Germline mosaicism and Duchenne muscular dystrophy mutations

Abstract

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disease with an incidence of approximately 1 in 3,500 newborn boys. The DMD locus has a high mutation frequency: one third of the cases is thought to result from a new mutation. Linkage studies using probes to detect restriction fragment length polymorphisms and DNA deletion studies have greatly improved DMD carrier detection and prenatal diagnosis. Here we report on two families in which a pERT87 (DXS164) deletion was transmitted to more than one offspring by women who showed no evidence for the mutation in their own somatic (white blood) cells. We also show that the deletion in both siblings in one of the families is identical, indicating that the deletion must have occurred during mitosis in early germline proliferation, leading to a germline mosaicism. This phenomenon may turn out to be a major factor contributing to the induction of DMD mutations, and has important implications for the counselling of DMD families.

Germline mosaicism in Coffin-Lowry syndrome

“…Mutation detection of genomic DNA from the proband was performed by PCR amplification of 6 exons (exons 5,6,7,13,16,20), for which flanking intron sequences were known. Single strand conformation polymorphism (SSCP), analysis of the PCR product containing exon 5 showed mobility shift in the proband, compared with control individuals.…”

“…Germline mosaicism, with or without somatic mosaicism, has been reported for many X-linked disorders, including Duchenne muscular dystrophy (DMD), haemophilia A, severe combined immunodeficiency (SCID) and X-linked hydrocephalus. [16][17][18][19][20] The incidence of germline mosaicism has been reported to be as high as 14% for the at-risk haplotype in new cases of DMD. Thus, possible germline mosaicism for RSK2 mutations has important counselling implications for CLS families, especially those with isolated cases.…”

Gene-deletion and carrier detections, and prenatal diagnosis of Duchenne muscular dystrophy by analysis of the dystrophin gene amplified by polymerase chain reaction

“…Thus, more studies are needed to find novel RFLPs in more intragenic loci. Another problem for carrier detection includes the presence of germinal mosaicism (Bakker et al, 1987). In this case, PCR analysis dose not in general contribute to find such a condition, and therefore, gene dose analysis with Southern hybridization is still important.…”

Germ-line intrachromosomal recombination restores fertility in transgenic MyK-103 male mice.

“…Deletion breakpoints have also been identified between different Alu sequences in the LDL receptor gene (Lehrman et al 1987), and frequently the entire steroid sulfatase gene is Cold Spring Harbor Laboratory Press on May 9, 2018 -Published by genesdev.cshlp.org Downloaded from deleted by recombination between flanking repeats in patients with ichthyosis (Ballabio et al 1990;Yen et al 1990). Although many deletions undoubtedly occur during meiosis, analysis of deletions in the Duchenne muscular dystrophy gene demonstrates that mitotic recombination does occur^ resulting in germ-line mosaicism and the transmission of new mutations to offspring (Bakker et al 1987;Darras and Francke 1987). Germ-line mosaicism was also found within certain repetitive DNA sequences of the VNTR family (Jeffreys et al 1990).…”