DMD Trp3X nonsense mutation associated with a founder effect in North American families with mild Becker muscular dystrophy

Abstract

A recurrent exon 1 nonsense mutation in the DMD gene, p.Trp3X (c.9G>A), was first ascertained in a proband with no symptoms until age 20 and who walked until the age of 62. Six other unrelated kindreds carrying a p.Trp3X mutation were subsequently ascertained, five from North America and one from Italy. In six of the seven kindreds, the proband presented in childhood incidental to elevated creatine kinase levels detected in the context of other illnesses, or in the setting of cramps with or without rhabdomyolysis. Genetic analysis by high density SNP genotyping demonstrates that the six North American families share a 3.7 Mbp haplotype surrounding the p.Trp3X allele, signifying that this is a founder mutation in these individuals. The size of the founder haplotype and the structure of shared genome-wide segments suggests that the minimal age of this mutation is >6 generations. The discovery of the first DMD founder mutation, associated with a mild Becker phenotype, suggests that the prevalence of hypomorphic dystrophin mutations should be re-examined with the use of improved genomic analysis.

Figure 1

DMD region IBS/IBD blocks determined by high density SNP genotyping of the seven p.Trp3X families. The allelic state of 390 SNP markers spanning ∼ 6.9 Mbp of the Xp21.1 region are shown for pairs of individuals, with patient 43194 (family I) as the reference. Light grey positions are alleles shared identical by state and black positions are non-shared alleles in this pairwise comparison. The location of the large IBD block (3.7 Mbp) is shown in relation to RefSeq annotations and the position of the p.Trp3X mutation in the NM_004006 transcript. The allele calls flanking the exon 1 c.9G>A, p.Trp3X mutation are shown in detail (A and B allele calls from Affymetrix 6.0 data) for families III, VI and VII.

Figure 2

Genome-wide heat map of shared chromosomal segments among seven p.Trp3X patients. The 6.7 cM-length region containing the p.Trp3X mutation at chromosome X: 32.8 – 36.5 Mbp has the greatest genome-wide −log₁₀P value (10.03). The patient pool contained the p.Trp3X patients and the control pool consisted of 53 unrelated European-American subjects. The P values for segmental homozygous haplotype sharing were calculated with the HHanalysis program using the representative strategy modified to analyze both autosomal and X regions.