Borderline CNBP CCTG Expansions in Myotonic Dystrophy Type 2 in over 16,000 Specimens Analyzed in a Clinical Laboratory (P3.118)

Objective: To determine the frequency of CNBP gene CCTG expansions in the “borderline” size range [177–372 base pairs (bp)] in specimens analyzed for myotonic dystrophy type 2 (DM2) in a clinical laboratory. Background: The main clinical feature of dominantly inherited DM2 is myotonia, but cardiac conduction defects, cataracts, diabetes mellitus, and testicular failure are sometimes present. The disorder typically begins in the third decade of life and is accompanied by large expansion of a CCTG repeat in the CNBP gene. Published reference ranges include a normal CNBP repeat size of ≤176 bp and an abnormal repeat size >372 bp. CNBP alleles in the size range of 177–372 bp have been reported in only four Slovak patients with 184 bp, 202 bp, 226 bp, and 338 bp repeat sizes. It is unclear if CNBP alleles in this borderline range are unstable pre-mutations that expand into the pathogenic range. Knowing the frequency of these borderline sizes may help determine if they are pre-mutations. Design/Methods: Routine PCR, PCR repeat-primed assay, and Southern blot were used to detect a CNBP gene CCTG expansion in 16,253 specimens sent for diagnostic testing for myotonic dystrophy. Results: The frequencies of borderline CNBP genotypes were the following: One borderline allele and one normal allele in 0.86% (n=139), two borderline alleles in 0.02% (n=4), and one expanded allele and one borderline allele in 0.08% (n=13). The 158 borderline alleles ranged in size from 177–338 bp, with the majority of alleles at 180 bp (8.86%), 182 bp (24.05%), 183 bp (5.06%), 184 bp (8.23%) and 186 bp (12.03%). Other borderline allele sizes were rare with individual allele frequencies Conclusions: Borderline CNBP alleles were found in 0.97% (158/16,253) of specimens received in a clinical laboratory for DM2 testing. The frequency of borderline allele sizes is larger than reported previously. Study Supported by: Quest Diagnostics Disclosure: Dr. Nedzweckas has received personal compensation for activities with Quest Diagnostics. Dr. Nedzweckas has received research support from Quest Diagnostics. Dr. Moore has received personal compensation for activities with Athena Diagnostics as an employee. Dr. Moore has received research support from Quest Diagnostics. Dr. Meservey has received personal compensation for activities with Quest Diagnostics as an employee. Dr. McNamara has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Tiebout has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Tiebout has received research support from Quest Diagnostics. Dr. Wang has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Wang has received research support from Quest Diagnostics. Dr. Batish has received personal compensation for activities with Quest Diagnostics as an employee. Dr. Batish has received research support from Quest Diagnostics. Dr. Higgins has received personal compensation for activities with Quest Diagnostics.