RESUMO
We used a combined approach of homozygosity mapping and whole exome sequencing (WES) to search for the genetic cause of autosomal recessive retinitis pigmentosa (arRP) in families of Yemenite Jewish origin. Homozygosity mapping of two arRP Yemenite Jewish families revealed a few homozygous regions. A subsequent WES analysis of the two index cases revealed a shared homozygous novel nucleotide deletion (c.1220delG) leading to a frameshift (p.Gly407Glufs*56) in an alternative exon (#15) of USH1C. Screening of additional Yemenite Jewish patients revealed a total of 16 homozygous RP patients (with a carrier frequency of 0.008 in controls). Funduscopic and electroretinography findings were within the spectrum of typical RP. While other USH1C mutations usually cause Usher type I (including RP, vestibular dysfunction and congenital deafness), audiometric screening of 10 patients who are homozygous for c.1220delG revealed that patients under 40 years of age had normal hearing while older patients showed mild to severe high tone sensorineural hearing loss. This is the first report of a mutation in a known USH1 gene that causes late onset rather than congenital sensorineural hearing loss. The c.1220delG mutation of USH1C accounts for 23% of RP among Yemenite Jewish patients in our cohort.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Exoma/genética , Éxons/genética , Efeito Fundador , Mutação da Fase de Leitura/genética , Perda Auditiva/genética , Retinose Pigmentar/genética , Idade de Início , Processamento Alternativo/genética , Audiometria , Sequência de Bases , Proteínas de Ciclo Celular , Segregação de Cromossomos/genética , Proteínas do Citoesqueleto , Análise Mutacional de DNA , Feminino , Genes Recessivos/genética , Genoma Humano/genética , Perda Auditiva/complicações , Homozigoto , Humanos , Israel/epidemiologia , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Retinose Pigmentar/complicações , Análise de Sequência de DNARESUMO
OBJECTIVES: To describe a family in which it was possible to perform prenatal diagnosis of Nance-Horan Syndrome (NHS). METHODS: The fetus was evaluated by 2nd trimester ultrasound. The family underwent genetic counseling and ophthalmologic evaluation. The NHS gene was sequenced. RESULTS: Ultrasound demonstrated fetal bilateral congenital cataract. Clinical evaluation revealed other family members with cataract, leading to the diagnosis of NHS in the family. Sequencing confirmed a frameshift mutation (3908del11bp) in the NHS gene. CONCLUSION: Evaluation of prenatally diagnosed congenital cataract should include a multidisciplinary approach, combining experience and input from sonographer, clinical geneticist, ophthalmologist, and molecular geneticist.
