Recent linkage studies in tuberous sclerosis. Chromosome 9 markers

Area of Science:

• Genetics
• Human Molecular Genetics

Background:

• Tuberous sclerosis (TSC) is a genetic disorder affecting multiple organs.
• Previous studies suggested a TSC gene locus on chromosome 9q.

Purpose of the Study:

• To confirm the TSC locus on chromosome 9q using linkage analysis in multiple families.
• To investigate potential genetic heterogeneity in TSC.

Main Methods:

• Linkage analysis was performed on eight large multigeneration TSC families.
• Nine polymorphic markers from chromosomes 9q and 11q were utilized.
• Multipoint and 2-point lod score analyses were conducted, including HOMOG programs.

Main Results:

• Overall data supported a TSC locus on distal 9q, with a peak lod score of 3.77 near the Abelson oncogene (ABL) locus.
• Significant evidence for genetic heterogeneity (p=0.01) was detected, with one family showing no linkage to ABL.
• Excluding the unlinked family, multipoint analysis yielded a peak lod score of 6.1 near ABL.
• The unlinked family showed no recombinants with chromosome 11 probes, but lacked statistical significance.

Conclusions:

• This study confirms a TSC locus on distal 9q but also reveals significant genetic heterogeneity.
• Genetic heterogeneity presents challenges for gene cloning via reverse genetics.
• The heterogeneity will impede the use of linked probes for TSC carrier detection and prenatal diagnosis.