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Genetics for the Practicing Dermatologist Jamison D Genetics for the Practicing Dermatologist Jamison D. Feramisco, MD, PhD, Hensin Tsao, MD, PhD, and Dawn H. Siegel, MD In the era of robust genome sequencing, a working understanding of genetics has become important for the clinician. For the dermatologist, understanding the flow of genetic information from genotype to phenotype can aid in the delivery of effective patient care. In this article, we will review concepts in genetics and the human genome and how they contribute to clinical dermatology. Semin Cutan Med Surg 29:127-136 © 2010 Published by Elsevier Inc. The “Gene” Redefined Phenotype Deconvolution The concept of the “gene” has been an ever evolving notion and Genetic Skin Disease 1 since its conception by Mendel in 1866. Initial work identi- The practice of medicine is focused upon linking a set of fying the basic structure of the gene was synthesized by Crick clinical phenotypes to specify and describe a single disease and presented as the central dogma of molecular biology, entity. In the past, blunt tools available for this task have outlining the linear flow of genetic information from DNA to made differentiating clinical disease difficult at times. In 2 RNA to protein. With the recent completion of the Human the era of advancing technology, molecular tools have become Genome Project, the Encyclopedia of DNA Elements (EN- more precise, and thus the ability to link basic science and clin- 3-9 CODE), and the International HapMap Project, the mean- ical medicine to define disease states has also sharpened. This ing of a genetic unit has undergone stark transformation and trend is particularly applicable to dermatology, where subtle is now defined by the set of functional products produced by differences in cutaneous phenotypes can partially discrimi- 10 a genomic sequence. This dictates that as clinicians we are nate between highly similar disease states whereas robust forced to consider more than principles of classical genetics tissue accessibility allows for frequent clinicopathologic in the evaluation of our patients with complex medical dis- correlation. Fine molecular correlation is often still unavail- eases. able. In a recent study that used the Online Mendelian inher- itance in Man database, the authors attempted to systemati- 1. The Human Genome Project is an international scientific cally organize genetic skin disease by phenotype and genotype, research project with a primary goal to determine the in what has been termed “phenotype deconvolution.”11,12 DNA sequence of all genes of the human genome. The From this, the current state of genodermatoses was defined to Project formally began in 1990 and a complete draft of include 560 distinct disorders associated with mutations in the human genome was published in 2003 501 unique protein-encoding genes.11 This comprehensive 2. The Encyclopedia of DNA Elements (ENCODE) repre- database and concept is only possible in part because of the sents a research consortium initiated by the US Na- knowledge gained during the past decade specifying molec- tional Human Genome Research Institute in September ular and genetic pathways. The goal of phenotype deconvo- 2003 with a goal to identify all functional elements in lution is to resolve complex disease phenotypes into elemen- the human genome tal features to discover hidden structure within the phenomic 3. The International HapMap Project began in 2002 and is space and to mechanistically link entities that share overlap- aimed to develop a complete haplotype map (HapMap) ping features. The ras/mitogen activated protein kinase path- of the human genome. It will focus on identifying com- way (MAPK) syndromes exemplify this method. Noonan mon single nucleotide polymorphisms (SNPs) syndrome, LEOPARD syndrome, neurofibromatosis type 1 (NF1), cardio-facio-cutaneous (CFC) syndrome and Costello syndrome have several overlapping clinical features, includ- Wellman Center for Photomedicine, Massachusetts General Hospital and ing craniofacial dysmorphology, congenital heart disease, Department of Dermatology, Harvard Medical School, Boston, MA. Address reprint requests to Dawn H. Siegel, MD, Department of Dermatol- neurocognitive impairment and ectodermal features (Fig. 1). ogy and Pediatrics, Oregon Health and Science University, 3303 SW The RAS/MAPK pathway is known to play an important role Bond Avenue, CH16D, Portland, OR 97239. E-mail: [email protected] in cell cycle regulation, differentiation and growth and in 1085-5629/10/$-see front matter © 2010 Published by Elsevier Inc. 127 doi:10.1016/j.sder.2010.04.006 128 J.D. Feramisco, H. Tsao, and D.H. Siegel Figure 1 Clinical features of the “Rasopathies.” oncogenesis; more recently this pathway has been implicated (several distinct genes causing an identical phenotype). Of the in developmental disorders. Noonan syndrome, LEOPARD RASopathies, Costello syndrome has been shown to be caused syndrome, NF1, CFC syndrome and Costello syndrome have by mutations in only 1 gene (HRAS) and CFC syndrome can be been called the “RASopathies” because each have been found caused by mutations in 4 