A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Estimating jaguar ( Panthera onca ) density in a preserved coastal area of French Guiana

Abstract Knowledge of the jaguar population is needed in French Guiana that faces an increase of human-jaguar conflicts. We carried out a camera trap survey to assess jaguar local density and home range size in a preserved coastal area of French Guiana. We ran spatially explicit capture recapture (SECR) models. In our model, the scale parameter σ , that is linked to the home range size, was larger for males ( σ =3.87±0.59 SE km) than for females ( σ =2.33±0.30 SE km). The assessed jaguar density was 3.22±0.87 SE ind. 100 km −2 , which should be considered as an optimal density in a French Guiana coastal area

Are ontogenetic shifts in foliar structure and resource acquisition spatially conditioned in tank-bromeliads?

The phenotypic plasticity of plants has been explored as a function of either ontogeny (apparent plasticity) or environment (adaptive plasticity), although few studies have analyzed these factors together. In the present study, we take advantage of the dispersal of Aechmea mertensii bromeliads by Camponotus femoratus or Pachycondyla goeldii ants in shaded and sunny environments, respectively, to quantify ontogenetic changes in morphological, foliar, and functional traits, and to analyze ontogenetic and ant species effects on 14 traits. Most of the morphological (plant height, number of leaves), foliar (leaf thickness, leaf mass area, total water content, trichome density), and functional (leaf δ13C) traits differed as a function of ontogeny. Conversely, only leaf δ15N showed an adaptive phenotypic plasticity. On the other hand, plant width, tank width, longest leaf length, stomatal density, and leaf C concentration showed an adaptation to local environment with ontogeny. The exception was leaf N concentration, which showed no trend at all. Aechmea mertensii did not show an abrupt morphological modification such as in heteroblastic bromeliads, although it was characterized by strong, size-related functional modifications for CO2 acquisition. The adaptive phenotypic variation found between the two ant species indicates the spatially conditioned plasticity of A. mertensii in the context of insect-assisted dispersal. However, ant-mediated effects on phenotypic plasticity in A. mertensii are not obvious because ant species and light environment are confounding variables

Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias

Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes-CACNA1A , ITPR1 , SPTBN2 , and KCNC3-were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1- associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A , ITPR1 , and SPTBN2 , the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist