A genetic study of the childhood eye disorder: Congenital Nystagmus

Abstract

Nystagmus is an ocular disorder characterised by uncontrolled, repetitive eye movements. Nystagmus may occur alongside a broad spectrum of other diseases, or may occur in isolation. The variety of causal clinical conditions can produce varying, overlapping, hypomorphic phenotypes making early nystagmus presentations hard to diagnose. A multitude of genes are associated with nystagmus, but a molecular diagnosis is not always possible. Here, a large cohort of patients with varying phenotypes were studied to determine the genetic cause of nystagmus. Next Generation Sequencing techniques (NGS) were combined with detailed phenotyping information to inform on the best genetic workflow for efficient diagnosis of infantile nystagmus syndrome (INS). One common cause of INS is albinism, which describes a broad group of pigmentary disorders that can be sub-grouped by genetic diagnosis and are usually considered phenotypically distinguishable. However, this work describes a hypomorphic albinism subtype that may be hidden behind a diagnosis of idiopathic INS. Cases of hypomorphic albinism are particularly susceptible to missing heritability which is prevalent through albinism and INS in general. A novel pattern of inheritance was identified in patients with hypomorphic albinism, whereby common population variants play a role in the disease. These SNPs are investigated in multiple family pedigrees as well as in a robust functional assay, providing proof of their pathogenicity. Furthermore, a gene panel was analysed for its effectiveness in diagnosing a cohort of 81 patients with various presentations of INS. The panel was able to provide a diagnosis for 43% of the cohort, which is a high yield for a young INS cohort. The identified genotypes were grouped based on detailed clinical phenotypes to assess the correlation between the two. Overall, the two phenotype groups ‘idiopathic nystagmus’ and ‘albinism’ correlate with the identified causal genotypes but without complete fidelity. Overall, this work has improved the diagnosis of nystagmus by improving the efficiency of genetic diagnosis and by providing evidence of a novel albinism genotype The commonality of the novel genotype provides an explanation for a large portion of the missing heritability in this cohort. It also sheds light on the complex inheritance of albinism disorders and how the current bioinformatics guidelines may need to be adjusted when analysing pigment gene variants.

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Identifiers

ORCID for James Self: orcid.org/0000-0002-1030-9963

ORCID for Diana Baralle: orcid.org/0000-0003-3217-4833

ORCID for Janaka Ratnayaka: orcid.org/0000-0002-1027-6938

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