Increased Frequency of Repeat Expansion Mutations Across Different Populations
MDF's Chief Scientific Officer, Dr. Andy Rohrwasser, summarizes a study “Increased frequency of repeat expansion mutations across different populations” published in Nature Medicine in October 2024, an important genetic study examining the presence of repeat expansions including myotonic dystrophy (DM) in over 82,000 individuals.
While this detailed summary below is for the scientific audience, the observations have worldwide implications for the care and patient communities. For our myotonic dystrophy community, the study confirms the high prevalence of DM1. The study also highlights the importance of vigilance for healthcare providers suspecting the disease as the repeat expansion might be present with low repeat numbers without any (yet) apparent symptoms. This is of importance for individual clinical monitoring and for family planning and related genetic counseling.
A Summary of “Increased Frequency of Repeat Expansion Mutations Across Different Populations.” for the Professional DM Community.
A seminal, very large population study examining the frequency of repeat expansions, showed that while such expansions are the most common cause of inherited neurological repeat expansion disorders (RED), they may be up to three times more frequent than currently estimated.
Higher frequencies have important implications for diagnostic guidelines as well as for the affected individuals. In the clinic, they suggest and recommend a higher index of suspicion of disease presence while for the patients they recommend addressing the potentially incomplete penetrance.
For myotonic dystrophy type 1 (DM1), the study observed a “carrier” frequency of 1:1,786 and estimated that 15.9 per 100,000 (or approximately 1 in 6,300) people would be actually affected by the condition. The DM1 estimates match those previously reported in prevalence studies using PCR-based approaches. The study also reported that pathogenic DMPK alleles are most common in European populations and essentially absent in the East Asian population. This difference between observed carrier frequency and estimated prevalence, seen in several REDs, can be attributed to the fact that very small repeat expansions are frequently asymptomatic. The authors hypothesize that their observed higher disease allele frequencies relative prior disease estimates can be based on their large, admixed study cohorts. Epidemiological studies are often based on small cohorts of clinically affected individuals that are typically much smaller in size. Based on the large variable clinical presentation and age at onset of REDs, individuals may remain undiagnosed in studies in which estimates of disease frequency rely on clinical ascertainment of patients. As such, the prevalence of these diseases might have been broadly underestimated. This might be true particularly for milder forms of the disease spectrum, including DM1.
In the context of rapidly emerging DNA sequencing technologies, the study discusses general limitation of today’s predominantly used short read sequencing technologies and their innate inability to accurately size repeats larger than their intrinsic read length of around 150 bps. For large repeat expansions, short read technologies are unable to distinguish between premutation and full mutations. Premutations are defined as minimally expanded alleles that are not normal but are not yet associated with clinical symptoms. Likewise, a lengths threshold is defined when the repeat length becomes larger and associated with clinical manifestations. Despite the intrinsic technological limitations of short-read sequencing. the technology can be used to determine the distribution of repeat lengths within each population, with the largest percentiles (99.9th percentiles) reflecting the variable presence of expanded alleles. For DM1, the 99.9th percentile of repeat sizes of DMPK is 39 in Europeans and 30 in Africans.
A key observation and study conclusion is that an appreciable proportion of the population carry alleles in the premutation range and are, therefore, at risk of having children with REDs. The finding that a much larger number of people in the general population carry pathogenic alleles of REDs has important implications both for diagnosis and genetic counseling. For diagnosis, when a patient presents with symptoms compatible with a RED, clinicians should have a higher index of suspicion; likewise clinical diagnostic infrastructure should facilitate genetic testing for REDs. From a diagnostic perspective, as REDs are clinically and genetically heterogeneous with a tendency of overlapping features, REDs may remain under- or undiagnosed. The wider adoption of short-read and long-read whole genome sequencing technologies can potentially address this by simultaneously covering an entire panel of RED loci. For genetic counseling, when a RED expansion is identified incidentally in an individual clinically not yet affected, it would be important to address the potentially incomplete penetrance of the repeat, especially for small expansions.
Reference:
Increased Frequency of Repeat Expansion Mutations Across Different Populations
Ibañez K, Jadhav B, Zanovello M, Gagliardi D, Clarkson C, Facchini S, Garg P, Martin-Trujillo A, Gies SJ, Deforie VG, Dalmia A, Hensman Moss DJ, Vandrovcova J, Rocca C, Moutsianas L, Marini-Bettolo C, Walker H, Turner C, Shoai M, Long JD; EUROSCA network; Fratta P, Langbehn DR, Tabrizi SJ, Caulfield MJ, Cortese A, Escott-Price V, Hardy J, Houlden H, Sharp AJ, Tucci A. Increased frequency of repeat expansion mutations across different populations. medRxiv [Preprint]. 2024 Jul 8:2023.07.03.23292162. doi: 10.1101/2023.07.03.23292162. PMID: 37461547; PMCID: PMC10350132.