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Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA) >300 and a further nine individuals with (GAA) >250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA) >300 and only 2/311 control individuals (0.6%) had a pure (GAA) >250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA) >335 and a further six had (GAA) >250 , whereas 10/190 (5.3%) control subjects had (GAA) >250 but none were (GAA) >335. The combined data suggest (GAA) >335 are disease causing and fully penetrant (p = 6.0 × 10−8, OR = 72 [95% CI = 4.3–1,227]), while (GAA) >250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2 = 0.44, p = 0.00045, slope = −0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia. [Display omitted] Pathogenic repeat expansions (RE) cause an array of neurogenetic disorders including cerebellar ataxia. While traditionally difficult to identify, new genomic tools and bioinformatic analyses are enabling rapid RE discovery and diagnosis. Here we characterize SCA50, an adult-onset ataxia caused by a pathogenic GAA repeat expansion within intron one of FGF14. [ABSTRACT FROM AUTHOR]

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG) exp ] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) 11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1 -negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders. [ABSTRACT FROM AUTHOR]

Antarctic krill (Euphausia superba) is Earth's most abundant wild animal, and its enormous biomass is vital to the Southern Ocean ecosystem. Here, we report a 48.01-Gb chromosome-level Antarctic krill genome, whose large genome size appears to have resulted from inter-genic transposable element expansions. Our assembly reveals the molecular architecture of the Antarctic krill circadian clock and uncovers expanded gene families associated with molting and energy metabolism, providing insights into adaptations to the cold and highly seasonal Antarctic environment. Population-level genome re-sequencing from four geographical sites around the Antarctic continent reveals no clear population structure but highlights natural selection associated with environmental variables. An apparent drastic reduction in krill population size 10 mya and a subsequent rebound 100 thousand years ago coincides with climate change events. Our findings uncover the genomic basis of Antarctic krill adaptations to the Southern Ocean and provide valuable resources for future Antarctic research. [Display omitted] • Assembly of the 48.01 Gb chromosome-level Antarctic krill genome • Extensive repeat expansions contributed to the giant Antarctic krill genome • Genetic adaptations to extreme variability of the Antarctic environment • Population analysis reveals no clear geographic differentiation in Antarctic krill The giant and highly repetitive Antarctic krill genome reveals environmental adaptations and population dynamics of Earth's most abundant wild animal. [ABSTRACT FROM AUTHOR]

Summary A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy. [ABSTRACT FROM AUTHOR]

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40–64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. For a Figure360 author presentation of this figure, see https://doi.org/10.1016/j.neuron.2020.11.005. • Pathogenic expansions in the HTT gene are a rare cause of FTD/ALS spectrum diseases • Autopsies showed both the expected TDP-43 pathology of FTD/ALS and polyQ inclusions • HTT repeat expansions were not seen in healthy subjects or Lewy body dementia cases • Clinicians should screen FTD/ALS patients for HTT repeat expansions Using large-scale whole-genome sequencing, Dewan et al. identify pathogenic HTT repeat expansions in patients diagnosed with FTD/ALS neurodegenerative disorders. Autopsies confirm the TDP-43 pathology expected in FTD/ALS and show polyglutamine inclusions within the frontal cortices but no striatal degeneration. These data broaden the phenotype resulting from HTT repeat expansions. [ABSTRACT FROM AUTHOR]