles that impact on clinical practice and patient care are perhaps the most valuable of all. If the same careful clinical descriptions and observations can be detailed in those upcoming and future reports, as was clearly evident in many of the earlier genetics publications in the BJD, then the place of publishing articles on the pathophysiology and treatment of genetic skin disease in the BJD will be secured, and the importance of the BJD as a high‐quality journal for genetics publications will be ensured. For genetics and inherited skin diseases, the BJD has much to be proud of and to reflect on over the last 125 years, and there will certainly be much more to look forward to in the years to come.