Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy

Autosomal recessive nemaline (rod) myopathy is clinically and genetically h eterogeneous. A clinically distinct, typical form, with onset in infancy an d a non-progressive or slowly progressive course, has been assigned to a re gion on chromosome 2q22 harbouring the nebulin gene. Mutations have now bee n found in this gene, confirming its causative role. The gene for slow trop omyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inh erited form, has recently been found to be homozygously mutated in one seve re consanguineous case. Here we wished to determine the degree of genetic h omogeneity or heterogeneity of autosomal recessive nemaline myopathy by lin kage analysis of 45 families from 10 countries. Forty-one of the families s howed linkage results compatible with linkage to markers in the nebulin reg ion, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 lo cus was excluded. Our results indicate that at least three genetic loci exi st for autosomal recessive nemaline myopathy. Studies of additional familie s are needed to localise the as yet unknown causative genes, and to fully e lucidate genotype-phenotype correlations. (C) 1999 Elsevier Science B.V. Al l rights reserved.