Dystrophic Epidermolysis Bullosa: COL7A1 Mutation Landscape in a Multi-Ethnic Cohort of 152 Extended Families with High Degree of Customary Consanguineous.

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Structural organization of the α1(VII) polypeptide of type VII collagen, as deduced by molecular cDNA cloning, and the distribution of COL7A1 mutations.

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Dystrophic Epidermolysis Bullosa: COL7A1 Mutation Landscape in a Multi-Ethnic Cohort of 152 Extended Families with High Degree of Customary Consanguineous Marriages Hassan Vahidnezhad, Leila Youssefian, Sirous Zeinali, Amir Hossein Saeidian, Soheila Sotoudeh, Nikoo Mozafari, Maryam Abiri, Abdol- Mohammad Kajbafzadeh, Mohammadreza Barzegar, Adam Ertel, Paolo Fortina, Jouni Uitto Journal of Investigative Dermatology Volume 137, Issue 3, Pages 660-669 (March 2017) DOI: 10.1016/j.jid.2016.10.023 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Candidate gene identification in families with DEB by homozygosity mapping. (a–j) Clinical features of patients with DEB, (k) examples of multiplex families, (l) homozygosity mapping in a family with RDEB, (m) distribution of ethnicity of DEB patients and total population of Iran, (n) types of DEB in Iranian versus US cohorts, and (o) degree of consanguinity among DEB patients versus the total population in Iran. (a–h) Note the characteristic phenotype with erosions and scarring with mitten deformities of the hands and feet as well as corneal erosions and hypodontia. (i) Radiography of barium swallowing shows esophageal strictures. (j) Immunofluorescence for type VII collagen shows markedly reduced or absent staining in RDEB patients’ skin (lower panel, the stars indicate blistering) compared with normal skin with linear staining at the dermal epidermal junction (arrows). (k) Note the presence of multiple affected individuals in extended families, consistent with autosomal recessive (two left pedigrees) and autosomal dominant (right pedigree) patterns. Probands are indicated by arrowheads. (l) Genome-wide homozygosity mapping identifies multiple homozygosity blocks of >2 Mb (blue) in the autosome of a patient (in f) with consanguineous parents with coefficient of inbreeding (of 0.1093). Alignment of multiple genes associated with heritable blistering diseases (red lines) shows an overlap with LAMC2 and COL7A1 with a homozygosity block in chromosome 3, identifying them as candidate genes in this family. (m) Among the Iranian ethnicities, the Lurish have a higher percentage of DEB patients than expected from their presence in the total population in Iran. (n) The Iranian DEB population studied in this cohort consists predominantly of patients with RDEB generalized severe (90%) disease, whereas only 2% of patients have dominant dystrophic EB. This distribution dramatically differs from that in the United States. (o) The impact of consanguinity on DEB is illustrated by the percentages of first and second cousin parents of the Iranian DEB patients (89%), as opposed to the degree of consanguinity in the total population in Iran, where 61% of married couples have no family relationship. DEB, dystrophic epidermolysis bullosa; EB, epidermolysis bullosa; RDEB, recessive dystrophic epidermolysis bullosa; Mb, mega-base pair. Journal of Investigative Dermatology 2017 137, 660-669DOI: (10.1016/j.jid.2016.10.023) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Schematic design of COL7A1-targeted next-generation sequencing array. (a) COL7A1 consists of 118 exons in the chromosomal region 3p21.31. Amplicon design resulted in approximately 99% coverage of the coding regions and of 100 base pairs of flanking intronic sequences. The coverage of families 7 and 27 is shown as an illustration of mutation detection, which shows c.461del76 and c.1637-240_3255del4063 deletion mutations spanning from exon 4 to intron 4 and from intron 12 to exon 24, respectively. (b) This approach identified recessive homozygous mutations in 90% of the families. (c) These mutations were confirmed by Sanger sequencing. Of the 104 mutations identified by this array or by Sanger sequencing of PCR amplified exons and flanking intronic sequences, 56% were previously unreported; distribution of splicing, nonsense, missense, and indel mutations is indicated. Journal of Investigative Dermatology 2017 137, 660-669DOI: (10.1016/j.jid.2016.10.023) Copyright © 2016 The Authors Terms and Conditions

Figure 3 Organization of type VII collagen cDNA consisting of 118 exons, with positions of the mutations identified in this study. Missense mutations are below and premature termination causing mutations are above the cDNA. The mutations in red are previously unreported to our knowledge, whereas mutations in black have been reported previously. The number in parentheses after each mutation indicates the number of families harboring this mutation. The protein domains of type VII collagen encoded by COL7A1 are identified by color code below the gene. Journal of Investigative Dermatology 2017 137, 660-669DOI: (10.1016/j.jid.2016.10.023) Copyright © 2016 The Authors Terms and Conditions

Figure 4 The geographic location of families in Iran with COL7A1 mutations identified in this study. The families harboring the recurrent mutations c.6269_6270delC, c.4233delT, and c.553C>T are identified by yellow, blue, and red colors, respectively. Journal of Investigative Dermatology 2017 137, 660-669DOI: (10.1016/j.jid.2016.10.023) Copyright © 2016 The Authors Terms and Conditions

Figure 5 Haplotype analysis of 17 families with SNP marker array on chromosomal locus 3p21.31 on and surrounding the COL7A1 locus. Sequences within a 1 Mb haplotype block indicated conservation consistent with founder effect in patients primarily of Lurish and Turkish ethnicity. One patient with Persian background (Family 113) had a different haplotype. A, adenine; C, cytosine; Chr., chromosome; G, guanine; MB, mega-base pair; SNP, single-nucleotide polymorphism; T, thymine. Journal of Investigative Dermatology 2017 137, 660-669DOI: (10.1016/j.jid.2016.10.023) Copyright © 2016 The Authors Terms and Conditions