Duchenne/Becker Muscular Dystrophy: advances in reproductive testing options

Duchenne/Becker Muscular Dystrophy (DMD/BMD) is an X-linked recessive disorder associated with progressive limb muscle weakness, atrophy, and cardiac disease in affected males. Approximately two-thirds of diagnosed cases have a carrier mother. Due to the size of the DMD gene, population-based genetic carrier screening for DMD/BMD was previously cost-prohibitive. However, recent advances in genetic testing now make carrier screening for DMD/BMD feasible. Retrospective review. Performed chart review of all samples tested for DMD/BMD via genetic carrier screening on next generation sequencing, qPCR, and multiplex ligation-dependent probe amplification, at a single reference laboratory. Identified carriers of a DMD mutation had additional chart review to determine if they chose to pursue preimplantation genetic diagnosis (PGD) for DMD/BMD at the same reference laboratory. PGD test development was performed using Illumina CytoSNP-12b microarrays with an informatics technique. PGD for embryo samples included or excluded direct mutation analysis based on mutation type. Of 30,232 patients screened for DMD/BMD, 55 (0.18%) were identified to be carriers of a pathogenic or likely pathogenic DMD variant. Of these patients, 3 elected to proceed with PGD test development for DMD/BMD. Maternal age range was 25-42 years. Patient 1 had a deletion of 7 exons in the DMD gene. Given the size of the deletion, direct mutation analysis could not reliably be performed on embryo biopsy samples. PGD test development using homolog phasing was not possible because clinical testing of the patient’s mother revealed the DMD variant was de novo in origin. Thus, PGD test development could not be completed. Patient 2 had a family history of an unspecified muscular dystrophy in her father. Genetic carrier screening identified a likely pathogenic point mutation in the DMD gene. PGD test development for the variant was successful, and the patient is planning her first IVF cycle. Patient 3 presented to an IVF clinic due to unexplained infertility and pursued genetic carrier screening prior to her IVF cycle. Family history of DMD/BMD was negative, but she was found to carry a point mutation in the DMD gene. PGD test development was successful, and the couple’s first IVF cycle produced 11 embryos, 6 of which were chromosomally normal and unaffected with the maternal DMD mutation. Previously, routine carrier testing for DMD/BMD was unavailable. As such, many at risk women had multiple children before learning of their carrier status for DMD, often following the diagnosis in a child. Due to recent advances in expanded carrier screening, women now have the option to screen for DMD/BMD prior to or during pregnancy, affording many opportunities for reproductive decision-making, including diagnostic testing in pregnancy, PGD, or alternative family planning methods.