RESUMO
BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study. METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families. RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes. CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.
Assuntos
Doenças Raras/genética , Dermatopatias Genéticas/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferase/genética , Aldeído Oxirredutases/genética , Vesícula/genética , Colágeno Tipo VII/genética , Consanguinidade , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Epidermólise Bolhosa/genética , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Simples/genética , Exoma , Feminino , Proteínas Filagrinas , Flavoproteínas/genética , Homozigoto , Humanos , Mutação INDEL , Eritrodermia Ictiosiforme Congênita/genética , Ictiose Vulgar/genética , Ictiose Lamelar/genética , Proteínas de Filamentos Intermediários/genética , Queratina-14/genética , Erros Inatos do Metabolismo Lipídico/genética , Lipoxigenase/genética , Masculino , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Doenças Musculares/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Linhagem , Doenças Periodontais/genética , Fenótipo , Transtornos de Fotossensibilidade/genética , Porfiria Variegada/genética , Protoporfirinogênio Oxidase/genética , Síndrome de Sjogren-Larsson/genética , Fatores de Transcrição/genética , Xeroderma Pigmentoso/genéticaRESUMO
Alopecia with mental retardation (APMR) is a very rare disorder. In this study, we report on a consanguineous Pakistani family (AP91) with mild-to-moderate intellectual disability, adolescent alopecia and dentogingival abnormalities. Using homozygosity mapping, linkage analysis and exome sequencing, we identified a novel rare missense variant c.898G>A (p.(Glu300Lys)) in ITGB6, which co-segregates with the phenotype within the family and is predicted to be deleterious. Structural modeling shows that Glu300 lies in the ß-propeller domain, and is surrounded by several residues that are important for heterodimerization with α integrin. Previous studies showed that ITGB6 variants can cause amelogenesis imperfecta in humans, but patients from family AP91 who are homozygous for the c.898G>A variant present with neurological and dermatological features, indicating a role for ITGB6 beyond enamel formation. Our study demonstrates that a rare deleterious variant within ITGB6 causes not only dentogingival anomalies but also intellectual disability and alopecia.