RESUMEN
BACKGROUND: Focal dermal hypoplasia (FDH) is rare X-linked dominant disease characterized by atrophy and linear pigmentation of the skin, split hand/foot deformities and ocular anomalies. FDH is caused by mutations of the Porcupine (PORCN) gene, which encodes an enzyme that catalyzes the palmitoylation of Wnt ligands required for their secretion. High resolution melting analysis (HRM) is a technique that allows rapid, labor-efficient, low-cost detection of genomic variants. In the present study, we report the successful implementation of HRM in the molecular diagnosis of FDH. METHODS: Polymerase chain reaction and HRM assays were designed and optimized for each of the coding exons of the PORCN gene, processing genomic DNA samples form a non-affected control and a patient complying with the FDH diagnostic criteria. The causal mutation was characterized by Sanger sequencing from an amplicon showing a HRM trace suggesting heterozygous variation and was validated using an amplification-refractory mutation system (ARMS) assay. RESULTS: The melting profiles suggested the presence of a variant in the patient within exon 1. Sanger sequencing revealed a previously unknown C to T transition replacing a glutamine codon for a premature stop codon at position 28, which was validated using ARMS. CONCLUSIONS: Next-generation sequencing facilitates the molecular diagnosis of monogenic disorders; however, its cost-benefit ratio is not optimal when a single, small or medium size causal gene is already identified and the clinical diagnostic presumption is strong. Under those conditions, as it is the case for FDH, HRM represents a cost- and labor-effective approach.
Asunto(s)
Aciltransferasas/genética , Exones/genética , Hipoplasia Dérmica Focal/diagnóstico , Hipoplasia Dérmica Focal/genética , Proteínas de la Membrana/genética , Desnaturalización de Ácido Nucleico/genética , Secuencia de Aminoácidos , Codón sin Sentido , Femenino , Hipoplasia Dérmica Focal/fisiopatología , Heterocigoto , Humanos , Lactante , Mutación , Filogenia , Reacción en Cadena de la Polimerasa/métodos , Alineación de SecuenciaRESUMEN
El síndrome de Goltz llamado también hipoplasia dérmica focal es una rara dermatosis que fue definida por primera vez por Goltz en el año 1962. Se la considera una genodermatosis de presentación esporádica (95% de los pacientes) aunque se han reportado casos de transmisión familiar. Compromete estructuras derivadas del mesodermo y ectodermo con predominio en el sexo femenino acompañada de herencia dominante ligada al cromosoma X. La mutación en el gen PORCN (locus Xp11.23) es letal en la mayoría de varones. La importancia de su publicación radica en su baja frecuencia y las manifestaciones clínicas características que ayudan al establecer el diagnóstico.
Goltz syndrome, also called focal dermal hypoplasia, is a rare dermatosis that was first defined by Goltz in 1962. It is considered a genodermatosis with sporadic presentation (95% of patients) although familiar aggregation has been reported. It compromises mesodermal and ectodermal structures, most frequently in female patients, its inheritance mode is dominant X linked. The mutation in the PORCN gene (locus Xp11.23) is lethal in the majority of males. The importance of its publication lies in its low frequency and clinical characteristic that helps in establishing the correct diagnosis.
Asunto(s)
Humanos , Adolescente , Hipoplasia Dérmica Focal , Cromosoma X , Enfermedades RarasRESUMEN
Focal dermal hypoplasia is a rare genetic disease characterized 8-year-old female who sought genetic counseling for multiple malformations, aggressive behavior and intellectual disability. Gene analysis confirmed focal dermal hypoplasia.