Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation.
The American Journal of Human Genetics. 1999-06-01; 64(6): 1594-1603
DOI: 10.1086/302406
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1. Am J Hum Genet. 1999 Jun;64(6):1594-603.
Molecular and clinical study of 18 families with ADCA type II: evidence for
genetic heterogeneity and de novo mutation.
Giunti P(1), Stevanin G, Worth PF, David G, Brice A, Wood NW.
Author information:
(1)Institute of Neurology, London, United Kingdom.
The SCA7 mutation has been found in 54 patients and 7 at-risk subjects from 17
families who have autosomal dominant cerebellar ataxia (ADCA) II with progressive
pigmentary maculopathy. In one isolated case, haplotype reconstruction through
three generations confirmed a de novo mutation owing to paternal meiotic
instability. Different disease-associated haplotypes segregated among the
SCA7-positive kindreds, which indicated a multiple origin of the mutation. One
family with the clinical phenotype of ADCA type II did not have the CAG expansion
that indicated locus heterogeneity. The distribution of the repeat size in 944
independent normal chromosomes from controls, unaffected at-risk subjects, and
one affected individual fell into two ranges. The majority of the alleles were in
the first range of 7-19 CAG repeats. A second range could be identified with
28-35 repeats, and we provide evidence that these repeats represent intermediate
alleles that are prone to further expansion. The repeat size of the pathological
allele, the widest reported for all CAG-repeat disorders, ranged from 37 to
approximately 220. The repeat size showed significant negative correlation with
both age at onset and age at death. Analysis of the clinical features in the
patients with SCA7 confirmed that the most frequently associated features are
pigmentary maculopathy, pyramidal tract involvement, and slow saccades. The
subjects with /=49 repeats. The degree of instability during meiotic transmission was
greater than in all other CAG-repeat disorders and was particularly striking in
paternal transmission, in which a median increase in repeat size of 6 and an
interquartile range of 12 were observed, versus a median increase of 3 and
interquartile range of 3.5 in maternal transmission.
DOI: 10.1086/302406
PMCID: PMC1377902
PMID: 10330346 [Indexed for MEDLINE]