{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T03:49:11Z","timestamp":1777866551393,"version":"3.51.4"},"reference-count":41,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AUB-MC"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Introduction: Recent advancements in genomic technologies have significantly improved the resolution of genetic variants driving rare genodermatoses, a heterogeneous group of inherited skin disorders caused by pathogenic variants affecting skin structure and function. However, many genodermatoses remain molecularly uncharacterized, particularly in Middle Eastern populations. Objectives: This study aimed to evaluate the diagnostic accuracy and inherent challenges of utilizing (WES) for genodermatoses within a Middle Eastern context. Methods: We performed WES on three unrelated Middle Eastern pediatric patients presenting with genodermatoses. Genetic variants were prioritized and adjudicated according to ClinVar and the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: WES identified pathogenic variants in three pediatric cases presenting with genodermatoses. Findings included a GJB2 missense variant (c.148G&gt;T; p.Asp50Asn) associated with keratitis\u2013ichthyosis\u2013deafness (KID) syndrome. This represents one of the first documented cases in a Middle Eastern population. Two additional patients presenting with epidermolysis bullosa harbored truncating variants in COL7A1 (c.497dup; p.Val168Glyfs12) and EXPH5 (c.5786del; p.Pro1929Leufs8), respectively; the latter also carried a KRT5 missense variant (c.1607G&gt;A; p.Ser536Asn). Conclusions: WES is a robust diagnostic adjunct for resolving ambiguity in rare genodermatoses, though its efficacy remains contingent on the availability of regional genomic references. Within pediatric dermatology, systematic exome sequencing serves as a powerful facilitator for transitioning from clinical suspicion to definitive molecular characterization. Collectively, these findings highlight the essential role of regionally representative genomic datasets in the accurate interpretation of novel variants and the advancement of precision dermatology.<\/jats:p>","DOI":"10.3390\/genes17050535","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T08:46:26Z","timestamp":1777538786000},"page":"535","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Leveraging Whole-Exome Sequencing to Decipher the Genetic Landscape of Three Genodermatoses\u2019 Cases in Middle Eastern Pediatric Patients"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2099-4316","authenticated-orcid":false,"given":"Ayat","family":"Kadhi","sequence":"first","affiliation":[{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar"},{"name":"Department of Human Genetics, Sidra Medicine, Doha P.O. Box 26999, Qatar"},{"name":"College of Health and Sciences, University of Doha for Science and Technology, Doha P.O. Box 24449, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre Abi","family":"Akl","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2014Head and Neck Surgery, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ossama","family":"Abbas","sequence":"additional","affiliation":[{"name":"Department of Dermatology, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elias","family":"El-Tayar","sequence":"additional","affiliation":[{"name":"Department of Dermatology, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2157-5279","authenticated-orcid":false,"given":"Georges","family":"Nemer","sequence":"additional","affiliation":[{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mazen","family":"Kurban","sequence":"additional","affiliation":[{"name":"Department of Dermatology, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1111\/cup.13520","article-title":"Review of genodermatoses with characteristic histopathology and potential diagnostic delay","volume":"46","author":"Ko","year":"2019","journal-title":"J. Cutan. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"a015172","DOI":"10.1101\/cshperspect.a015172","article-title":"The genetics of human skin disease","volume":"4","author":"DeStefano","year":"2014","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S203","DOI":"10.4103\/0975-7406.155903","article-title":"Genodermatoses","volume":"7","author":"Babu","year":"2015","journal-title":"J. Pharm. Bioallied Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"116","DOI":"10.4103\/idoj.IDOJ_87_19","article-title":"KID Syndrome: A Rare Genodermatosis","volume":"11","author":"Dey","year":"2020","journal-title":"Indian Dermatol. Online J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41431-019-0508-0","article-title":"Estimating cumulative point prevalence of rare diseases: Analysis of the Orphanet database","volume":"28","author":"Lambert","year":"2020","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Chen, L., Wen, C., Li, W., Zhang, B., Cui, C., Yu, S., Ye, C., Li, W., Lu, Y., and Liu, H. (J. Genet. Genom., 2026). Natural history and