ClinVar

In a father and his 2 children with Emery-Dreifuss muscular dystrophy (EDMD5; 612999), Zhang et al. (2007) identified a heterozygous 466C-T transition in exon 3 of the SYNE2 gene, resulting in a thr89-to-met (T89M) substitution in the first spectrin repeat. The father had general weakness since age 37 years, ptosis, increased serum creatine kinase, and left ventricular hypertrophy. His daughter had transient cardiac arrhythmia at age 10 to 14 years, and his son had limb weakness and winged scapulae at age 8 years, minor respiratory insufficiency, but no cardiac involvement. In an unrelated family with EDMD5, an affected woman was heterozygous for the T89M mutation and her affected son was heterozygous for T89M and a variant in the SYNE1 gene (V572L; 608441.0009), which was also present in heterozygosity in the unaffected father, calling into question the pathogenicity of the SYNE1 V572L variant. The mother had a history of muscle weakness and died at 30 years of age from cardiomyopathy, and her son had muscular dystrophy combined with severe dilated cardiomyopathy requiring heart transplant at age 26. The T89M mutation was not found in 384 control alleles. In vitro functional expression assays showed no change in binding of the SYNE2 T89M protein to emerin (EMD; 300384), but patient fibroblasts and muscle cells showed decreased localization of EMD, LMNA (150330), and SYNE2 to the nuclear envelope, impaired binding interactions of these 3 proteins, and disruptions in the organization of intranuclear heterochromatin.