Early onset Dilated Cardiomyopathy and Aortopathy in Siblings with Duchenne Muscular Dystrophy

Topic:

Other

Poster Number: P109

Author(s):

Melyssa Garner, MS, CGC, Department of Pediatrics, Baylor College of Medicine, Rebecca Littlejohn, MS,CGC, Department of Pediatrics, Baylor College of Medicine, Sreenivas Avula, MD, Department of Neurology, Baylor College of Medicine, Benjamin Akman, ScM, CGC, Department of Pediatrics, Baylor College of Medicine, Elizabeth Roeder, MD, Department of Pediatrics, Baylor College of Medicine, Bandana Sharma Chapagain, MS, Department of Molecular and Human Genetics, Baylor College of Medicine, Blake Vuocolo, MS, CGC, Department of Molecular and Human Genetics, Baylor College of Medicine, Monesha Gupta, MD, Division of Pediatric Cardiology, Baylor College of Medicine

Objective:

To describe the combined phenotype of early onset cardiomyopathy and aortic dilatation in brothers with DMD and explore the impact of an incidental DSC2 variant.

Background:

Duchenne Muscular Dystrophy (DMD) is a progressive neuromuscular disorder affecting dystrophin expression. Nearly all males affected with DMD develop dilated cardiomyopathy, with an estimated 5% exhibiting symptoms by age 5. Here we present a case of two brothers with an early onset DMD phenotype, a novel phenotype of aortic dilatation, and an incidental finding in DSC2.

Case Study:

The proband is an 8-year-old male with a pathogenic duplication of DMD exon 44. Cascade testing identified the duplication in his 5-year-old brother and their mother. The proband received initial cardiac evaluation at age 6, which identified a dilated aortic root of 25 mm (Boston Z-score +3.2). Serial measurements were 25 mm and 25.5 mm, and the aortic root measured 23.8 x 25.5 mm on cardiac MRI. The younger brother was found to have slight dilation of the aortic root of 20.8 mm (Z-score +2.4), which has remained stable. Both the proband and younger brother exhibit evidence of early dilated cardiomyopathy, with end-systolic dimensions of 28.8 mm (Z-score +2.0) and 38.3 mm (Z-score +2.5), respectively.

There is no personal or family history suggestive of syndromic aortopathies.

Review of literature did not identify an association between aortic root dilatation and DMD. A 29-gene aortopathy panel was ordered and returned negative. Hence exome sequencing via the Texome Project was pursued.

Results:

Exome sequencing identified a heterozygous, likely pathogenic variant in DSC2, c.2200C>T, p.Q734, in the proband, brother, and mother. DSC2 is associated with autosomal dominant/recessive arrhythmogenic ventricular dysplasia (AVD/C). AVD/C typically presents in adulthood and affects desmosomal proteins in both ventricles.

Conclusions:

Additional research is needed to ascertain the origin of the dilated aortic root. The finding of the DSC2 variant may further worsen the function of both ventricles; although further research is needed to better understand the interplay of DMD and DSC2 variants regarding cardiac phenotype