Current state of the art in ocular genetics

Ana Luísa Carvalho speaking at the WSPOS sub-specialty day Genetic ocular disease was the subject of a special session at the WSPOS Subspecialty Day yesterday. Chaired by Eduardo Silva, Portugal, and Carmen Ayuso, Spain, the four presentations provided delegates with highly detailed, in-depth discussions on the current state of the art in ocular genetics. Dr José María Millán, Health Research Institute Hospital La Fe, Valencia, Spain, shared his knowledge of Usher syndrome, the most common cause of genetic deaf-blindness. This autosomal recessive disease has a prevalence of approximately four per 100,000 people, and a high clinical variability and genetic heterogeneity. Its three subtypes are characterised by retinitis pigmentosa, sensorineural hearing loss and occasional vestibular dysfunction. “We use the Next Generation Sequencing (NGS) technology to screen all the known Usher genes in each patient,” said Dr Millán. The NGS panel can detect any of the 13 genes known to cause Usher syndrome, as well as intronic mutations in USH2A, the most commonly encountered gene mutation. This has led to the detection of at least one mutation in 89%, and allele ratio detection in 80% of the more than 100 patients analysed by NGS. Dr Millán’s team uses comparative genomic hybridisation (CGH) array to detect large deletions or duplications of these genes. But why don’t we detect 100% of the mutations? “Most likely, this is due to mutations in non-coding regions,” he said. Dr Carmen Ayuso, University Hospital Fundación Jiménez Díaz, Madrid, Spain, then presented “Ciliopathies: Where do we stand?” “The major challenges regarding the ciliopathies are early recognition that something is abnormal, and making a specific diagnosis,” said Dr Ayuso. These complex, multi-systemic conditions are caused by dysfunction in both motile and non-motile cilia. Because they share many common clinical features, diagnosis of these occasionally lethal diseases can be challenging. The retina is involved because photoreceptors are modified cilia, and ciliopathies represent 40% of the genetic causes of retinitis pigmentosa (RP). Among these are Leber congenital amaurosis, various types of non-syndromic retinal dystrophies and several syndromic retinal dystrophies such as Bardet-Biedl and Senior-Løken syndromes. “We have to consider the possibility of a ciliopathy when there is early onset of retinal dystrophy associated with extraocular symptoms,” said Dr Ayuso. The next speaker was introduced by Dr Silva as the world’s leading expert on choroideremia. Professor Miguel Seabra, CEDOC, Lisbon, Portugal, brought delegates up to date on his many years of research into the disease. “Choroideremia is a systemic disease. Despite the presence of the defective protein in all cells, the disease manifests itself only in the eye,” said Dr Seabra. And although, “genetically speaking, choroideremia is quite a simple disease, there are several things that we still don’t know”, he said. For example, what are the exact mechanisms of RPE and photoreceptor cell death? And why is the disease restricted to the retina? Dr Seabra has played a lead role in the choroideremia gene therapy clinical trial, resulting in improved retinal sensitivity in advanced disease. Closing the session, Ana Luísa Carvalho, HP-CHUC, Coimbra, Portugal, detailed the advanced testing her team performs in patients with microphthalmia-anophthalmia-coloboma (MAC) spectrum disease. These patients, who have extraocular abnormalities in up to 80%, require not only genetic testing but also referral to a clinical geneticist for further evaluation and genetic counselling.