Epidermolysis Bullosa Carrier Frequencies in the US Population

Abstract

To the Editor: Epidermolysis bullosa (EB) is a group of heritable blistering disorders in which three major subtypes have been recognized on the basis of clinical, genetic, and ultrastructural features: the simplex (EBS: OMIM 601001, 131800, 131900, 131950, 131760), junctional (JEB: OMIM 226700, 226650, 226730), and dystrophic (DEB: OMIM 226600, 131705, 131850, 131750, 132000) forms (Fine et al., 2000Fine J.-D. Eady R.A.J. Bauer E.A. et al.Revised classification system for inherited epidermolysis bullosa: Report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa.J Am Acad Dermatol. 2000; 42: 1051-1066Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). Our laboratory has been involved in the elucidation of the genes and mutations causing two of the major subtypes, JEB and DEB, and has been performing genetic analysis of patients and their families over the last several years (Pulkkinen and Uitto, 1999Pulkkinen L. Uitto J. Mutation analysis and molecular genetics of epidermolysis bullosa.Matrix Biol. 1999; 18: 29-42Crossref PubMed Scopus (230) Google Scholar). During the course of these studies we are frequently consulted about families with an affected child as to the recurrence risk and the type of genetic testing available. Frequently, siblings and other family members become involved and are concerned about their carrier status and their risk of having affected children. Through these inquiries, it has come to our attention that there is no published estimate of the population carrier risk of each of the three forms of EB. Recent information compiled by the National EB Registry (NEBR) (Fine et al., 1999Fine J.-D. Bauer E.A. McGuire J. Moshell A. Epidermolysis Bullosa: Clinical, Epidemiologic and Laboratory Advances and the Findings of the National Epidermolysis Bullosa Registry. The Johns Hopkins University Press, Baltimore1999Google Scholar) estimates the incidence of each form of EB in the US population. From these data population carrier frequencies can be calculated assuming Hardy–Weinberg equilibrium. The data in Table 1 indicate the results of these calculations using the incidence data presented byFine et al., 1999Fine J.-D. Bauer E.A. McGuire J. Moshell A. Epidermolysis Bullosa: Clinical, Epidemiologic and Laboratory Advances and the Findings of the National Epidermolysis Bullosa Registry. The Johns Hopkins University Press, Baltimore1999Google Scholar. Since both dominant and recessive forms of EBS and DEB are recognized, some caution must be exercised in interpreting the data. Until mutation analysis has proven otherwise, inheritance pattern is generally inferred from the pedigree. EBS, usually autosomal dominant, may manifest with relatively mild phenotype, which is elucidated only upon close examination and questioning of the patient and his/her family. Alternately, EBS may manifest with a much more severe phenotype, which is usually identified in the neonatal period. In addition, a few cases of recessively inherited EBS have been described (Chan et al., 1994Chan Y. Anton-Lamprecht I. Yu Q.C. et al.A human keratin 14 ‘‘knockout’': the absence of K14 leads to severe epidermolysis bullosa simplex and a function for an intermediate filament protein.Genes Dev. 1994; 8: 2574-2587Crossref PubMed Scopus (155) Google Scholar;Rugg et al., 1994Rugg E.L. Mclean W.H.I. Lane E.B. et al.A functional ‘‘knockout’' of human keratin 14.Genes Dev. 1994; 8: 2563-2573Crossref PubMed Scopus (144) Google Scholar;Jonkman et al., 1996Jonkman M.F. Heeres K. Pas H.H. et al.Effects of keratin 14 ablation on the clinical and cellular phenotype in a kindred with recessive epidermolysis bullosa simplex.J Invest Dermatol. 1996; 5: 764-769Crossref Scopus (90) Google Scholar), which may be more severe than most dominant cases, although the EBS phenotype may not be a good predictor of inheritance pattern. Based on this information, the majority of EBS cases may be considered to have a dominant inheritance pattern. Similarly, dominant DEB is generally milder than the recessive forms of dystrophic EB, particularly the Hallopeau-Siemens type; however, a number of cases in which mutations have been identified by this laboratory (Christiano et al., 1996Christiano A. Mcgrath J. Uitto J. Influence of the second COL7A1 mutation in determining the phenotypic severity of recessive dystrophic epidermolysis bullosa.J Invest Dermatol. 