D.P.13 Targeted array CGH analysis of the nebulin gene: Identification of large deletions causing nemaline myopathy

Abstract

Nemaline myopathy (NM) constitutes a heterogeneous group of disorders among the congenital myopathies. Mutations in the nebulin gene (NEB) are a main cause of recessively inherited NM. Sixty-eight different mutations causing NM have been published in NEB to date. Almost all are point mutations or small deletions. The only large mutation described in NEB thus far is the 2.5kb deletion of exon 55 in the Ashkenazi Jewish population. To investigate any copy number variations in NEB we designed a novel custom NM-CGH microarray targeted towards the seven known NM genes. During the validation and optimization of the NM-CGH array we identified three novel disease-causing aberrations in three different families. Two of these aberrations are the largest deletions characterized in NEB to date (53kb and 88kb) encompassing 24 and 68 exons, respectively. The third mutation is a 1kb deletion, covering two exons. In two of the families, the copy number change was the second mutation to be characterized. The novel aberrations were shown to have been inherited from one of the healthy carrier parents. However, the largest aberration was detected in a family with three affected family members in three different generations. Further studies are ongoing to refute or corroborate the potentially dominant effect of this mutation. In addition to these aberrations, copy number variation, both deletions and duplications, in the triplicate region of NEB, have been identified in 11 samples from six different families. Further study is ongoing to elucidate the potential pathogenicity of these variants. We conclude that the NM-CGH-array appears promising for the detection of copy number variations in NEB, and already, it has given a lot of new information about the vast nebulin gene.