phenotype-genotype correlations in GJB2-related hearing loss: A systematic and comprehensive review, J. Genet. Genom., in press.","DOI":"10.1016\/j.jgg.2026.02.006"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kafley, P. (2025). Epidermolysis Bullosa: Fragile Skin, Fragile Hope. Pediatr. Dermatol., Online ahead of print.","DOI":"10.1111\/pde.70103"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1001\/jamadermatol.2016.2473","article-title":"Epidemiology of Inherited Epidermolysis Bullosa Based on Incidence and Prevalence Estimates From the National Epidermolysis Bullosa Registry","volume":"152","author":"Fine","year":"2016","journal-title":"JAMA Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sattar, S., Bharadwaj, T., Kalsoom, U.E., Acharya, A., Khan, S., Leal, S.M., and Schrauwen, I. (2025). A pathogenic COL7A1 variant highlights semi-dominant inheritance in dystrophic epidermolysis bullosa. BMC Med. Genom., 18.","DOI":"10.1186\/s12920-024-02077-1"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1002\/humu.23592","article-title":"Next generation sequencing identifies double homozygous mutations in two distinct genes (EXPH5 and COL17A1) in a patient with concomitant simplex and junctional epidermolysis bullosa","volume":"39","author":"Vahidnezhad","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"297","DOI":"10.5582\/irdr.2025.01033","article-title":"Clinical and genetic study of a family with epidermolysis bullosa simplex caused by a novel KRT5 gene mutation c.987C>G (p.Asn329Lys)","volume":"14","author":"Zhang","year":"2025","journal-title":"Intractable Rare Dis. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1111\/bjd.18921","article-title":"Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility","volume":"183","author":"Has","year":"2020","journal-title":"Br. J. Dermatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"a006225","DOI":"10.1101\/mcs.a006225","article-title":"A Novel Pathogenic CDH3 Variant underlying Heredity Hypotrichosis Simplex detected by Whole-Exome Sequencing (WES)-A Case Report","volume":"8","author":"Kadhi","year":"2022","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"E3","DOI":"10.1038\/s41586-021-03758-y","article-title":"Addendum: The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"597","author":"Gudmundsson","year":"2021","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nmeth.3739","article-title":"The mutation significance cutoff: Gene-level thresholds for variant predictions","volume":"13","author":"Itan","year":"2016","journal-title":"Nat. Methods"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1007\/s00439-002-0750-2","article-title":"Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression","volume":"111","author":"Thonnissen","year":"2002","journal-title":"Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e14493","DOI":"10.1111\/dth.14493","article-title":"Keratitis-ichthyosis-deafness syndrome: Phenotypic heterogeneity and treatment perspective of patients with p.Asp50Asn GJB2 mutation","volume":"33","author":"Asgari","year":"2020","journal-title":"Dermatol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dalamon, V.K., Buonfiglio, P., Larralde, M., Craig, P., Lotersztein, V., Choate, K., Pallares, N., Diamante, V., and Elgoyhen, A.B. (2016). Connexin 26 (GJB2) mutation in an Argentinean patient with keratitis-ichthyosis-deafness (KID) syndrome: A case report. BMC Med. Genet., 17.","DOI":"10.1186\/s12881-016-0298-y"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Wonkam, A., Noubiap, J.J., Bosch, J., Dandara, C., and Toure, G.B. (2013). Heterozygous p.Asp50Asn mutation in the GJB2 gene in two Cameroonian patients with keratitis-ichthyosis-deafness (KID) syndrome. BMC Med. Genet., 14.","DOI":"10.1186\/1471-2350-14-81"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"E34","DOI":"10.1002\/lary.24332","article-title":"GJB2-associated hearing loss: Systematic review of worldwide prevalence, genotype, and auditory phenotype","volume":"124","author":"Chan","year":"2014","journal-title":"Laryngoscope"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1016\/j.ijporl.2006.03.015","article-title":"Effects of GJB2 genotypes on the audiological phenotype: Variability is present for all genotypes","volume":"70","author":"Hismi","year":"2006","journal-title":"Int. J. Pediatr. Otorhinolaryngol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1086\/497996","article-title":"GJB2 mutations and degree of hearing loss: A multicenter study","volume":"77","author":"Snoeckx","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1111\/j.1365-2133.2009.09333.x","article-title":"Forty-two novel COL7A1 mutations and the role of a frequent single nucleotide polymorphism in the MMP1 promoter in modulation of disease severity in a large European dystrophic epidermolysis bullosa cohort","volume":"161","author":"Kern","year":"2009","journal-title":"Br. J. Dermatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1083\/jcb.103.4.1577","article-title":"Type VII collagen is a major structural component of anchoring fibrils","volume":"103","author":"Sakai","year":"1986","journal-title":"J. