My concerns about carrier screening for Duchenne muscular dystrophy (DMD) were first piqued during a presentation I attended at the Advances in Prenatal Molecular Diagnostics in November 2017. The presentation given by the chief diagnostic officer of genetic testing lab, Sema4, highlighted the lab’s experience with expanded carrier screening. Of 1,200 males in the series who underwent screening for both autosomal and X-linked conditions, Sema4 reported that five males in their 30’s-40’s were identified to have DMD variants interpreted as pathogenic for Duchenne. Upon follow-up, one reported a history of cardiomyopathy and four denied any symptoms or concerns related to DMD.
To learn that there were cases of adult males with pathogenic/likely pathogenic variants in the DMD gene, with most having no known symptoms in their 30’s-40’s, was surprising and confusing to me. This confusion primarily stems from what we have been taught and what continues to remain in current resources surrounding DMD – that penetrance for the condition is complete for males. It is possible that these individuals could have had subclinical Becker muscular dystrophy (BMD), and perhaps if evaluated they would have had cardiomyopathy or other symptoms that hadn’t yet surfaced to medical attention. But still, five males out of 1,400 screened is far higher than what we would expect with an estimated prevalence of ~1 in 5,000 male births with BMD or DMD per the CDC.
Sema4 also presented their finding of a very high carrier rate in females who were screened, with 1 in 522 females reported as carriers. This is far higher than anything that had been previously reported and also gave me pause as it would imply that about 1 in 1,000 males would inherit the DMD variant and the expectation to be affected, which is also much greater than what has actually been reported (and this doesn’t even account for de novo mutations).
What could explain this disparity between the high carrier frequency numbers, compared to the past reports of incidence and prevalence of these conditions? Perhaps it could be explained by variable expressivity and under recognition of individuals with subclinical BMD. Or perhaps, contrary to what we have thought, not all DMD variants are 100% penetrant in males? Maybe there is another genetic phenomenon that mitigates the pathogenic variants in some people? Could labs be over-calling DMD variants wherein many variants that are called pathogenic or likely pathogenic are actually benign?
An important study (Ding et al., 2025) published in Genetics in Medicine this month provides an explanation for some of the higher than expected carrier calls for DMD. The study highlighted that intragenic duplications in the DMD gene can be tandem or interspersed. Importantly, interspersed duplications often aren’t pathogenic. This brings forward an existing weakness in carrier screening, in that most clinical screening assays aren’t able to distinguish between tandem and interspersed duplications. Adding to this limitation are the current guidelines on variant interpretation that recommend to err on the side of assuming intragenic duplications are in tandem unless proven otherwise, a practice that has been named the “tandem presumption.” While this presumption may make sense when interpreting a duplication in a patient with clinical signs of the condition, what does it mean when we are making this tandem presumption with general population carrier screening, when patients have no symptoms or family history of the condition? According to the study, by applying the presumption broadly, many duplications will be incorrectly classified as pathogenic. The authors caution, “if the tandem presumption is inaccurate in these patients, it could lead to overestimation of variant pathogenicity—potentially resulting in unnecessary invasive procedures and/or pregnancy termination.”
Given that DMD has been included on expanded carrier screening panels for about a decade now, and we know that more “carriers” have been reported than makes sense when compared to the clinical prevalence of DMD-associated conditions, it seems highly likely that many people have made reproductive decisions based on DMD carrier results that may have been inaccurately assumed to definitively cause a dystrophinopathy. Five minutes searching Reddit for people’s experience with DMD carrier screening will give you a sense of how many people are agonizing about these results and what to do about prenatal diagnostic testing, whether to continue a pregnancy, or grappling with decisions around assisted reproductive technologies including IVF with preimplantation genetic testing.
Over the years, I have seen multiple patients with positive DMD carrier screening results, provided by more than one lab, and have noticed the following:
- Some deletions and duplications reported on carrier screens are absent from the medical literature of people who have DMD-associated conditions. There are also some deletions that are seen in individuals with DMD-associated conditions, but exist on a spectrum from asymptomatic to mild Becker or isolated cardiomyopathy.
