Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range

Abstract

In some Huntington disease (HD) patients, the "loss of interruption" (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among manifest HD patients. Additionally, we combined published data with clinical data from newly identified patients to accurately characterize the LOI's effect on AOO. Methods: We developed a LOI detection polymerase chain reaction (PCR) assay, and screened patients to estimate the frequency of the LOI variant and its effect on AOO. Results: Mean onset for LOI carriers (n = 49) is 20.4 years earlier than expected based on diagnosed CAG size. After correcting for CAG size underestimation, the variant is still associated with onset 9.5 years earlier. The LOI is present in 1.02% of symptomatic HD patients, and in 32.2% of symptomatic reduced penetrance (RP) range patients (36-39 CAGs). Conclusion: The LOI causes significantly earlier onset, greater than expected by CAG length, particularly in persons with 36-39 CAG repeats. Detection of this variant has implications for HD families, especially for those in the RP range.

Newborn screening of duchenne muscular dystrophy specifically targeting deletions amenable to exon-skipping therapy

“…Experience shows that qPCR assays dedicated to the NBS of spinal muscular atrophy (i.e. a technically similar assay) have very high sensitivities and specificities 30 – 32 . We suggest that there is a reasonable expectation that the DMD assay we describe could perform similarly in larger cohorts.…”

“…It is also not economically burdensome (less than 5 euros per sample), considering that the DNA is already extracted for NBS of other molecular genetic diseases. These other targets include spinal muscular atrophy 33 , 34 another devastating genetic condition without circulating diagnostic biomarkers for which innovative medications have dramatically changed the prognosis when administered early, and that has prompted several NBS programs 30 – 32 . In the future, societal and medical cost-effectiveness evaluations could be carried out on large population to compare the “qPCR/MLPA” protocol we describe with the two-tier “CKMM DMD genotyping” strategy proposed by Mendell et al 24 .…”

DNA Mismatch Repair and its Role in Huntington’s Disease

“…Moreover, HD gene expanded carriers (HDGEC) display high levels of CAG repeat expansion, not only in the germline, but also in somatic cells wherein such expansions occur in a tissue-specific manner: the greatest degree of expansion is observed in the terminally differentiated neurons of the striatum and cortex [131,[150][151][152] [153]. Recent studies have established that the inherited length of uninterrupted CAG repeats rather than the length of the encoded polyQ tract, (since both CAA and CAG can encode glutamine) modifies disease onset [103,[154][155][156]. Because uninterrupted repeats are thought to have a higher propensity to expand than repeat tracts harboring CAA interruptions, it has been suggested that somatic CAG instability is a key driver of CAG length dependent HD pathogenesis [103,154,155].…”

Genetic epidemiological characteristics of a Hungarian subpopulation of patients with Huntington’s disease

“…In conclusion, the genetic and clinical features of the populations examined in the present study were in accordance with the previous Hungarian study as well as with international literature data, except for the higher frequency of intermediate alleles and individuals with reduced penetrance alleles. The presence of these alleles is gaining importance in light of increasing evidence of disease modifying genetic factors, such as the loss of interruption variants, which have been extensively investigated in the past 2 years [ 31 , 32 ], owing to developments in analytic technologies. They are considered to cause CAG repeat length underestimation with the currently, most widely, used diagnostic methods.…”

“…They are considered to cause CAG repeat length underestimation with the currently, most widely, used diagnostic methods. Additionally, some authors suggest that these variants not only influence the age of onset, but, in individuals carrying reduced penetrance alleles, they might play a major role in the manifestation of the disease [ 31 , 32 ]. These factors have not yet been thoroughly analysed in individuals carrying intermediate alleles and presenting neurological symptoms, which could serve as a target for future studies.…”