different genes (BRAF, MEK1, MEK2 to be linked to genetic loci in the RAS/MAPK pathway.13,14 and, rarely, KRAS; Fig. 2A).15-17 For the genetic skin conditions, In some genetic syndromes, only 1 gene is known to cause a mutations at single genetic loci are attributed in 84% of disor- disorder, whereas in other conditions, multiple genes may be ders whereas alterations at 2 or more genetic loci are identified in implicated. Genetic heterogeneity is attributed to situations in 15% of disorders.11 which identical clinical phenotypes are associated with muta- In contrast, clinical heterogeneity is defined by situations tions in several genes. An example of this is lamellar ichthyosis (a whereby mutations in single gene loci result in multiple dif- single disease entity with a single set of phenotypes), which can ferent phenotypes and thus diseases. An example of this is be produced by mutations in keratinocyte transglutaminase mutations in connexin 26 or GJB2 (a single gene) causing (TGM1), ATP-binding cassette member A12 (ABCA12), cyto- Vohwinkel syndrome, keratitis-ichthyosis-deafness (KID) chrome P450 protein CYP4F22, or another unidentified gene syndrome, and Bart–Pumphrey syndrome (3 distinct dis- Figure 2 Genetic heterogeneity and clinical heterogeneity. (A) Genetic heterogeneity: CFC can be caused by mutations in 4 different genes. (B) Clinical heterogeneity: mutations in the same gene, CIAS1, can lead to different phenotypes as demonstrated in the auto-inflammatory diseases. Genetics for the practicing dermatologist 129 eases with different phenotypes). This concept can be further skin lesions (fibrofolliculomas) and renal cancer, whereas demonstrated with the cold-induced autoinflammatory syn- others may have pulmonary cysts and pneumothorax.21 Vari- drome 1 (CIAS1) gene which encodes the cryopyrin protein. able expressivity may be explained in some cases by the Mutations in the CIAS1 gene can lead to autoinflammatory Knudson “two hit” hypothesis, as in the case of tuberous diseases, including familial cold urticaria syndrome, Muckle- sclerosis (TS). TS is caused by mutations in either of 2 tumor Wells Syndrome, and neonatal-onset multisystem inflamma- suppressor genes, hamartin (TSC1) and tuberin (TSC2). In tory disorder.18-20 The clinical features of these conditions are this model, the first hit is the germline presence of a mutation shown in Fig. 2B. Finally, mutations in 82% of the 501 in TSC1 or TSC2 and the second hit occurs randomly in unique protein-encoding genes associated with genetic skin somatic tissues and can result in the growth of various tu- disease cause a single unique disease, while only 3% were mors, such as cardiac rhabdomyomas, renal angiomyolipo- found to be causal in 4 or more unique diseases. mas and facial angiofibromas.22 In the near future, we suspect that by using phenotype In NF1, variable expressivity is demonstrated when a par- deconvolution in conjunction with the expected exponential ent with numerous neurofibromas and hypertension has an increase of molecular knowledge that we will soon be able to affected child with a plexiform neurofibroma and an optic redefine the meaning of both genetic and clinical heteroge- glioma but few neurofibromas. Of note, a subgroup of pa- neity in medical disease. This is likely to be accomplished by tients previously thought to exhibit a variant of NF1 with way of sharpening our ability to discern the relationship be- multiple café-au-lait macules and axillary freckling failed to tween molecular mechanisms and clinical phenotypes. reveal mutations in the NF1 gene. With the new molecular tools described previously now available, a new syndrome known as Legius syndrome has been described and is attrib- Genetic Modes utable to mutations in the SPRED1 gene.23 Affected individ- of Inheritance and uals present with multiple café-au-lait macules, axillary Genetic Skin Disease freckling, and macrocephaly. Legius syndrome differs from NF1 in that Lisch nodules, neurofibromas, and central ner- When a patient presents to the dermatology clinic with signs vous system tumors are absent. These subtle variations dem- of a genetic skin condition, it is helpful to be aware of the onstrate how features (eg, café-au-lait macules vs freckling vs modes of transmission and inheritance of the disorder both macrocephaly) may be more tractable currency for pheno- to aid in the diagnosis and in family counseling. Mendelian typic comparison than disease complexes (eg, NF1 vs Legius inheritance patterns for single gene conditions include auto- syndrome), and thus the NF1 and Legius syndrome overlap somal dominant (AD), autosomal recessive (AR), and X-linked. represents an ideal case for phenotype deconvolution. Additional mechanisms of inheritance include mitochon- When a patient presents with a genetic skin disorder, such drial, imprinting, and complex or polygenic inheritance. Of as TS or NF1, the individual’s parents and siblings should be the genetic skin conditions, AR inheritance is the most com- carefully examined to determine if they express mild features mon (46%), followed by AD (37%), X-linked (6%), and mi- of the disorder.
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