#apaperaday: De Novo p.Asp3368Gly Variant of Dystrophin Gene Associated with X-Linked Dilated Cardiomyopathy and Skeletal Myopathy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: De Novo p.Asp3368Gly Variant of dystrophin Gene Associated with X-Linked Dilated Cardiomyopathy and Skeletal Myopathy: Clinical Features and In Silico Analysis

Today’s pick is about a missense variant in the dystrophin gene that might be associated with dilated cardiomyopathy and skeletal myopathy from d’Apolito et al in @IJMS_MDPI DOI: 10.3390/ijms25052787

Dilated cardiomyopathy leads to heart failure. This is a common disease and ~40% of cases have a genetic cause. Familial cardiomyopathy means 2 first degree individuals have cardiomyopathy at a young age – then there is definitely a genetic cause.

Many causative genes have been found, with titin being the most common culprit. Here authors focus on the DMD encoding dystrophin gene. Pathogenic variants can cause Duchenne and Becker, which also both involve cardiomyopathy, but also cardiomyopathy in isolation in men and women

Authors here present a case of a 33 year old woman presenting with severe cardiomyopathy: ejection fractions of 27% and 34% for left and right ventricles (55% or higher is normal), in the absence of coronary abnormalities (so heart pathology not blood vessel pathology)

The woman has an ICD now & medication in the ejection fractions have improved now fortunately. As this severe heart failure at a young age suggests a genetic cause, authors looked for one with whole exome sequencing. They did not find any pathogenic or likely pathogenic variants

However, they did find a variant of unknown significance in the dystrohpin gene, i.e. a aspartane to glycine missense variant in exon 70. This variant had never been reported in healthy individuals or in patients with heart failure.

Authors performed segregation analysis: the variant was not present in either parent, so it was de novo. The variant was present however in the 8 year old son of the woman. This boy did not have cardiomyopathy but he did have elevated CK (3500-19000, normal is 200).

This is indicative of a myopathy. The boy had hypertrophy and sleep apnea and constipation, but did not have clinical muscle symptoms. This mouse doctor thinks the patient might develop clinical symptoms as these look like Becker muscular dystrophy symptoms.

Authors used prediction tools to study the impact of the missense variant on protein folding, which suggested the variant was deleterious. They conclude that it might be of clinical importance, but they do not have enough data for confirm it is causative.

What authors neglected to do was to study how this variant would impact on dystroglycan binding as the exon 63-70 encoded dystrophin domain binds to dystroglycan. Missense variants in this domain have been found before in Duchenne patients.

Another thing they neglected was to analyze whether the variant had an impact on splicing. It might not be (only) a missense variant – if part of the exon is suddenly spliced out due to the generation of a new splice site, this will have another impact.

Authors do discuss that dystrophin variants in females can cause cardiomyopathy. This is important to remember for known carriers but also when individuals present with cardiomyopathy. Too often people discard this possibility in females (same for muscle pathology).

I appreciate the authors reporting this case, but ideally they had consulted some dystrophinopathy experts to discuss possible causes, e.g. Dongshengh Duan. Then they would have done a more complete analysis for (predicted) protein binding or missplicing.

Based on the presented finding I believe the variant is likely causative for both the boy’s myopathy and the mother’s cardiomyopathy but the extra work (computer predictions, not extra experiments) would have made the paper stronger.