Trusting new age weapons to tackle titin

Abstract

The advent of next-generation sequencing technologies available at an increasingly affordable price is revolutionizing the discovery and diagnosis of human disease genes. We are without doubt, witnessing the dawn of a new era of disease gene discovery that will radically impact the field of human genetics. Next-generation sequencing technologies are already having a significant impact on neurological disorders, with huge further potential for improved clinical service delivery. In late 2010, Brain first published a paper (Wang et al. , 2010) detailing the identification of a disease gene for spinocerebellar ataxia by sequencing the exomes of four affected family members. An exome comprises ∼1% of the entire genome, encompassing all coding and coding-flanking regions, and is estimated to account for ∼85% of all disease-causing mutations. Notably, Wang et al . (2010) demonstrated that when they allied linkage data with their exome sequencing results, exome data from only one affected individual were sufficient to find the mutation. There have been further illustrations of the power of next-generation sequencing technologies in the past 2 years. Combining linkage and exome sequencing data was again effectively harnessed to identify mutations for familial amyotrophic lateral sclerosis (Johnson et al. , 2010), a dominant form of limb girdle muscular dystrophy with a vacuolar pathology (Harms et al. , 2012 b ), and paroxysmal kinesigenic dyskinesias (Wang et al. , 2011). Homozygosity mapping in consanguineous families can also be partnered with exome sequencing for successful gene discovery, for example, for an autosomal recessive spinocerebellar ataxia (Doi et al. , 2011), and also in the mammoth efforts of Najmabadi et al. (2011), who studied 136 consanguineous families leading to identification of 50 novel genes for intellectual disability or related neurological disorders. Targeted capture and next-generation sequencing of the …