Dyskeratosis congenita caused by a 3 ' deletion: Germline and somatic mosaicism in a female carrier

X-linked dyskeratosis congenita (DC) is a bone marrow failure syndrome caus ed by mutations in the DKC1 gene located at Xq28. By 20 years of age, most affected boys develop bone marrow failure, whereas female carriers show a s kewed pattern of X-chromosome inactivation. The gene product, dyskerin, is homologous to a yeast protein involved in ribosomal RNA biogenesis, providi ng a unique insight into a cause of aplastic anemia. Whereas most causative mutations are single amino acid substitutions, and nonsense or frameshift mutations have not been observed, we present here a case of DC caused by a 2-kb deletion that removes the last exon of the gene. Normal levels of mRNA are produced from the deleted gene, with the transcripts using a cryptic p olyadenylation site in the antisense strand of the adjacent MPP1 gene, norm ally located 1 kb downstream of DKC1 in a tail to tail orientation. The pre dicted truncated protein lacks a lysine-rich peptide that is less conserved than the rest of the dyskerin molecule and is dispensable in yeast, suppor ting the contention that it may retain some activity and that null mutation s at this locus may be lethal. The affected boy had an unaffected brother w ith the same haplotype around the DKC1 gene and a sister who was heterozygo us for the deletion. We conclude therefore that the mother must be a germli ne mosaic with respect to this deletion. Investigation of her blood cells a nd other somatic tissues showed that a small proportion of these cells also carried the deletion, making her a somatic mosaic and indicating that the deletion took place early in development. (C) 1999 by The American Society of Hematology.