This epidemiological study is the first to investigate the incidence of DMD in an Australian state or territory since the early 21st century. Our results are in addition to data from only three international studies that have evaluated the changing incidence of this disease over the past two decades. [26].
Despite annual fluctuations, the incidence of DMD disease in NSW / ACT was comparable to the overall incidence of disease of 18.6 per 100,000 live births, (equivalent to a risk of new cases of DMD of 1 in every 5,377 men born alive), during the period 1960. –1971 [22]. This contrasted with subsequent studies spanning the 25-year period from 1975 to 2001 that observed significant falls in the incidence of the disease in NSW / ACT up to 1 in 6022 live male births, attributed to the advent of genetic technologies and active cascade screening and counseling. [16].
Our results align with the current global prevalence of DMD of 15.1 to 19.5 per 100,000 live male births observed in the most recent studies in Europe and the US. [19, 26] a drop from a maximum global incidence of 22.6 cases per 100,000 men born alive between 1950 and 1980 [32]. Thus, despite fluctuations in the incidence of DMD over the decades [16]the overall incidence of DMD remained essentially unchanged not only during the study period, but in comparison over the past forty years, with an epidemiological plateau replicated in international jurisdictions. [33, 34]. Subsequently, our results, both from a national and international perspective, indicate that despite the evolution of new genetic technologies along with dedicated neurogenetic services that facilitate targeted cascade screening, the impact on the incidence of DMD disease d ‘this approach has reached saturation over the last two decades. [31].
The role of targeted variant analysis and cascade screening aims to restore the reproductive confidence of non-carriers and identify “at-risk” carriers, to report on their reproductive options (prenatal testing, DGP, donation of eggs / embryos) and effectively manage the high risk of disease. to reduce long-term morbidity and mortality [35].
In contrast, the results of our study indicate that there is no significant change in the incidence of theoretically preventable cases over time, mainly due to a combination of factors that are beyond the capacity of the current clinical framework, despite the best efforts. These include delays in diagnosing older siblings that prevented reproductive options from being made possible for later generations, an unknown family history prior to proband diagnosis, and the parents ’option to reject prenatal / prenatal testing. However, it is important to note that two children in our cohort were born due to poor communication and / or misunderstanding of maternal carrier risk, secondary to difficulties in determining and / or communicating carrier risk based only on CK despite a strong family history of neuromuscular disease (before arrival). of molecular technologies to determine causative variants), leading to the loss of timely genetic counseling opportunities in this subgroup.
The incidence of “theoretically preventable” cases during the current study period was similar to the incidence of 2.4 “theoretically preventable” cases per 100,000 live male births observed between 1960 and 1971 in NSW / ACT [22]. In correlation with the stable incidence of the disease and the number of “theoretically preventable” cases, the proportion of isolated cases remained comparable from 2005, underlining the suggestion that current strategies aimed at changing the epidemiology of DMD to NSW / ACT had no impact on a population. level.
The etiology of the stable incidence of the disease in DMD seems multifactorial. Family cases, for the most part, occur in the absence of any family history of DMD, and cascading screening and reproductive strategies are only activated when an index case is clinically recognized. Despite the evolution of technologies, the complexity of the varying spectrum within the dystrophin gene may make a minority of cases undetectable to cascade screening and impervious to the optimization of reproductive choice. [13].
The high mutation rate of the dystrophin gene leads to a large number of sporadic cases that contribute to the invariable incidence of the disease. [36]. It is also theorized that gonadal mosaicism, where pathogenic variants arise early in spermatogenesis or oogenesis, contributes to 10–15% of “sporadic” cases.[37] make a risk assessment for a genetic counseling complex for families of seemingly “new” cases. [38].
