Dataset Information

Genetic characteristics of 234 Italian patients with macular and cone/cone-rod dystrophy.

ABSTRACT: Two-hundred and thirty-four Italian patients with a clinical diagnosis of macular, cone and cone-rod dystrophies (MD, CD, and CRD) were examined using next-generation sequencing (NGS) and gene sequencing panels targeting a specific set of genes, Sanger sequencing and-when necessary-multiplex ligation-dependent probe amplification (MLPA) to diagnose the molecular cause of the aforementioned diseases. When possible, segregation analysis was performed in order to confirm unsolved cases. Each patient's retinal phenotypic characteristics were determined using focal and full-field ERGs, perimetry, spectral domain optical coherence tomography and fundus autofluorescence. We identified 236 potentially causative variants in 136 patients representing the 58.1% of the total cohort, 43 of which were unpublished. After stratifying the patients according to their clinical suspicion, the diagnostic yield was 62.5% and 53.8% for patients with MD and for those with CD/CRD, respectively. The mode of inheritance of all cases confirmed by genetic analysis was 70% autosomal recessive, 26% dominant, and 4% X-linked. The main cause (59%) of both MD and CD/CRD cases was the presence of variants in the ABCA4 gene, followed by variants in PRPH2 (9%) and BEST1 (6%). A careful morpho-functional evaluation of the phenotype, together with genetic counselling, resulted in an acceptable diagnostic yield in a large cohort of Italian patients. Our study emphasizes the role of targeted NGS to diagnose MDs, CDs, and CRDs, as well as the clinical usefulness of segregation analysis for patients with unsolved diagnosis.

SUBMITTER: Falsini B

PROVIDER: S-EPMC8904500 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Genetic characteristics of 234 Italian patients with macular and cone/cone-rod dystrophy.

Falsini Benedetto B Placidi Giorgio G De Siena Elisa E Chiurazzi Pietro P Minnella Angelo Maria AM Savastano Maria Cristina MC Ziccardi Lucia L Parisi Vincenzo V Iarossi Giancarlo G Percio Marcella M Piteková Barbora B Marceddu Giuseppe G Maltese Paolo Enrico PE Bertelli Matteo M

Scientific reports 20220308 1

Two-hundred and thirty-four Italian patients with a clinical diagnosis of macular, cone and cone-rod dystrophies (MD, CD, and CRD) were examined using next-generation sequencing (NGS) and gene sequencing panels targeting a specific set of genes, Sanger sequencing and-when necessary-multiplex ligation-dependent probe amplification (MLPA) to diagnose the molecular cause of the aforementioned diseases. When possible, segregation analysis was performed in order to confirm unsolved cases. Each patien ...[more]

PMID: 35260635

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Project description:To identify the causative mutation in a canine cone-rod dystrophy (crd3) that segregates as an adult onset disorder in the Glen of Imaal Terrier breed of dog.Glen of Imaal Terriers were ascertained for crd3 phenotype by clinical ophthalmoscopic examination, and in selected cases by electroretinography. Blood samples from affected cases and non-affected controls were collected and used, after DNA extraction, to undertake a genome-wide association study using Affymetrix Version 2 Canine single nucleotide polymorphism chips and 250K Sty Assay protocol. Positional candidate gene analysis was undertaken for genes identified within the peak-association signal region. Retinal morphology of selected crd3-affected dogs was evaluated by light and electron microscopy.A peak association signal exceeding genome-wide significance was identified on canine chromosome 16. Evaluation of genes in this region suggested A Disintegrin And Metalloprotease domain, family member 9 (ADAM9), identified concurrently elsewhere as the cause of human cone-rod dystrophy 9 (CORD9), as a strong positional candidate for canine crd3. Sequence analysis identified a large genomic deletion (over 20 kb) that removed exons 15 and 16 from the ADAM9 transcript, introduced a premature stop, and would remove critical domains from the encoded protein. Light and electron microscopy established that, as in ADAM9 knockout mice, the primary lesion in crd3 appears to be a failure of the apical microvilli of the retinal pigment epithelium to appropriately invest photoreceptor outer segments. By electroretinography, retinal function appears normal in very young crd3-affected dogs, but by 15 months of age, cone dysfunction is present. Subsequently, both rod and cone function degenerate.Identification of this ADAM9 deletion in crd3-affected dogs establishes this canine disease as orthologous to CORD9 in humans, and offers opportunities for further characterization of the disease process, and potential for genetic therapeutic intervention.

Dataset Information

Genetic characteristics of 234 Italian patients with macular and cone/cone-rod dystrophy.

Publications

Genetic characteristics of 234 Italian patients with macular and cone/cone-rod dystrophy.

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