Genetics in Medicine

Journal Information
ISSN / EISSN : 1098-3600 / 1530-0366
Current Publisher: Springer Science and Business Media LLC (10.1038)
Former Publisher: Ovid Technologies (Wolters Kluwer Health) (10.1097)
Total articles ≅ 4,355
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Florence Riccardi, Alexandre Astier, Margot Grisval, Arnaud Maillard, Vincent Michaud, Catherine Badens, Christopher T. Gordon, Aurélien Trimouille, Laurence Faivre, Jeanne Amiel, et al.
Genetics in Medicine pp 1-2; doi:10.1038/s41436-021-01208-8

, Jaya Punetha, Jeshurun C. Kalanithy, Enrico Mingardo, Haktan B. Erdem, Zeynep C. Akdemir, Ender Karaca, Tadahiro Mitani, Dana Marafi, Jawid M. Fatih, et al.
Genetics in Medicine; doi:10.1038/s41436-021-01196-9

Abstract:
Purpose To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development. Methods We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype–phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b. Results Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye. Conclusion We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
, Simona Bianconi, Andrew Smith, Niamh X. Cawley, An Dang Do, Dylan Hammond, Julia F. Grafstein, Audrey Thurm, Judith Miller, John Perreault, et al.
Genetics in Medicine pp 1-9; doi:10.1038/s41436-021-01224-8

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Genetics in Medicine, Volume 23, pp 978-978; doi:10.1038/s41436-021-01221-x

Genetics in Medicine, Volume 23, pp 977-977; doi:10.1038/s41436-021-01220-y

Francis Rossignol, Marvid S. Duarte Moreno, Jean-François Benoist, Manfred Boehm, Emmanuelle Bourrat, Aline Cano, Brigitte Chabrol, Claudine Cosson, José Luís Dapena Díaz, Arthur D’Harlingue, et al.
Genetics in Medicine pp 1-12; doi:10.1038/s41436-021-01200-2

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Samuel A. Crawford, Cynthia L. Gong, Leah Yieh, Linda M. Randolph, Joel W. Hay
Genetics in Medicine pp 1-10; doi:10.1038/s41436-021-01210-0

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, Sairah Yousaf, James Liu, Wendy K. Chung, Lindsay Rhodes, Michael Marble, Regina M. Zambrano, Nara Sobreira, Parul Jayakar, Mary Ella Pierpont, et al.
Genetics in Medicine pp 1-12; doi:10.1038/s41436-021-01182-1

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Catherine E. Cottrell, Nicole R. Bender, Michael T. Zimmermann, Jonathan W. Heusel, Meagan Corliss, Michael J. Evenson, Vincent Magrini, Donald J. Corsmeier, Matthew Avenarius, Jeffrey N. Dudley, et al.
Genetics in Medicine pp 1-7; doi:10.1038/s41436-021-01211-z

Abstract:
Purpose Somatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1. Methods Affected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity. Results The phenotypic and variant spectrum associated with somatic variation in PIK3R1 is reported herein. Variants occurred in the inter-SH2 or N-terminal SH2 domains of all three PIK3R1 protein products. Phenotypic features overlapped those of the PIK3CA-related overgrowth spectrum (PROS). These overlapping features included mixed vascular malformations, sandal toe gap deformity with macrodactyly, lymphatic malformations, venous ectasias, and overgrowth of soft tissue or bone. Conclusion Somatic PIK3R1 variants sharing attributes with cancer-associated variants cause complex vascular malformations and overgrowth. The PIK3R1-associated phenotypic spectrum overlaps with PROS. These data extend understanding of the diverse phenotypic spectrum attributable to genetic variation in the PI3K-AKT pathway.
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