Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.

Cell adhesion molecules are membrane-bound proteins predominantly expressed in the central nervous system along principal axonal pathways with key roles in nervous system development, neural cell differentiation and migration, axonal growth and guidance, myelination, and synapse formation. Here, we describe ten affected individuals with bi-allelic variants in the neuronal cell adhesion molecule NRCAM that lead to a neurodevelopmental syndrome of varying severity; the individuals are from eight families. This syndrome is characterized by developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity. Computational analyses of NRCAM variants, many of which cluster in the third fibronectin type III (Fn-III) domain, strongly suggest a deleterious effect on NRCAM structure and function, including possible disruption of its interactions with other proteins. These findings are corroborated by previous in vitro studies of murine Nrcam-deficient cells, revealing abnormal neurite outgrowth, synaptogenesis, and formation of nodes of Ranvier on myelinated axons. Our studies on zebrafish nrcamaΔ mutants lacking the third Fn-III domain revealed that mutant larvae displayed significantly altered swimming behavior compared to wild-type larvae (p < 0.03). Moreover, nrcamaΔ mutants displayed a trend toward increased amounts of α-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections. Taken together, our study provides evidence that NRCAM disruption causes a variable form of a neurodevelopmental disorder and broadens the knowledge on the growing role of the cell adhesion molecule family in the nervous system.

De-identified data quality assessment approaches by data vendors who license data to healthcare and life sciences researchers.

Objective: To gain insights into how data vendor companies (DVs), an important source of de-identified/anonymized licensed patient-related data (D/ALD) used in clinical informatics research in life sciences and the pharmaceutical industry, characterize, conduct, and communicate data quality assessments to researcher purchasers of D/ALD. Materials and Methods: A qualitative study with interviews of DVs executives and decision-makers in data quality assessments (n = 12) and content analysis of interviews transcripts. Results: Data quality, from the perspective of DVs, is characterized by how it is defined, validated, and processed. DVs identify data quality as the main contributor to successful collaborations with life sciences/pharmaceutical research partners. Data quality feedback from clients provides the basis for DVs reviews and inspections of quality processes. DVs value customer interactions, view collaboration, shared common goals, mutual expertise, and communication related to data quality as success factors. Conclusion: Data quality evaluation practices are important. However, no uniform DVs industry standards for data quality assessment were identified. DVs describe their orientation to data quality evaluation as a direct result of not only the complex nature of data sources, but also of techniques, processes, and approaches used to construct data sets. Because real-world data (RWD), eg, patient data from electronic medical records, is used for real-world evidence (RWE) generation, the use of D/ALD will expand and require refinement. The focus on (and rigor in) data quality assessment (particularly in research necessary to make regulatory decisions) will require more structure, standards, and collaboration between DVs, life sciences/pharmaceutical, informaticists, and RWD/RWE policy-making stakeholders.

Role of ectonucleotide pyrophosphatase/phosphodiesterase 2 in the midline axis formation of zebrafish.

Lysophosphatidic acid (LPA) is a unique bioactive lysophospholipid that induces pleiotropic effects in various cell types and organisms by acting on its specific receptors. LPA is mainly synthetised extracellularly by the ectonucleotide pyrophosphatase/phosphodiesterase 2/autotaxin (enpp2). Altered LPA signalling is associated with embryonic abnormalities, suggesting critical roles for LPA during development. However, the role of LPA signalling during early embryogenesis is not well established. We demonstrate that enpp2/LPA signalling in the early zebrafish embryo results in altered axis and midline formation, defects in left right (L-R) patterning, ciliogenesis of the Kupffer's vesicle (KV), through the modulation of cell migration during gastrulation in a lpar1-3 Rho/ROCK-dependant manner. Overall, this study demonstrates an essential role of enpp2/LPA signalling during early embryogenesis.