CONFIRMATION OF PRENATAL-DIAGNOSIS RESULTS OF X-LINKED RECESSIVE MYOTUBULAR MYOPATHY BY MUTATIONAL SCREENING, AND DESCRIPTION OF 3 NEW MUTATIONS IN THE MTM1 GENE

X-linked recessive myotubular myopathy (XLMTM; MTM1) is a severe neona tal 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 f or causing mutations in three families, previously investigated by lin kage analysis. Using exon amplification, single strand conformation po lymorphism, and subsequent sequencing analysis, three new mutations an d their mutational origin were characterized by analyzing 10 exons, An acceptor splice site and a frame-shift mutation were correlated with the concurrent appearance of XLMTM in two families. A third intronic m utation was also analyzed by reverse transcription PCR and revealed a cryptic splice site mutation cosegregating with the presumed XLMTM hap lotype in the third family. These results further support the implicat ion 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 halotype analysis avoid the d rawbacks using only linkage analysis, make genetic counselling far mor e reliable, and early clinical management of this disease more appropr iate. Moreover, pedigree analyses provide first information on de novo mutation frequency in this newly identified human disease gene. (C) 1 998 Wiley-Liss, Inc.