The Power of Molecular Genetics in Understanding Heritable Skin Disorders:Introd

Qiaoli Li,Yong Yang,Jouni Uitto,*

1Department of Dermatology and Cutaneous Biology,The Sidney Kimmel Medical College,and Jefferson Institute of Molecular Medicine,Thomas Jefferson University,Philadelphia,PA 19107,USA;2Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs,Hospital for Skin Diseases(Institute of Dermatology),Chinese Academy of Medical Science and Peking Union Medical College,Nanjing,Jiangsu 210042,China.

Among the over 7,000 heritable disorders,at least 1,000 of them have cutaneous manifestations.Some of these conditions are exclusively limited to the skin,thus being non-syndromic,while some of them are associated with a number of extracutaneous manifestations,that is,they are syndromic,with protean manifestations.These conditions,heritable skin diseases,display a tremendous collection of phenotypes as well as a broad spectrum of severity and the overall outcome.In most severe forms,some of these conditions are lethal at the early stages of life,while at the other end of the spectrum they may present with a relatively minor skin involvement primarily of cosmetic concern,with no effect on the longevity of the affected individuals.Considering the plethora of clinical manifestations,frequently with overlapping clinical features and complex classification schemes often riddled with eponyms,the heritable skin disorders frequently pose a diagnostic challenge for practicing dermatologists.

Significant progress towards understanding the pathomechanisms of heritable skin disorders has been made through application of genetic approaches,particularly identification of underlying mutations in the candidate genes.Initially,with the advent of human genome project,the mutation detection strategy was based on polymerase chain reaction amplification of relatively small segments of candidate genes identified by clinical presentation or based on histopathological,ultrastructural,and/or immunofluorescent labeling observations,followed by nucleotide sequencing,first by Maxam and Gilbert and subsequently by Sanger methods.While these approaches were successful in identifying a number of candidate genes and mutations,this approach turned out to be cumbersome,time consuming and costly,and it has been replaced more recently by next-generation sequencing approaches,including gene targeted sequencing arrays,whole exome sequencing,whole genome sequencing,and whole transcriptome analysis(RNAseq).Examination of a number of patients in any diagnostic category with heritable skin diseases by these techniques has clarified many of these conditions.For example,it has been demonstrated that different subtypes of a disease previously distinguished by clinical presentations are in fact allelic with common mutations in the same gene,or the mutation information has allowed delineation of completely new,previously unrecognized entities.

Knowledge of the mutant genes and specific mutations has profound implications for diagnosis,subclassification,and management of many of these disorders.First,examination of the mutations provides confirmation of the clinical diagnosis as well as means for prognostication of the severity and the overall outcome of the disease process.As an example,mutation analysis in patients diagnosed at the early prenatal period with epidermolysis bullosa will aid in precise subclassification and allows,in general terms,determination of the prognosis of the disease.Second,identification of a mutation with assessment of co-segregation in the individual family members provides precise information of the mode of inheritance,as exemplified by distinction between autosomal recessive,autosomal dominant,and novel de novo mutations,thus allowing counseling of the families for the risk of recurrence in subsequent pregnancies.Thirdly,knowledge of the precise mutation is a prerequisite for prenatal diagnosis,which can be performed by chorionic villus sampling or noninvasive analysis of the fetal DNA in the maternal blood at the early stages of pregnancy.The mutation information is also a prerequisite for preimplantation genetic diagnosis which can be performed in the context of in vitro fertilization before the pregnancy is initiated.Finally,knowledge of the mutated genes and the types of mutations is a prerequisite for the development of allele-specific therapies that are currently in the pipeline of drug development for a number of heritable disorders.For example,a gene therapy approach delivering type VII collagen to the skin of patients with epidermolysis bullosa is applicable only to those patients who harbor mutations in this gene.As another example,new therapies are being developed which allow read-through of premature termination codon mutations in the genes,and this approach obviously is applicable only to those patients who have been shown to harbor this type of mutation causing the disease.Thus,collectively,mutation analysis has significantly expanded our understanding of the heritable skin diseases and provided information toward better diagnosis,subclassification,and prognostication,as well as management of this complex set of disorders,opening new windows to therapy development for these currently intractable disorders.

This theme of the International Journal of Dermatology and Venereology is dedicated to genodermatoses,and a number of articles provide new insights into several diagnostic entities.One of the articles(Zeinali et al.)1illustrates the power of homozygosity mapping as a tool towards identification of candidate genes.Specifically,this article compared the genomic positions of homozygosity blocks in the candidate genes for two patients in a large consanguineous family with hereditary hypotrichosis,and narrowed the candidate gene from eleven to one,HR,which was shown to harbor a novel homozygous mutation.The paper by Dasgeb et al.2reports on examination of the presence of mutations in oncogenic candidate genes in an unusual patient with multiple,rapidly growing basal cell carcinomas of exceptionally large size.Their analysis excluded basal cell nevus(Gorlin)syndrome but identified a PTCH1 mutation limited to the tumors,complemented with germline mutations in three other oncogenic genes.Thus,the patient’s unusual phenotype may reflect synergistic oncogenic interactions of these genes.This genetic analysis also provided a basis for treatment of the patient with nivolumab,a checkpoint inhibitor,and this approach was noted to have a robust and sustained regression of all basal cell carcinomas in this unusual patient.A set of additional papers contribute to the expansion of the mutation databases and provide new genotype-phenotype correlations in a number of genodermatoses.For example,the study by Li et al.3identified a recurrent MLH1 mutation in Lynch syndrome,an autosomal dominant disorder with propensity to colorectal cancer.The authors report also the presence of sebaceous neoplasms which may serve as cutaneous signs alerting the clinicians for this syndrome.The paper by Pan et al.4reported novel mutations in the RECQL4 gene in patients with Rothmund-Thomson syndrome,noting an unusually mild phenotype accompanying the mutations.This phenotype was explained by differences in the splicing of the RNA as a consequence of the splice-site mutations,thus expanding the genotype-phenotype correlations in this disease.The review article by Preda-Naumescu et al.5explores the immunological aspects of hidradenitis suppurativa in the context of a genetic underpinning,thus providing novel insight into the pathogenesis of this complex disorder.Specifically,the genetic mutations linked to this disorder may explain the immune perturbations and provide novel information useful for identification of therapeutic targets.Finally,a case report by Zhao et al.6highlights the clinical and histopathological features of a young patient with Papillon-Lefèvre syndrome,a rare autosomal recessive disorder.The authors also reported improvement of skin lesions following treatment with oral retinoids and antibiotics.

This special theme on genodermatosis provides a wealth of new information helpful for the clinicians to interpret and apply genetic data towards accurate diagnosis and improved treatment of these,often intractable disorders.The reports in this theme also expand the repertoire of mutations in a number of heritable disorders,and they collectively attest to the power of technologies and strategies of genetics,particularly those of the next-generation sequencing,in clarifying the phenotypic features of such conditions with therapeutic implications.