A novel, heritable, expanding CTG repeat in an intron of the SEF2-1 gene on chromosome 18q21.1

There are currently 13 diseases known to be caused by unstable triplet repeat mutations; however, there are some instances (as with FRAXF and FRA16) when these mutations appear to be asymptomatic, In a search for polymorphic CTG repeats as candidate genes for bipolar disorder, we screened a genomic human chromosome 18-specific library and identified a 1.6 kb clone (7,6A) with a CTG(24) repeat that maps to 18q21.1. The CTG repeat locus, termed CTG18.1, is located within an intron of human SEF2-1, a gene encoding a basic helix-loop-helix DNA binding protein involved in transcriptional regulation. The CTG(n) repeat is highly polymorphic and very enlarged alleles, consistent with expansions of up to CTG(2100), were identified, PCR and Southern blot analysis in pedigrees ascertained for a Johns Hopkins University bipolar disorder linkage study and in CEPH reference pedigrees revealed a tripartite distribution of CTG18.1 alleles with stable alleles (CTG(10)-CTG(37)), moderately enlarged and unstable alleles (CTG(53)-CTG(250)), and very enlarged, unstable alleles (CTG(800)-CTG(2100)). Moderately enlarged alleles were not associated with an abnormal phenotype and have a combined enlarged allele frequency of 3% in the CEPH and bipolar populations. Very enlarged alleles, detectable only by Southern blot analysis of genomic digests, have thus far been found in only three individuals from our bipolar pedigrees, and to date, have not been found in any of the CEPH reference pedigrees. These enlarged alleles may arise, at least in part, via somatic mutation.