RESUMO
Two siblings, from a consanguineous Iraqi family, were investigated to identify the underlying genetic cause of their high myopia, esotropia, vitreous changes and cataract. Subsequent investigation identified low molecular weight proteinuria as part of their syndrome. Exome sequencing of one of the probands revealed a new non-synonymous variant in the LRP2 gene. Sanger sequencing confirmed the mutation and segregation in the family. No mutation was identified in COL9A1/2, COL11A1/2, or COL2A1 genes. The variant (c.11483A>G; p.Asp3828Gly) is predicted to be damaging and is conserved among vertebrate species. Mutations in LRP2 have been shown to cause the Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR) syndrome, a syndrome associated with facial dysmorphism, ocular anomalies, sensorineural hearing loss, low molecular weight proteinuria, and diaphragmatic hernia and absent corpus callosum, although there is variability in the expression of some features. This family shows a milder phenotype with a predominant eye phenotype similar to the Stickler syndrome and only a few features of the DBS, including microglobulinuria. The presence of microglobulinuria was only detected after molecular results were known. In conclusion, with the identification of a new mutation in LRP2 associated with a predominant eye phenotype similar to the Stickler syndrome, we have broadened the phenotypic spectrum of LRP2 mutations.
Assuntos
Olho/patologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Artrite , Sequência de Bases , Doenças do Colágeno/genética , Doenças do Colágeno/patologia , Doenças do Tecido Conjuntivo , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Hérnias Diafragmáticas Congênitas/genética , Hérnias Diafragmáticas Congênitas/patologia , Humanos , Imageamento por Ressonância Magnética , Dados de Sequência Molecular , Miopia/genética , Miopia/patologia , Linhagem , Proteinúria/genética , Proteinúria/patologia , Erros Inatos do Transporte Tubular Renal/genética , Erros Inatos do Transporte Tubular Renal/patologia , Descolamento Retiniano , Análise de Sequência de DNARESUMO
Hearing loss is the most common sensory disorder in children, with an incidence of 1 in 500 newborns. Most cases are caused by mutations in a single gene. However, DNA diagnostics for hearing loss are challenging, since it is an extremely heterogeneous trait. Although more than 47 causative genes have been identified for the nonsyndromic forms of hearing loss alone, diagnostic application of the scientific progress has lagged behind. The reason for this is the cost: screening all the known causative genes for hearing loss in one patient with the current golden standard for DNA diagnostics, Sanger sequencing, would be extremely expensive. Consequently, current routine DNA diagnostic testing for hearing loss is restricted to one or two of the most common causative genes, and the responsible gene is identified in only 10-20% of cases. Several recent reports have shown that "next-generation DNA sequencing techniques" have the potential to provide a novel testing platform that could test all known genes in a sensitive, specific and cost-efficient manner. It is to be expected that these new tests will greatly improve DNA diagnostics in the coming years.