X-linked recessive myotubular myopathy (XLMTM; MTM1) is a severe neonatal 
disorder often causing perinatal death of the affected males. The responsible 
gene, designated MTM1, was localized to proximal Xq28 and recently isolated. The 
characterization of MTM1 allowed us to screen for causing mutations in three 
families, previously investigated by linkage analysis. Using exon amplification, 
single strand conformation polymorphism, and subsequent sequencing analysis, 
three new mutations and their mutational origin were characterized by analyzing 
10 exons. An acceptor splice site and a frameshift mutation were correlated with 
the concurrent appearance of XLMTM in two families. A third intronic mutation 
was also analyzed by reverse transcription PCR and revealed a cryptic splice 
site mutation cosegregating with the presumed XLMTM haplotype in the third 
family. These results further support the implication of the MTM1 gene in XLMTM 
and allow efficient and reliable carrier and prenatal diagnosis in these 
families. Direct mutational diagnosis of families at risk in combination with 
haplotype analysis avoid the drawbacks using only linkage analysis, make genetic 
counselling far more reliable, and early clinical management of this disease 
more appropriate. Moreover, pedigree analyses provide first information on de 
novo mutation frequency in this newly identified human disease gene.