RESUMEN
Oculocutaneous albinism (OCA) is associated with a wide range of clinical presentations and has been categorized with syndromic and non-syndromic features. The most common causative genes in non-syndromic OCA are TYR and OCA2 and HSP1 is in the syndromic albinism. The objective of this study was to identify pathogenic variants in congenital OCA families from Pakistan. Eight consanguineous families were recruited, and clinical and ophthalmological examination was carried out to diagnose the disease. Whole blood was collected from the participating individuals, and genomic DNA was extracted for sequencing analysis. TruSight one-panel sequencing was carried out on one affected individual of each family, and termination Sanger sequencing was carried out to establish the co-segregation of the causative gene or genes. In silico analysis was conducted to predict the causative pathogenic variants. Two families were found to have novel genetic pathogenic variants, and six families harbored previously reported variants. One novel compound heterozygous pathogenic variant in the TYR gene, c.1002delA; p.Ala335LeufsTer20, a novel frameshift deletion pathogenic variant and c.832C>T; and p.Arg278Ter (a known pathogenic variant) were found in one family, whereas HPS1; c.437G>A; and p.Trp146Ter were detected in another family. The identification of new and previous pathogenic variants in TYR, OCA2, and HPS1 genes are causative of congenital OCA, and these findings are expanding the heterogeneity of OCA.
Asunto(s)
Albinismo Oculocutáneo , Proteínas de la Membrana , Proteínas de Transporte de Membrana , Monofenol Monooxigenasa , Albinismo Oculocutáneo/diagnóstico , Albinismo Oculocutáneo/genética , Pueblo Asiatico , Humanos , Proteínas de la Membrana/genética , Proteínas de Transporte de Membrana/genética , Monofenol Monooxigenasa/genética , Pakistán , LinajeAsunto(s)
Genes Recesivos , Predisposición Genética a la Enfermedad , Variación Genética , Ictiosis Lamelar/diagnóstico , Ictiosis Lamelar/genética , Lipooxigenasa/genética , Receptores de Superficie Celular/genética , Alelos , Sustitución de Aminoácidos , Consanguinidad , Familia , Femenino , Estudios de Asociación Genética/métodos , Genotipo , Humanos , Masculino , Pakistán , LinajeRESUMEN
BACKGROUND: Inherited palmoplantar keratodermas (PPKs) are clinically and genetically heterogeneous and phenotypically diverse group of genodermatoses characterized by hyperkeratosis of the palms and soles. More than 20 genes have been reported to be associated with PPKs including desmoglein 1 (DSG1) a key molecular component for epidermal adhesion and differentiation. Mal de Meleda (MDM) is a rare inherited autosomal recessive genodermatosis characterized by transgrediens PPK, associated with mutations in the secreted LY6/PLAUR domain containing 1 (SLURP1) gene. METHODS: This study describes clinical as well as genetic whole exome sequencing (WES) and di-deoxy sequencing investigations in two Pakistani families with a total of 12 individuals affected by PPK. RESULTS: WES identified a novel homozygous nonsense variant in SLURP1, and a novel heterozygous nonsense variant in DSG1, as likely causes of the conditions in each family. CONCLUSIONS: This study expands knowledge regarding the molecular basis of PPK, providing important information to aid clinical management in families with PPK from Pakistan.
