Presymptomatic DNA-testing for Huntington's disease has made it possible to predict whether or not at-risk individuals are gene-carriers with a reliability of about 98%. In our retrospective study of 18 tested individuals, most of the newly identified carriers function apparently well. They use avoidance and repression of affect as psychological defense strategies. However, 8 out of 9 non-carriers do not experience the expected relief about their test results. They experience survivor guilt and emotional numbness and find it difficult to cope with the effects of the test results on the family system. The partners of gene-carriers are at risk of becoming emotionally isolated by putting aside their own feelings for fear of seeming self-centered. Appreciation of these effects on tested individuals is important and professional support is needed to prevent post-traumatic stress disorders. Whatever the test result may be, the working through process may take years rather than months. These findings have important implications for patient care and necessitate an extended period of observation after presymptomatic testing.

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Presymptomatic, testing, prenatal diagnosis, or exclusion testing are now available for persons at risk for Huntington disease. These tests will reduce uncertainty, assist in life planning, and prevent the birth of potentially affected children. We present the results of presymptomatic tests for 37 applicants including two prenatal and one exclusion test in 23 families. We initially used the markers G8, H5.52, F5.53, and pTV20 (D4S10), p8 (D4S62), and pRB1.6 (D4S81) and extended the informativity of the test at a later stage with the markers pKP1.65, C4H, S1.5 (D4S43), 674 (D4S95), 157.9 (D4S111), and YNZ32 (D4S125). Applicants with an unsuitable family structure were not admitted to the test. Of the 37 applicants, 33 were informative. In our hands the most efficient strategy is first to use the markers H5.52 (D4S10), pRB1.6 (D4S81), 674 (D4S95), pKP1.65 (D4S43), 157.9 (D4S111), YNZ32 (D4S125), and 252.3 (D4S115). The overall informativity in our data set was 84% and in the most recent test we achieved a 90-95% informativity. The other markers are used only when the first set is not informative.

Facioscapulohumeral muscular dystrophy (FSHD) is a relatively common autosomal dominant neuromuscular disorder. The gene for FSHD has recently been assigned to chromosome 4q35. Although abnormal mitochondrial and biochemical changes have been observed in FSHD, the molecular defect is unknown. In addition to the FSHD gene, the human muscle adenine nucleotide translocator gene (ANT1) is located on chromosome 4. Interestingly, biochemical studies recently showed a possible defect of ANT1. In order to evaluate the potential role of ANT1 in the etiology of FSHD, the human ANT1 gene was isolated by cosmid cloning and localized to 4q35, in the region containing the FSHD gene. However, in situ hybridization and physical mapping of somatic cell hybrids localized the ANT1 gene proximal to the FSHD gene. In addition, a polymorphic CA-repeat 5 kb upstream of the ANT1 gene was used as a marker in FSHD and Centre d'Etude du Polymorphisme Humain families to perform linkage analysis. These data together exclude ANT1 as the primary candidate gene for FSHD. The most likely order of the loci on chromosome 4q35 is cen-ANT1-D4S171-F11-D4S187-D4S163-D4S139-+ ++FSHD-tel.

We have isolated a random cosmid cX5 (DXS148), which maps into a small Xp21 deletion associated with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CGD), retinitis pigmentosa (RP) and McLeod syndrome, cX5 maps proximally outside several other deletions associated with DMD, glycerol kinase deficiency (GK) and adrenal hypoplasia (AHC). The following order of loci is proposed: centromere-OTC-cX5 (DXS148)-754 (DXS84)-PERT87 (DXS164)/DMD-telomere. A subclone cX5.7, isolated from this cosmid, identifies an MspI RFLP, with a minor allele frequency of 35%. This probe forms an important adjunct to the existing RFLPs for family studies in Duchenne muscular dystrophy.