Abstracts from the 50th European Society of Human Genetics Conference: Posters

International audienc

Digenic inheritance of human primary microcephaly delineates centrosomal and non-centrosomal pathways.

Primary microcephaly (PM) is characterized by a small head since birth and is vastly heterogeneous both genetically and phenotypically. While most cases are monogenic, genetic interactions between Aspm and Wdr62 have recently been described in a mouse model of PM. Here, we used two complementary, holistic in vivo approaches: high throughput DNA sequencing of multiple PM genes in human patients with PM, and genome-edited zebrafish modeling for the digenic inheritance of PM. Exomes of patients with PM showed a significant burden of variants in 75 PM genes, that persisted after removing monogenic causes of PM (e.g., biallelic pathogenic variants in CEP152). This observation was replicated in an independent cohort of patients with PM, where a PM gene panel showed in addition that the burden was carried by six centrosomal genes. Allelic frequencies were consistent with digenic inheritance. In zebrafish, non-centrosomal gene casc5 -/- produced a severe PM phenotype, that was not modified by centrosomal genes aspm or wdr62 invalidation. A digenic, quadriallelic PM phenotype was produced by aspm and wdr62. Our observations provide strong evidence for digenic inheritance of human PM, involving centrosomal genes. Absence of genetic interaction between casc5 and aspm or wdr62 further delineates centrosomal and non-centrosomal pathways in PM

Congenital microcephaly: Case definition & guidelines for data collection, analysis, and presentation of safety data after maternal immunisation.

Need for developing case definitions and guidelines for data collection, analysis, and presentation for congenital microcephaly as an adverse event following maternal immunisation Congenital microcephaly, also referred to as primary microcephaly due to its presence in utero or at birth, is a descriptive term for a structural defect in which a fetus or infant’s head (cranium) circumference is smaller than expected when compared to other fetuses or infants of the same gestational age, sex and ethnic background

Hierarchical Quatsome-RGD Nanoarchitectonic Surfaces for Enhanced Integrin-Mediated Cell Adhesion

The synthesis and study of the tripeptide Arg-Gly-Asp (RGD), the binding site of different extracellular matrix proteins, e.g., fibronectin and vitronectin, has allowed the production of a wide range of cell adhesive surfaces. Although the surface density and spacing of the RGD peptide at the nanoscale have already shown a significant influence on cell adhesion, the impact of its hierarchical nanostructure is still rather unexplored. Accordingly, a versatile colloidal system named quatsomes, based on fluid nanovesicles formed by the self-assembling of cholesterol and surfactant molecules, has been devised as a novel template to achieve hierarchical nanostructures of the RGD peptide. To this end, RGD was anchored on the vesicle's fluid membrane of quatsomes, and the RGD-functionalized nanovesicles were covalently anchored to planar gold surfaces, forming a state of quasi-suspension, through a long poly(ethylene glycol) (PEG) chain with a thiol termination. An underlying self-assembled monolayer (SAM) of a shorter PEG was introduced for vesicle stabilization and to avoid unspecific cell adhesion. In comparison with substrates featuring a homogeneous distribution of RGD peptides, the resulting hierarchical nanoarchitectonic dramatically enhanced cell adhesion, despite lower overall RGD molecules on the surface. The new versatile platform was thoroughly characterized using a multitechnique approach, proving its enhanced performance. These findings open new methods for the hierarchical immobilization of biomolecules on surfaces using quatsomes as a robust and novel tissue engineering strategy.This work was supported by MICINN (PID2019-105622RBI00, MAT2016-80826-R, PID2019-111682RB-I00, PID2020-115296RA-I00, CTQ2015-66194-R; SAF2014-60138-R, RTI2018-093831-B-I00, and PDC2021-121481-I00); Instituto de Salud Carlos III (ISCIII) through the Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN (FlexQS-skin, FlexCAB, BBN18PI01, BBN20PIV02, and CB/06/0074); Generalitat de Catalunya (grants 2017-SGR-918, 2017-SGR-229, 2017-SGR-1442, 2017-SGR-1439); the Fundació Marató de TV3 (Nr. 201812); the COST Action CA15126 Between Atom and Cell, and “ERDF A way of making Europe”. J.G. acknowledges financial support from the Ramón y Cajal Program (RYC-2017-22614) from MICINN and the Max Planck Society through the Max Planck Partner Group “Dynamic Biomimetics for Cancer Immunotherapy” in collaboration with the Max Planck Institute for Medical Research (Heidelberg, Germany). This work has received funding from the European Union’s Horizon 2020 research and innovation program through grant agreements 953110 (PHOENIX), 720942 (Smart4Fabry), 101007804 (MICRO4NANO), and 801342 (granted to the Agency for Business Competitiveness ACCIÓ through a Tecniospring Industry fellowship (TECSPR19-1-0065)). ICMAB acknowledges support from MICINN through the “‘Severo Ochoa”’ Programme for Centres of Excellence in R&D (CEX2019-000917-S). J.M. acknowledges a “Juan de la Cierva” fellowship from MICINN. J.T-M. acknowledges an FI-AGAUR grant (2020FI_B2 00137) from Generalitat de Catalunya and the European Social Fund. We also acknowledge the ICTS “NANBIOSIS for the support of the Synthesis of Peptides Unit (U3) at IQAC–CSIC (https://www.nanbiosis.es/portfolio/u3-synthesis-of-peptides-unit/) and the Biomaterial Processing and Nanostructuring Unit (U6) at ICMAB-CSIC (https://www.nanbiosis.es/portfolio/u6-biomaterial-processing-and-nanostructuring-unit/). We are grateful to the SMP unit of the Scientific and Technological Centers of University of Barcelona (CCiTUB). This work has been developed under the “Biochemistry, Molecular Biology and Biomedicine” and “Materials Science” Ph.D. programs of Universitat Autònoma de Barcelona (UAB).With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).Peer reviewe

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

Mission en Syrie et au Liban

Passemard. M. E. Mission en Syrie et au Liban. In: Bulletin de la Société préhistorique de France, tome 24, n°1-2, 1927. pp. 70-72