2-LOCI FOR TUBEROUS-SCLEROSIS - ONE ON 9Q34 AND ONE ON 16P13

32 families informative for the segregation of Tuberous sclerosis (TSC ) have been examined for genetic markers on chromosomes 9, 11, 12 and 16. In one large family there was clear evidence of linkage to markers on chromosome 16p13.3 (lodscore with D16S291 of 4.7 at theta = 0) but other families were too small to give individually convincing lodscor es. Combined results for all families gave positive results with ABO/D BH on chromosome 9 (max lod 2.63) and with D16S291 on chromosome 16 (m ax lod 3.98) at values of theta of 0.2 in each case. Further analysis showed strong evidence for heterogeneity with approximately half the f amilies linked to a locus TSC1 on chromosome 9 between ASS and D9S298 and half to TSC2 on chromosome 16 close to D16S291. There was no defin ite support for a third locus although in many families this could not be excluded. In three families the segregation pattern of TSC remains unexplained. In two of these the family apparently segregates for TSC 1 but in each case a single affected individual appeared to exclude th e whole of the candidate region. Preliminary analysis of clinical feat ures did not reveal any definite differences in incidence of mental ha ndicap between individuals in different linkage groups or with differe nt sex of the parent of origin. The frequencies of periungual. fibroma s and facial angiofibromas were also similar in both linkage groups. T he difficulties of detecting linkage in small families where there is locus heterogeneity are discussed. The program ZZ was found to be help ful in this respect.