Heterozygous variants in SPTBN1 cause intellectual disability and autism

Spectrins are common components of cytoskeletons, binding to cytoskeletal elements and the plasma membrane, allowing proper localization of essential membrane proteins, signal transduction, and cellular scaffolding. Spectrins are assembled from alpha and beta subunits, encoded by SPTA1 and SPTAN1 (alpha) and SPTB, SPTBN1, SPTBN2, SPTBN4, and SPTBN5 (beta). Pathogenic variants in various spectrin genes are associated with erythroid cell disorders (SPTA1, SPTB) and neurologic disorders (SPTAN1, SPTBN2, and SPTBN4), but no phenotypes have been definitively associated with variants in SPTBN1 or SPTBN5. Through exome sequencing and case matching, we identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities). Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset. Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis. Our findings support the essential roles of SPTBN1 in human neurodevelopment and expand the knowledge of human spectrinopathy disorders.Genetics of disease, diagnosis and treatmen

Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability [ID] syndrome) (MIM# 300966) caused by pathogenic variants involving the X‐linked gene TATA‐box binding protein associated factor 1 (TAF1), which participates in RNA polymerase II transcription. The initial study reported 11 families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into ID and/or autism spectrum disorder. We have now identified an additional 27 families through a genotype‐first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modeling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of the TAF1/MRXS33 ID syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for a gene mapping to chromosome X

Data and models for exploring sustainability of human well-being in global environmental change

This position paper proposes a vision for the research activity about sustainability in global environmental change (GEC) taking place in the FuturICT flagship project. This activity will be organised in an "Exploratory", gathering a core network of European scientists from ICT, social simulation, complex systems, economics, demographics, Earth system science. These research teams will collaborate in building a self-organising network of data sources and models about GEC and in using new facilities fostering stakeholder participation. We develop examples of concrete directions for this research: world wide virtual population with demographic and some economic descriptors, ecosystem services production and distribution, governance systems at various scales

MUC1 Story: Great Expectations, Disappointments and the Renaissance

International audienc