Introduction
Duchenne [DMD, MIM: 310200] and Becker [BMD, MIM: 300376]
muscular dystrophies are X-linked disorders which result in progressive
proximal muscle weakness and degeneration, in conjunction with
characteristic elevation of creatine phosphokinase (CK) in blood. DMD is
rapidly progressive and typically presents in early childhood with motor
delays and gait instability, while BMD is characterized by a later-onset
phenotype of skeletal muscle weakness [1]. Both DMD and BMD are
caused by mutations in DMD , a ~2.2Mbp sized gene
containing 79 exons encoding the dystrophin protein. Dystrophin
maintains the structural integrity of striated muscle cells through the
formation of a dystrophin-glycoprotein complex, linking the cytoskeleton
to the extracellular matrix and thus providing tensile strength to
muscle fibers [2].
Given its size (roughly 0.1% of the human genome), a high degree ofDMD allelic heterogeneity exists for DMD and BMD. Deletions are
the most common pathogenic variants in DMD (~64%
of cases), followed by nucleotide substitutions (22%), duplications
(12%), and others (inversions, insertions, etc., ~2%)
[3]. These alterations disrupt dystrophin’s reading frame in diverse
ways, which can lead to mutated transcripts susceptible to nonsense
mediated decay, truncated unstable proteins products targeted for
degradation, or reduced activity protein variants [4].
DMD duplications are up to five times under-represented compared
to deletions in public databases [3]. DMD duplications have
historically posed a technical detection challenge as exonic
duplications could not be captured by PCR-based techniques, fell outside
interrogated probes by multiplex ligation-dependent probe amplification
(MLPA), or were under the limit of detection of chromosome microarray
(CMA). Such technical difficulties are coupled with the fact that
duplications can adopt different structural configurations in the
genome. These include duplications in tandem direct or inverted
orientations, or insertions into an entirely different chromosome, which
can significantly alter the functional impact of duplications. These
limitations can challenge the clinical assessment of newly identified
duplications in young asymptomatic individuals based solely on genomic
data; for these individuals, further molecular and protein truncation
characterizations need to be performed in order to provide an accurate
diagnosis.
In this report, we illustrate the molecular characterization of a
1.18Mbp DMD duplication spanning exons 1-7 in a 2-month-old male
with mildly elevated CK levels. The duplication was found to expand up
to 698Kb beyond DMD ’s promoter regions and had a tandem
configuration in direct orientation, which led to our reclassification
of the variant as likely benign. Follow-up studies at 13 months of age
indicated decreasing CK levels and normal development in this
individual, further supporting the likely benign classification of the
duplication. We hope our study prompts further characterization ofDMD duplications not only in young asymptomatic individuals but
also in symptomatic patients, to further elucidate the impact of genomic
duplications on DMD transcription and dystrophin structure and
improve our technical and interpretative capabilities for DMD and BMD
diagnosis.