Fetal de novo heterozygous variant in the isocitrate dehydrogenase 1 gene associated with growth restriction, skeletal, cerebral and vascular anomalies.

Germline pathogenic variants in isocitrate dehydrogenase 1 (IDH1) can lead to a rare neurodevelopmental disorder called metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, including severe skeletal and cerebral anomalies. To the best of our knowledge, no prenatal case of an IDH1 pathogenic variant has been reported in literature. Somatic sequence variants in IDH1/2 genes are described in distinct cancers, premalignant diseases and rare inherited metabolic disorders. Amniocentesis and further genetic testing including trio exome sequencing were performed due to suspicious findings on a second trimester routine prenatal ultrasound examination. The fetus was found to have growth restriction, cerebral abnormalities (ex vacuo hydrocephalus, cerebellar and vermian hypoplasia, corpus callosum dysgenesis), brachycephaly, narrow chest, persistent left superior vena cava, liver calcifications, hyperechogenic bowel, short tubular bones and joint contractures. A de novo heterozygous variant in the IDH1 gene was detected via trio exome sequencing. The prenatal diagnosis of a de novo pathogenic variant in IDH1 in a fetus with the described phenotype, obtained through trio exome sequencing, helped parents and providers with an informed decision making about pregnancy management.

Novel adapter CAR-T cell technology for precisely controllable multiplex cancer targeting.

Chimeric antigen receptor (CAR)-T therapy holds great promise to sustainably improve cancer treatment. However, currently, a broad applicability of CAR-T cell therapies is hampered by limited CAR-T cell versatility and tractability and the lack of exclusive target antigens to discriminate cancerous from healthy tissues. To achieve temporal and qualitative control on CAR-T function, we engineered the Adapter CAR (AdCAR) system. AdCAR-T are redirected to surface antigens via biotin-labeled adapter molecules in the context of a specific linker structure, referred to as Linker-Label-Epitope. AdCAR-T execute highly specific and controllable effector function against a multiplicity of target antigens. In mice, AdCAR-T durably eliminate aggressive lymphoma. Importantly, AdCAR-T might prevent antigen evasion by combinatorial simultaneous or sequential targeting of multiple antigens and are capable to identify and differentially lyse cancer cells by integration of adapter molecule-mediated signals based on multiplex antigen expression profiles. In consequence the AdCAR technology enables controllable, flexible, combinatorial, and selective targeting.