Abstract Details

Title Lack of Genotype-Phenotype Correlation in Individuals with DMPK Expansions

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P5 - Poster Session 5 (5:30 PM-6:30 PM)

Poster/Presentation
Number 12-014

Objective Evaluate the degree of correlation between DMPK repeat length and disease prognosis.

Background Myotonic Dystrophy type 1 (DM1) is caused by expansions of a CTG repeat in the DMPK gene. Mild to classic DM1 presents with myotonia, cataracts, and muscle weakness, but the more severe congenital DM1 includes hypotonia and cognitive delay. Age of onset ranges from birth to late adulthood. Current perceptions accept that large expansions present with earlier-onset and more severe symptoms than smaller expansions. Subsequently, repeat length is often considered a predictor of prognosis. Traditionally, congenital disease has been defined as >1000 repeats and onset before age 10 and mild disease as <150 repeats and onset from 20-70 years. However, some literature has contradicted this convention.

Design/Methods Establish the correlation between DMPK repeat length (determined by repeat-primed PCR or Southern blot) and clinical features and age-of-onset in 230 affected individuals with >50 repeats.

Results For the 53 individuals with ≥1000 repeats, 54% were ≥30 years old at diagnosis and presented with clinical features of classic/mild DM1, whereas 23% were ≤10 years old at diagnosis and clinically presented with congenital DM1. For the 92 individuals with ≤150 repeats, 99% were ≥20 years old at diagnosis and clinically presented with classic/mild DM1. On average, individuals with ≥1000 repeats were younger at age of testing (29.8 years) compared to individuals with ≤150 repeats (53 years), likely signifying a younger age of disease onset.

Conclusions Our data suggests that larger repeat expansions correlate with an earlier age of disease onset. However, our data highlight that repeat length cannot reliably predict if a patient will present with congenital vs. classic/mild DM1 as >50% of patients with ≥1000 repeats did not present with congenital DM1. These data raise questions about the clinical utility of obtaining and reporting specific repeat numbers in excess of 150 repeats.

Authors/Disclosures
Amanda S. Lindy, PhD (GeneDx, Inc.) PRESENTER	Dr. Lindy has received personal compensation for serving as an employee of GeneDx.
	No disclosure on file
	No disclosure on file
Hui Yang, PhD (GeneDx)	No disclosure on file
Dianalee McKnight, PhD (InVitae)	Dr. McKnight has nothing to disclose.

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