Mapping The Disease Genes For Four Families With Inherited Defects

Chapter one Mapping the disease gene in a Congenital Accessory Auricular Anomaly familyObjective To map the gene for autosomal dominant accessory auricular anomaly(ADAAA).Methods A Chinese ADAAA family with 11 affected individuals was investigated.Linkage analysis with microsatellite markers spanning the whole human-genome in the family was carried out.Results The inheritance pattern of the ADAAA family was autosomal dominant with complete penetrance.Two-point linkage analysis revealed signifcant maximum LOD scores of 4.20(D14S990 and D14S264,sita=0)in the family.Haplotype construction and multipoint linkage analysis also confirmed the locus and defined the isolated ADAAA locus to a 9.84cM interval between the markers D14S283 and D14S297.Conclusions Our study assigned an isolated ADAAA locus to 14q11.2-q12.This is the first time ADAAA locus reported to date.Objective To map and to identify the causal gene for autosomal dominant congenital cataract(ADCC)in a Chinese family. Methods A four-generation family with a history of congenital cataracts was investigated.Twenty-three members of the family were examined ophthalmologically.Blood samples were collected from twenty-nine family members for genetic linkage analysis.Two-point LOD scores were calculated.Multi-point linkage analysis and haplotype construction were performed to define the optimal cosegregating interval.Direct sequence analysis of the candidate gene,beaded filament structural protein 1, filensin(BFSP1)in the critical region was carried out.Results Fifteen family members were affected with autosomal dominant progressive congenital zonular nuclear cataract(ADPCZNC).The maximum two-point LOD Score of 6.02 was obtained for marker D20S904(=0). The cataract locus in this family was mapped to chromosome 20p11.23-p12.2,a 9.34 Mb(16.37 cM)interval between markers D20S 186 and D20S912.Although BFSP1 was in this critical region,no evidence was found that the condition in the family was caused by a BFSP1 mutation.Conclusions We have mapped the genetic locus of ADPCZNC to chromosome 20p11.23-p12.2 in an ADCC family.This is the first time ADPCZNC has been linked to this region.Chapter three Mapping the disease gene in two Congenital motor nystagmus familiesObjective In order to narrow down the candidate region and to identify the candidate gene for X-linked CMN.Methods Two families with CMN were investigated.Genotyping and linkage analysis were conducted in these two Chinese families.Results These two families were affected by X-linked CMN with incomplete penetrance. Two-point linkage analysis revealed significant maximum logarithm of odds(LOD)scores of 8.55(DXS10.47,sita=0)and 3.91(DXS1211 and DXS1205,=0)at the family nys-01 and the family nys-02 respectively. Haplotype construction and multipoint linkage analysis also confirmed the locus and refined the locus to a 7.1-cM interval between the markers DXS8044 and DXS8041 on chromosome Xq25-q26.3.Conclusion We have mapped the nystagemus gene to aninterval of 7.1 cM,at the location of Xq15-q26.3,such interval shares no overlap with previous Xq26-q27 locus.