Preimplantation genetic diagnosis for familial dysautonomia.

Familial dysautonomia (FD) is the most common congenital sensory neuropathy in Ashkenazi Jews, caused by a single major mutation in the IKBKAP gene. Effective management for this severe debilitating disease is still not available, making preimplantation genetic diagnosis (PGD) a useful option for at-risk couples to establish an FD free pregnancy from the outset. PGD was performed for a couple with a previous affected child with FD, using first and second polar body testing to preselect mutation-free oocytes, based on mutation analysis with simultaneous testing of two closely linked markers, D9S58 and D9S1677. Of 15 tested oocytes, 11 carried information about both polar bodies' genotype, of which seven were predicted to be free of the FD gene. Three embryos resulting from these oocytes were transferred back to the patient, resulting in a triplet pregnancy and the birth of three unaffected children confirmed to be free of FD. This is the first PGD for FD, providing an alternative for those at-risk couples who cannot accept prenatal diagnosis and termination of pregnancy as an option for avoiding FD.

Fine mapping of the split-hand/split-foot locus (SHFM3) at 10q24: evidence for anticipation and segregation distortion.

Split-hand/split-foot malformation (SHFM, ectrodactyly, or lobster-claw deformity) is a human limb malformation characterized by aberrant development of central digital rays with absence of fingers and toes, a deep median cleft, and fusion of remaining digits. SHFM is clinically heterogeneous, presenting both in an isolated form and in combination with additional abnormalities affecting the tibia and/or other organ systems, including the genitourinary, craniofacial, and ectodermal structures. Three SHFM disease loci have been genetically mapped to chromosomes 7q21 (SHFM1), Xq26 (SHFM2), and 10q24 (SHFM3). We mapped data from a large Turkish family with isolated SHFM to chromosome 10q24 and have narrowed the SHFM3 region from 9 cM to an approximately 2-cM critical interval between genetic markers D10S1147 and D10S1240. In several instances we found evidence for a more severe phenotype in offspring of a mildly affected parent, suggesting anticipation. Finally, data from this family, combined with those from six other pedigrees, mapped to 10q24, demonstrate biased transmission of SHFM3 alleles from affected fathers to offspring. The degree of this segregation distortion is obvious in male offspring and is possibly of the same magnitude for female offspring.