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Oscar Francisco Chacon-Camacho, RAUL EDUARDO PIÑA-AGUILAR, Angel Nava-Castaneda, Juan Carlos Zenteno, ; Exome sequencing in Nasopalpebral-Lipoma-Coloboma Syndrome identifies a pathogenic mutation in an imprinted locus. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5987.
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© ARVO (1962-2015); The Authors (2016-present)
Nasopalpebral lipoma-coloboma syndrome is an extremely rare autosomal dominant disease characterized by bilateral congenital nasopalpebral lipomas, bilateral upper and lower eyelid colobomata, telecanthus, and maxillary hypoplasia. To date, few cases have been reported and its etiology is unknown. We described the clinical, radiological, and histopathological findings in a Mexican patient with nasopalpebral-lipoma coloboma syndrome and the results of exome sequencing analysis.
A 2-month-old Mexican female was studied. Examination, imagen studies, and histopathological analysis of tumor were carried-out. Genomic DNA was extracted from peripheral blood leucocites and exome sequencing was performed using Illumina's protocol. The captured DNA library was loaded on a HiSeq 2000 plataform for sequencing with a mean exome coverage of 30x. Variants with MAF >0.01, SNPs located in non-coding regions, synonymous variants, and homozygous variants were excluded. All other variants were considered potentially pathogenic and summarized for validation. Direct automated Sanger sequencing was performed for mutation validation.
Clinical examination disclosed the typical phenotypic characteristics previously described for this syndrome. Eye ultrasound showed bilateral nanophthalmos, which is a novel anomaly associated to this entity. Computed tomography with three-dimensional reconstruction of facial soft tissues and bones, and histopathologic tumor biopsy confirmed lipomatous tissue in nasopalpebral region. Exome sequencing identified a de novo c.6245_6246 insTT (p.H2082Hfs*67) in a gene located in an imprinted locus at chromosome 2. The frameshifting mutation was absent from parental DNA, from a set of 300 ethnically matched alleles, and from public databases as Exome Variant Server, dbSNP, Exome Aggregation Consortium, and 1000 Genomes.
Results of exome sequencing supports the identification of a gene associated to the nasopalpebral lipoma-coloboma syndrome. This gene exhibits genomic imprinting and nothing is known about of its protein function, except for the inclusion of a zinc finger domain that has a role in DNA replication and it has been associated with small eyes and enlarged periocular region in a tadpole model. The development of a mammalian knock-out model for this gene will be of great importance for confirming our results.
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