RESUMO
Isolated ectopia lentis (IEL) can lead to blindness as result of severe complications, such as retinal detachment and secondary glaucoma. Pathogenic variants in the fibrillin 1 (FBN1) gene are a common cause of IEL. The aim of the present study was to investigate the frequency of pathogenic FBN1 variants in twelve probands with IEL and to evaluate their associated phenotypes. Systemic clinical examination of the twelve probands indicated that all had bilateral EL with a median age at diagnosis of three years. High myopia was the most common feature among the probands (83.3%; 10/12 cases). No extraocular symptoms (either cardiovascular or skeletal) were observed among these patients. Genomic DNA was extracted from peripheral blood leukocytes from all patients for targeted exome sequencing. Seven heterozygous missense variants in FBN1 were identified by bioinformatics analysis and further verified using Sanger sequencing. The seven variants were all classified as pathogenic after segregation analysis on available family members according to the American College of Medical Genetics and Genomics standards and guidelines. Of the seven variants, three were novel, namely c.2179T>C, c.2496T>G and c.3346G>C. The remaining four, namely c.184C>T, c.367T>C, c.1879C>T and c.4096G>A have been reported in previous studies. The seven pathogenic variants were identified in 8/12 (66.7%) probands with IEL. These results expand the variant spectrum of the FBN1 gene as well as the understanding of the molecular pathogenesis of IEL.
Assuntos
Ectopia do Cristalino/genética , Fibrilina-1/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Mutação , Adolescente , Adulto , Povo Asiático/genética , Sequência de Bases , Criança , Pré-Escolar , China , Análise Mutacional de DNA/métodos , Ectopia do Cristalino/diagnóstico , Ectopia do Cristalino/etnologia , Feminino , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Adulto JovemRESUMO
The term isolated ectopia lentis (EL; subluxation or dislocation of the human crystalline lens) is applied to patients with EL, without skeletal features and in the absence of aortic root dilatation. To date, the only gene shown to cause autosomal-recessive isolated EL is ADAMTSL4. Here we report a novel founder mutation in ADAMTSL4 gene in children of Bukharian Jewish origin presenting with early-onset bilateral EL. A carrier frequency of 1:48 was determined among unrelated healthy Bukharian Jews. Given the complications associated with disease and the allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, pre-implantation or early postnatal diagnosis.
Assuntos
Ectopia do Cristalino/etnologia , Ectopia do Cristalino/genética , Heterozigoto , Judeus , Cristalino/patologia , Mutação de Sentido Incorreto , Trombospondinas/genética , Proteínas ADAMTS , Pré-Escolar , Ectopia do Cristalino/patologia , Feminino , Efeito Fundador , Frequência do Gene , Genótipo , Homozigoto , Humanos , Lactente , Masculino , Linhagem , Adulto JovemRESUMO
PURPOSE: To examine the fibrillin-1 (FBN1) gene for mutations in members of a Chinese family with isolated ectopia lentis. DESIGN: Clinically relevant laboratory investigation. METHODS: Family members underwent clinical examinations. Genomic DNA was extracted from leukocytes of peripheral blood from the available members and 100 controls for mutation analysis. The 65 exons of FBN1 were amplified by polymerase chain reaction and screened for mutations by a combination of denaturing high-performance liquid chromatography analysis and direct DNA sequencing. RESULTS: A mutation, c.184C-->T in exon 2 of FBN1, which results in substitution of arginine by cysteine at position 62 of the fibrillin-1 protein (p.R62C) in all affected family members but in none of the unaffected individuals. CONCLUSIONS: A recurrent mutation of FBN1 gene resulted in an arginine-to-cysteine residue (p.R62C), is responsible for the patients with isolated ectopia lentis in a Chinese family.
