<body><div><figure><img src="https://img.particlenews.com/image.php?type=thumbnail_580x000&amp;url=1quCVX_0w3ayZ5C00" alt="https://img.particlenews.com/image.php?url=1quCVX_0w3ayZ5C00" width="580" height="395" ><figcaption>A systematic analysis evaluates the incidence of germline mosaicism in Duchenne muscular dystrophy (DMD), as well as recurrence risks.</figcaption></figure><p>Duchenne muscular dystrophy (DMD) is a rare, X-linked musculoskeletal disorder caused by mutations in the <i>DMD</i> gene, which codes for the dystrophin protein. While this disease is often inherited from parents who are somatic carriers of a mutated <i>DMD</i> gene, de novo variants are responsible for approximately one-third of cases.</p><p>Evaluation of germline mutations is not the current standard of care in prenatal genetic counseling, even though the literature suggests that DMD is more prone to germline mosaicism than other genetic diseases. Thus, it is essential not only to assess the incidence of germline mosaicism in parents of children with DMD but also to improve our understanding of the recurrence risk in these families.</p><h2>Germline Mosaicism and Recurrence Risk</h2><p>A recent systematic analysis by Verebi and colleagues in the <i>Journal of Genetic Counseling</i> sought to determine the average incidence and recurrence risk associated with germline mosaicism among families affected by DMD and Becker muscular dystrophy (BMD).</p><p>According to the authors, “the recurrence risks for de novo causing variants are theoretically low in siblings, [but] existing knowledge indicates evidence of germline mosaicism in DMD and BMD.” Therefore, they carried out a review of 37 publications and conducted a retrospective cohort study of their own to establish these baseline values.</p><p>The authors’ review of 17 case studies and 20 original studies found that the overall mean incidence of germline mosaicism was 3.6%, while the mean incidence of germline mosaicism among families with de novo events was 8.3%. The authors also identified all types of pathogenic variants known to cause DMD and BMD in mothers with germline mosaicism, including duplications, deletions, and point mutations.</p><p>Verebi and colleagues calculated the mean risk of recurrence in mothers of patients with DMD or BMD due to de novo pathogenic variants to be 5.8% for male fetuses. For male fetuses with an at-risk haplotype, the mean recurrence risk was 11.5%.</p><p>“As a clinical practice and in the light of this review, we recommend that mothers who have a DMD or BMD child should be offered pre-natal diagnosis during their pregnancies, even in cases of de novo transmission to alleviate the risk of DMD germline mosaicism,” the authors emphasize.</p><p>This review highlights the pressing need for germline mosaicism screening, particularly among mothers of children with BMD or DMD for whom genetic testing does not reveal somatic mutations. Knowing whether they carry a mutation in their germline should be a critical aspect of prenatal genetic counseling.</p><h2>Genetic Testing Considerations</h2><p>In a study published in <i>Prenatal Diagnosis</i>, Zemet and colleagues discuss the barriers to genetic counseling when it comes to parental mosaicism.</p><p>For the purposes of genetic testing and counseling, DNA from peripheral blood leukocytes is often utilized. However, this method will not reveal the presence of mutations in some tissues, such as the germline. While some models exist to calculate recurrence risk for patients with de novo variants, these tools are only used for research and not in practice at this time.</p><p>The authors propose that “clinical implementation of recently developed bioinformatics pipelines with sensitive and precise genotyping techniques to more robustly screen for parental mosaicism, determine the parent-of-origin, and analyze multiple accessible tissues to detect low-level mosaicism should be studied in larger trials.”</p><p>Although researchers have developed several bioinformatics tools to efficiently detect pathogenic variants in individuals with somatic mosaicism, few focus on germline mosaicism.</p><h2>The Future of Genetic Counseling for Germline Mosaicism</h2><p>As it stands, a mother of a child with DMD who has negative carrier testing may be falsely informed that there is no risk of recurrence. However, these studies demonstrate that this isn’t the case for many families.</p><p>Researchers including Verebi et al. are working to “promote the development of effective strategies and reliable data for occurrence risk assessment in genetic counseling of de novo event families.” Until that becomes a reality, though, it is imperative to raise awareness about the occurrence of germline mosaicism in families affected by DMD or BMD.</p><p>More work must be done to develop tools that can be used in a clinical setting to detect germline mosaicism in diseases, including DMD. In doing so, genetic counselors can provide more precise and accurate information to families regarding prenatal diagnosis.</p><h2>References</h2><p>Verebi C, Gravrand V, Bienvenu T, Leturcq F, Nectoux J. A retrospective cohort study and review of the literature about germline mosaicism in Duchenne/Becker muscular dystrophy prenatal counseling: how to estimate the recurrence risk in clinical settings?. <i>J Genet Couns</i>. Published online June 19, 2024. doi:10.1002/jgc4.1932</p><p>Zemet R, Van den Veyver IB, Stankiewicz P. Parental mosaicism for apparent de novo genetic variants: Scope, detection, and counseling challenges. <i>Prenat Diagn</i>. Published online April 8, 2022. doi:10.1002/pd.6144</p></div></body>

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Trends in Germline Mosaicism Reported in DMD

Duchenne muscular dystrophy (DMD) is a rare, X-linked musculoskeletal disorder caused by mutations in the DMD gene, which codes for the dystrophin protein. While this disease is often inherited from parents who are somatic carriers of a mutated DMD gene, de novo variants are responsible for approximately one-third of cases.