Molecular Genetic Analysis of Families with Nystagmus

Abstract

Genetic studies provide an opportunity to discover the basis of inherited diseases. Identification of new disease-causing variants provides important insights into the molecular genetic basis of an inherited disease. Once the genetic cause of a disorder is established, diagnostic testing may be performed to provide affected families the chance of early diagnosis and treatment intervention, support may be provided via premarital or prenatal counseling, and educational benefits may be provided regarding the causes and nature of the inherited disease. Nystagmus, characterized by abnormal eye movement can be non-syndromic or syndromic (associated most commonly with albinism and OCA). Most commonly observed form of eyes movement is horizontal (to-and-fro), but some other like vertical, rotary, jerk and pendular have also been reported. Idiopathic congenital nystagmus (ICN) refers to a group of abnormal eye movements which can be observed within the first 6 months after birth (early infancy). The worldwide Frequency of nystagmus is unknown but one study revealed 1in 1,500 live births. There is no report available about its prevalence in the Pakistani population. This study involves the genetic investigation of nystagmus and associated syndromes in selected families from different regions of Pakistan. During this work, six (6) novel mutations were uncovered in four genes, associated with non-syndromic (FRMD7) and syndromic (TYR, OCA2, and CNGA3) nystagmus. These mutations are one novel nonsense mutation p.leu133* in the FRMD7 gene in a family (Family-01) with congenital nystagmus, a novel missense mutation p.Trp80Cys in the first coding exon of TYR in two families (Family-02 and 03), two novel heterozygous OCA2 gene mutations p.Arg588Trp and p.Arg137Ilefs*83 in two families (Family-05 & and 06) and a novel missense mutation c.1540G>A (p.D514N) in family-08 along with one reported TYR mutation, three OCA2 heterozygous and one CNGA3 mutation in different families (Family04, Family-07, and Family-09).In order to establish the pathogenic potential of the described variants, different in-silico analyses were performed. Further, normal and mutated protein structures were predicted by expand current knowledge of the molecular causes of nystagmus and associated clinical conditions. More in-depth investigation of the disease mechanisms underlying these conditions may, in turn, translate into providing treatment therapies for affected families in near future.