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1136\/jmg.2006.045302","article-title":"Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes","volume":"44","author":"Varki","year":"2007","journal-title":"J. Med. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"262","DOI":"10.2340\/00015555-1053","article-title":"Identical glycine substitution mutations in type VII collagen may underlie both dominant and recessive forms of dystrophic epidermolysis bullosa","volume":"91","author":"Almaani","year":"2011","journal-title":"Acta Derm. Venereol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1111\/1523-1747.ep12345508","article-title":"A common insertion mutation in COL7A1 in two Italian families with recessive dystrophic epidermolysis bullosa","volume":"106","author":"Christiano","year":"1996","journal-title":"J. Investig. Dermatol."},{"key":"ref_29","first-page":"784","article-title":"Frequent Occurrence of Aplasia Cutis Congenita in Bullous Dermolysis of the Newborn","volume":"96","author":"Diociaiuti","year":"2016","journal-title":"Acta Derm. Venereol."},{"key":"ref_30","first-page":"209","article-title":"Compound heterozygosity for a nonsense mutation and a splice site mutation in the type VII collagen gene (COL7A1) in recessive dystrophic epidermolysis bullosa","volume":"76","author":"Tamai","year":"1997","journal-title":"Lab. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1053\/gast.2002.30428","article-title":"Esophageal stenosis in childhood: Dystrophic epidermolysis bullosa without skin blistering due to collagen VII mutations","volume":"122","author":"Zimmer","year":"2002","journal-title":"Gastroenterology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.jid.2016.10.023","article-title":"Dystrophic Epidermolysis Bullosa: COL7A1 Mutation Landscape in a Multi-Ethnic Cohort of 152 Extended Families with High Degree of Customary Consanguineous Marriages","volume":"137","author":"Vahidnezhad","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e694","DOI":"10.1111\/jdv.16372","article-title":"Autosomal recessive epidermolysis bullosa simplex due to EXPH5 mutation: Neonatal diagnosis of the first Italian case and literature review","volume":"34","author":"Diociaiuti","year":"2020","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"658","DOI":"10.5021\/ad.2015.27.6.658","article-title":"Recently Identified Forms of Epidermolysis Bullosa","volume":"27","author":"McGrath","year":"2015","journal-title":"Ann. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.ajhg.2012.10.012","article-title":"Germline Mutation in EXPH5 Implicates the Rab27B Effector Protein Slac2-b in Inherited Skin Fragility","volume":"91","author":"McGrath","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4068","DOI":"10.1091\/mbc.e10-08-0703","article-title":"Novel function of keratins 5 and 14 in proliferation and differentiation of stratified epithelial cells","volume":"22","author":"Alam","year":"2011","journal-title":"Mol. Biol. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Panzaru, M.C., Caba, L., Florea, L., Braha, E.E., and Gorduza, E.V. (2022). Epidermolysis Bullosa-A Different Genetic Approach in Correlation with Genetic Heterogeneity. Diagnostics, 12.","DOI":"10.3390\/diagnostics12061325"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.jdcr.2019.03.025","article-title":"A homozygous frameshift variant in the KRT5 gene is compatible with life and results in severe recessive epidermolysis bullosa simplex","volume":"5","author":"Tryon","year":"2019","journal-title":"JAAD Case Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.matbio.2019.07.002","article-title":"Biallelic KRT5 mutations in autosomal recessive epidermolysis bullosa simplex, including a complete human keratin 5 \u201cknock-out\u201d","volume":"83","author":"Vahidnezhad","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1002\/humu.20981","article-title":"Cytokines as genetic modifiers in K5-\/- mice and in human epidermolysis bullosa simplex","volume":"30","author":"Roth","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Sproule, T.J., Philip, V.M., Chaudhry, N.A., Roopenian, D.C., and Sundberg, J.P. (2023). Seven naturally variant loci serve as genetic modifiers of Lamc2jeb induced non-Herlitz junctional Epidermolysis Bullosa in mice. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0288263"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/5\/535\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T08:51:59Z","timestamp":1777539119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/5\/535"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,30]]},"references-count":41,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["genes17050535"],"URL":"https:\/\/doi.org\/10.3390\/genes17050535","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,30]]}}}