- Lab reports typically don’t give any indication that these results are uncertain or incomplete; nor do they imply a possibility of variable expression or reduced penetrance. Lab reports typically provide a description of DMD and BMD with a very definitive prediction such as, “Each of this individual’s sons has a 50% chance of being affected and each of her daughters has a 50% chance of being a carrier.”
- My follow-up calls to the labs to speak with a genetic counselor have confirmed that their internal data to the lab shows a much higher carrier frequency than we would expect based on the incidence of DMD-associated conditions.
I find these conversations with patients about DMD carrier results challenging because it often feels like my questions about the results are at odds with the wording included on the official lab report.
When I have the benefit of talking to patients about carrier testing before they proceed with it, I always discuss the possibility of uncertain information, even though that feature of screening is not clearly promoted as inherent to the test. Unfortunately though, most often we only have the opportunity to meet with patients after the results have returned, and I imagine that many with positive DMD carrier results may never meet with a genetic counselor at all.
Ding and colleagues offer a recommended decision tree for patients who receive results with a DMD duplication in the absence of personal or family history of dystrophinopathy. In this they recommend additional testing (long-read sequencing) to determine the structural configuration if possible. And if this is not possible they recommend familial segregation analysis. I hope that this study will prompt labs providing carrier screening to strengthen their protocols by recommending or providing additional clinical studies to clarify if these duplications are interspersed or tandem. If labs cannot do this, we need to be realistic about the complexity and time required in coordinating follow-up studies for patients with these results.
What is our role and responsibility of genetic counselors when considering DMD carrier screening? I believe any genetic counselors and any prenatal care clinicians involved in ordering carrier testing for patients should have careful conversations with patients prior to testing about the possible uncertainty that may arise from carrier screening results for not only DMD but from other conditions included on these panels as well. And in follow-up of positive results there are other steps we can take to help clarify the possible meaning of carrier results – not just with DMD duplications, but with all positive results.
I encourage all genetic counselors to reach out to advocacy organizations and colleagues with strong expertise in this area. It is understandable that many prenatal counselors don’t have the knowledge or time to complete or interpret literature reviews on a particular variant. Consider reaching out to colleagues through our NSGC Discussion forums or other trusted resources that offer peer contact. For example, the genetic counselors who work for Parent Project Muscular Dystrophy (PPMD) welcome contact from peers who need support in variant review.
I was thankful to recently learn that the genetic counselors with PPMD are open to helping with variant review and follow-up studies for families. PPMD manages the Duchenne Registry which holds genotype and phenotype data on thousands of patients with DMD and BMD, including mild and asymptomatic phenotypes. PPMD also runs the Decode Duchenne sponsored testing program, which provides both diagnostic testing and carrier or asymptomatic familial variant testing. This program may be utilized for cascade testing of both male and female relatives following a positive carrier screen. PPMD’s Genetics team, consisting of individuals who are certified genetic counselors, can often provide valuable information from their direct experience with the dystrophinopathy community.
The average age at diagnosis for Duchenne is between 4-5 and is often preceded by years of emotional, physical, and financial strain as parents struggle to find answers for their child’s symptoms. Identifying DMD variants may provide an opportunity for family planning and early treatment that is usually missed. As we learn that some DMD results are less straightforward than originally thought, it’s important that carrier screening results are carefully interpreted so that families who elect carrier screening can receive the benefits of this screening without introducing unfounded worry, or irreversible and potentially costly decisions based on misunderstood results. For now, it is up to our community of genetic counselors to help patients navigate these testing options and results and it is prudent for us to take a cautious and careful approach that goes beyond reading what is printed on the lab report.
I gratefully acknowledge the Parent Project Muscular Dystrophy Registry Team for their thoughtful review of this work and the valuable feedback that strengthened this post. I especially thank Ann Martin MS CGC, Kayla Banks MS CGC, Lauren Bogue MS CGC, and Katherine Anderson ScM CGC who provided detailed review and who also express their openness to collaboration in interpreting and following up on carrier screening results for our broader genetic counseling community. Their clinical expertise combined with resources to allow for variant follow-up and testing in families will improve and inform our approach to DMD carrier screening and follow-up for all.
The DNA Exchange 