Subsequently, despite centralized and long-established integrated laboratory services and neurogenetic care models aimed at the systematic identification of genetic carriers, almost 20% of first-degree relatives (mostly female siblings of men affected) did not access carrier screening despite high counseling rates. For second-degree relatives, access to appropriate counseling appeared to be a rate-limiting step, with just over a third of documented potential carriers receiving risky genetic counseling. The declining family involvement in cascading screening across the pedigree, replicates previous European studies that have suggested barriers to the effective implementation of cascading screening, including psychosocial, logistical, and information factors, i.e. family notification and factors related to health literacy. [18, 20].
While current cascade screening models facilitate reproductive choice in individual circumstances, new models that change the paradigm toward improving the timing and quality of genetic information are now essential to facilitate reproductive choice based on best evidence for all families and break the plateau in the incidence of diseases highlighted in this study. Although neonatal screening (NBS) for DMD is emerging as a model to accelerate timely diagnosis and facilitate early access to new genomic therapeutic pathways for probands internationally,[39] its role as a strategy to influence the incidence of the disease is in theory limited to reducing cases of “generational DMD” which account for 12% of all children born with DMD. [32]. In our cohort, 4 families with symptomatic siblings <6 years and may have benefited from NBS for DMD to facilitate early diagnosis and offer reproductive options, prior to proband birth. [24].
Prenatal testing for DMD is only offered to women who have a known high risk of developing DMD and therefore a significant proportion of women, represented by 92/107 (86%) in our cohort, who give light to an affected child, would have no recourse to this preventive strategy due to the absence of a family history of illness [40]. Most couples known to be at risk for an affected man historically access prenatal testing to prevent the birth of an affected second child. [40].
Alternatively, screening for reproductive carriers informs future parents of their risk of transmitting a genetic disorder such as DMD, facilitating individualized counseling and reproductive planning, to improve reproductive autonomy and informed decision-making. [41, 42]. This especially improves reproductive opportunities for most (family) cases, and these options become especially relevant as health policy extends to publicly funded preimplantation genetic diagnosis (PGD) for single-gene disorders. as the DMD in Australia from November 2021. [43, 44]. Although extended carrier testing for DMD is the next frontier to improve reproductive choice, barriers to implementation, including technological limitations, make dystrophin sequencing not universally or routinely incorporated into dystrophin sequestration. commercial multiplex reproductive screening panels, currently. [45, 46].
If extrapolated to our study, screening of reproductive carriers may have facilitated the reported reproductive options for nearly 60% of our cohort couples. The possible clinical utility and validity of reproductive carrier screening for DMD (within an expanded carrier screening panel of 22 monogenic hereditary diseases) has been recognized in a study of 766 couples with no family history of genetic conditions. Here, DMD occurred with an incidence of 0.1% in couples at risk and was therefore the sixth most common disease found in this cohort. [47]. Determination of the reproductive risk of the disease, guided access to the DGP for DMD to facilitate the management of reproductive risk in this subgroup [47]. Accordingly, an Australian reproductive genetic carrier screening pilot project is underway, which includes a panel of 1300 genes and includes the analysis of dystrophin variants to assess reproductive risk in 10,000 pairs. [30]. A multi-layered approach that includes screening for reproductive carriers, prenatal / preimplantation genetic testing, and newborn screening for DMD, along with improving the clinical detection of symptomatic cases, can be considered the most holistic model of care. and effective in reducing the impact and changing the epidemiology of the disease. this neurodegenerative and life-limiting condition [40].
Limitations of the study include the retrospective nature of the study design, which precludes full analysis of genetic carrier counseling and screening throughout the pedigree. The potential for underdetermination of carrier screening adoption may be related to genetic testing outside the jurisdiction of our neurogenetic center and not accurately documented in the proband record. The epidemiological definition of “theoretically preventable” cases used in this study has inherent limitations, including its inability to account for the nuances of individual reproductive options offered to families. This is especially relevant in our cohort where a proportion of older siblings were diagnosed with DMD in close temporal relationship with a pregnancy with an affected second child.
This study covered an era prior to next-generation sequencing and at least one theoretically preventable case was determinant for not finding a causal variant in the proband and for determining carrier risk based on …