P.145 Identification of potential genetic modifiers underlying phenotypic variability in a French family with striated muscle laminopathies

Abstract

<i>LMNA</i> gene mutations are responsible for a wide spectrum of disorders called laminopathies, the majority of which affecting striated muscles. Among them, Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular type 1B (LGMD1B) show skeletal muscle involvement of different severity but share the same cardiac involvement, i.e., dilated cardiomyopathy with conduction system disease (DCM-CD) that can also be present in an isolated manner. Clinical heterogeneity is well known among the <i>LMNA</i> mutation carriers. Modifier genes have been suggested to explain such variability. The <i>LMNA</i> mutation (p.Gln6*), identified in a large French family (named here EMD1), is associated with a wide range of age at onset of myopathic symptoms (AOMS). According to this latter, three phenotypic subgroups have been described within the family: AOMS before 20 years (early AOMS), AOMS after 30 years (late AOMS) and isolated cardiac disease without musculo-skeletal symptoms. Our objective was to identify genetic modifiers underlying the intrafamilial phenotypic variability within EMD1 family. Whole genome sequencing (WGS) was performed in 16 <i>LMNA</i>-mutation carriers exhibiting the 3 phenotypic subgroups in EMD1 family. Among the 12 million variants annotated, 2 splice variants with a potential aggravating effect and 1 intronic variant with a potential protective effect have been identified and are currently under functional validation. Moreover, 4 structural variants have been detected only in early AOMS patients. An identity by descent analysis specific to phenotypic subgroups was performed and identified one region shared on chromosome 1, containing the <i>LMNA</i> gene. Our results suggest that a single genetic modifier may not be solely responsible for phenotypic variability in this family, but that a combination of several factors is more likely.