Secondary mutation (c.94_95delAG) in a -α3.7 allele associated with Hb H disease in two unrelated African American individuals homozygous for the -α(3.7) deletion (-α3.7/-α3.7T).

Hb H disease is rarely seen in individuals of African descent although α-thalassemia (α-thal) is common in this population. Usually α-thal is due either to heterozygosity or homozygosity for the -α(3.7) deletion in this population. We report Hb H disease that is caused by a frameshift mutation on one -α(3.7) allele in two unrelated individuals homozygous for the -α(3.7) deletion. These two cases highlight the importance of further investigation by direct sequencing of the -α(3.7) allele when the thalassemic phenotype does not correlate with the genotype obtained by initial molecular testing.

Development of a genomic DNA reference material panel for Rett syndrome (MECP2-related disorders) genetic testing.

Rett syndrome is a dominant X-linked disorder caused by point mutations (approximately 80%) or by deletions or insertions (approximately 15% to 18%) in the MECP2 gene. It is most common in females but lethal in males, with a distinctly different phenotype. Rett syndrome patients have severe neurological and behavioral problems. Clinical genetic testing laboratories commonly use characterized genomic DNA reference materials to assure the quality of the testing process; however, none are commercially available for MECP2 genetic testing. The Centers for Disease Control and Prevention's Genetic Testing Reference Material Coordination Program, in collaboration with the genetic testing community and the Coriell Cell Repositories, established 27 new cell lines and characterized the MECP2 mutations in these and in 8 previously available cell lines. DNA samples from the 35 cell lines were tested by eight clinical genetic testing laboratories using DNA sequence analysis and methods to assess copy number (multiplex ligation-dependent probe amplification, semiquantitative PCR, or array-based comparative genomic hybridization). The eight common point mutations known to cause approximately 60% of Rett syndrome cases were identified, as were other MECP2 variants, including deletions, duplications, and frame shift and splice-site mutations. Two of the 35 samples were from males with MECP2 duplications. These MECP2 and other characterized genomic DNA samples are publicly available from the NIGMS Repository at the Coriell Cell Repositories.