Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension.

BACKGROUND: Mapping the genetic component of molecular mechanisms responsible for the reduced penetrance (RP) of rare disorders constitutes one of the most challenging problems in human genetics. Heritable pulmonary arterial hypertension (PAH) is one such disorder characterised by rare mutations mostly occurring in the bone morphogenetic protein receptor type 2 (BMPR2) gene and a wide heterogeneity of penetrance modifier mechanisms. Here, we analyse 32 genotyped individuals from a large Iberian family of 65 members, including 22 carriers of the pathogenic BMPR2 mutation c.1472G>A (p.Arg491Gln), 8 of them diagnosed with PAH by right-heart catheterisation, leading to an RP rate of 36.4%. METHODS: We performed a linkage analysis on the genotyping data to search for genetic modifiers of penetrance. Using functional genomics data, we characterised the candidate region identified by linkage analysis. We also predicted the haplotype segregation within the family. RESULTS: We identified a candidate chromosome region in 2q24.3, 38 Mb upstream from BMPR2, with significant linkage (LOD=4.09) under a PAH susceptibility model. This region contains common variants associated with vascular aetiology and shows functional evidence that the putative genetic modifier is located in the upstream distal promoter of the fidgetin (FIGN) gene. CONCLUSION: Our results suggest that the genetic modifier acts through FIGN transcriptional regulation, whose expression variability would contribute to modulating heritable PAH. This finding may help to advance our understanding of RP in PAH across families sharing the p.Arg491Gln pathogenic mutation in BMPR2.

GenomicScores: seamless access to genomewide position-specific scores from R and Bioconductor.

Summary: Genomewide position-specific scores, such as those estimating conservation, constraint, fitness or mutation tolerance, are ubiquitous in current genome analyses. The diversity of sources and formats of these scores, as well as their size, increase the burden to use them. We present GenomicScores, a Bioconductor package that provides efficient storage and seamless access of genomewide position-specific scores from R, facilitating their use in genome analysis workflows. Availability and implementation: GenomicScores is implemented in R and available at https://bioconductor.org/packages/GenomicScores under the open source 'Artistic-2.0' license. Supplementary information: Supplementary data are available at Bioinformatics online.

Somatic mutations alter the differentiation outcomes of iPSC-derived neurons.

The use of induced pluripotent stem cells (iPSC) as models for development and human disease has enabled the study of otherwise inaccessible tissues. A remaining challenge in developing reliable models is our limited understanding of the factors driving irregular differentiation of iPSCs, particularly the impact of acquired somatic mutations. We leveraged data from a pooled dopaminergic neuron differentiation experiment of 238 iPSC lines profiled with single-cell RNA and whole-exome sequencing to study how somatic mutations affect differentiation outcomes. We found that deleterious somatic mutations in key developmental genes, notably the BCOR gene, are strongly associated with failure in dopaminergic neuron differentiation and a larger proliferation rate in culture. We further identified broad differences in cell type composition between incorrectly and successfully differentiating lines, as well as significant changes in gene expression contributing to the inhibition of neurogenesis. Our work calls for caution in interpreting differentiation-related phenotypes in disease-modeling experiments.