1996; 106: 766-770Crossref PubMed Scopus (40) Google Scholar;Järvikallio et al., 1997Järvikallio A. Pulkkinen L. Uitto J. Molecular basis of dystrophic epidermolysis bullosa: mutations in the type VII collagen gene (COL7A1).Hum Mut. 1997; 10: 338-347Crossref PubMed Scopus (85) Google Scholar) and colleagues (Gardella et al., 1996Gardella R. Belletti L. Zoppi N. et al.Identification of two splicing mutations in the collagen type VII gene (COL7A1) of a patient affected by the localisata variant of recessive dystrophic epidermolysis bullosa.Am J Hum Genet. 1996; 59: 292-300PubMed Google Scholar;Tamai et al., 1999Tamai K. Murai T. Mayama M. et al.Recurrent COL7A1 mutations in Japanese patients with dystrophic epidermolysis bullosa: positional effects of premature termination codon mutations on clinical severity.J Invest Dermatol. 1999; 112: 991-993Crossref PubMed Scopus (30) Google Scholar) indicate that milder forms of recessive dystrophic EB are not uncommon, and these cases, in the absence of family history, are clinically indistinguishable from mild, de novo dominantly inherited DEB. On the other hand, dominant DEB cases are more numerous and have been generally inferred from the pedigree, giving rise to the dominant and recessive incidence values (Fine et al., 1999Fine J.-D. Bauer E.A. McGuire J. Moshell A. Epidermolysis Bullosa: Clinical, Epidemiologic and Laboratory Advances and the Findings of the National Epidermolysis Bullosa Registry. The Johns Hopkins University Press, Baltimore1999Google Scholar).Table ICarrier frequency of major EB subtypes in the US populationEB typeIncidence per 106Prevalence per 106Carrier frequencyaFor dominant disorders the carrier frequency is quoted as incidence in US population.Carrier frequency as fractionEB simplex10.754.610.75 × 10-6Junctional EB All2.040.442.86 × 10-31/333 Herlitz0.410.071.28 × 10-31/781Dystrophic EB Dominant2.860.992.86 × 10-6 Recessive2.040.922.86 × 10-31/345 Unknown0.820.471.81 × 10-31/556a For dominant disorders the carrier frequency is quoted as incidence in US population. Open table in a new tab The new mutation rate for any of the forms of EB has not been calculated; however, a number of sporadic cases of DEB have been analyzed for mutations in the COL7A1 gene and are presumed to result from germline mosaicism (Rouan et al., 1998Rouan F. Pulkkinen L. Jonkman M. et al.Novel and de novo glycine substitution mutations in the type VII collagen gene (COL7A1) in dystrophic epidermolysis bullosa: implications for genetic counseling.J Invest Dermatol. 1998; 111: 1210-1213Crossref PubMed Scopus (28) Google Scholar;Hashimoto et al., 1999Hashimoto I. Kon A. Tamai K. Uitto J. Diagnostic dilemma of ‘‘sporadic’' cases of dystrophic epidermolysis bullosa: a new dominant or mitis recessive mutation?.Exp Dermatol. 1999; 8: 140-142Crossref PubMed Scopus (29) Google Scholar;Lee et al., 2000Lee J.Y.-Y. Li C. Chao S.-C. Pulkkinen L. Uitto J.A. De novo glycine substitution mutation in the collagenous domain of COL7A1 in dominant dystrophic epidermolysis bullosa.Arch Dermatol Res. 2000; 292: 159-163Crossref PubMed Scopus (13) Google Scholar). Continued elucidation of the mutations involved in all forms of EB will allow us to further understand the relative numbers of new mutations, and to correlate type of mutation and pattern of inheritance. The carrier incidence information provided in Table 1 should enable genetics professionals to accurately calculate the risk of recurrence to individual family members based on the family history and provide up-to-date risk estimates that will facilitate accurate counselling of extended families at risk. Supported by grants from NIAMS/NIH (PO1 AR38923) of the United States Public Health Service, and from the Dystrophic Epidermolysis Bullosa Research Association of America (DebRA).