Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson’s coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I–V β = −1.06, P < 0.001; lobules VI–VII β = −0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion

Communication complexity of approximate matching in distributed graphs

In this paper we consider the communication complexity of approximation algorithms for maximum matching in a graph in the message-passing model of distributed computation. The input graph consists of n vertices and edges partitioned over a set of k sites. The output is an alpha-approximate maximum matching in the input graph which has to be reported by one of the sites. We show a lower bound on the communication complexity of Omega(alpha^2 k n) and show that it is tight up to poly-logarithmic factors. This lower bound also applies to other combinatorial problems on graphs in the message-passing computation model, including max-flow and graph sparsification

Atrial size and function in athletes

We wanted to explore if change in LA size would influence LA function, or increase regurgitation in the atrioventricular valves. 595 male elite football players and 47 non-athletic controls were included. End-systolic LA volume and RA area and end-diastolic LV volume and RV area were measured by two-dimensional (2D) echo. Pulsed and colour Doppler were used to estimate tricuspid and mitral regurgitations. 2D longitudinal strain of the 50 football players with the largest LA volumes were compared with the 50 players with the smallest LA volumes. The LA volumes in some athletes were more than tripled, compared to athletes with small atria. 2D strain however, could not reveal any impairment of LA function in the players with the largest atria, compared to those with the smallest LA. Tricuspid valve regurgitation was found in 343 (58%) of the athletes, compared to 17 (36%) of the controls (p<0.01), while mitral regurgitation was found in 116 (20%) football players and seven (15%) controls (NS). Furthermore, the RA area was significantly larger in athletes with tricuspid regurgitation compared to athletes without. The present study demonstrated a huge variation in atrial size between the athletes. This variation, however, had no impact on LA function. Tricuspid regurgitation was significantly more prevalent among the athletes, than among the controls