SNP within DYT1 Reduces Penetrance of GAG Deletion

Subject: SNP within DYT1 Reduces Penetrance of GAG Deletion

Date: 6/11/2007

Intragenic cis and trans modification of genetic susceptibility in DYT1 torsion dystonia
NJ Risch, SB Bressman, G Senthil, LJ Ozelius
Am J Human Genetics 2007;80:1188-1193

A sequence variant within the normal DYT1 gene greatly reduces penetrance of the GAG-deleted allele in DYT1 dystonia, according to this report.

DYT1 dystonia is an autosomal dominant disorder with approximately 30% penetrance, and most patients are heterozygous for the deletion. D216H is a single nucleotide polymorphism in DYT1 that encodes either aspartic acid (D) or histidine (H) at amino acid 216 of torsinA.

Manifesting carriers (i.e., those with clinical DYT1 dystonia) and non-manifesting carriers were genotyped for the D216H SNP within the non-GAG-deleted allele. The frequency of the H form was 0.017 (2/119) in manifesting carriers, versus 0.212 (24/113) in non-manifesting carriers (p<0.000002).

“Thus, the penetrance associated with carrying the D216 allele in trans [i.e., on the non-GAG-deleted chromosome] is ~35%, and for the 216H allele, it is ~3%,” the authors state. Further analysis suggested that D216 within the GAG-deleted allele may be required for penetrance.

Because the 216H allele is uncommon (maximum frequency of 19% in whites), the authors conclude, “clinical application of our finding in genetic counseling is important but will have a significant impact for only a minority of subjects. It allows assessment of a much-reduced risk individuals who are 216H carriers and predicts a slightly increased risk for D216 carriers.”

E-MOVE Editor: Richard Robinson, NASW, WE MOVE

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