Novel insights into the phenotypic spectrum and pathogenesis of Hardikar syndrome.

Autor:	Strong A; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. Electronic address: strong.alanna@gmail.com., March ME; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA., Cardinale CJ; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA., Liu Y; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA., Battig MR; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA., Finoti LS; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA., Matsuoka LS; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA., Watson D; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA., Sridhar S; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA., Jarrett JF; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA., Cannon I; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA., Li D; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA., Bhoj E; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Zackai EH; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Rand EB; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Division of Gastroenterology and Hepatology, Children's Hospital of Philadelphia, Philadelphia, PA., Wenger T; Division of Genetic Medicine, University of Washington, Seattle, WA., Lerman BB; Department of Medicine, Division of Cardiology, Greenberg Institute for Cardiac Electrophysiology, Cornell University Medical Center, New York, NY., Shikany A; Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH., Weaver KN; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH., Hakonarson H; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, PA. Electronic address: hakonarson@chop.edu.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2024 Jul 20; Vol. 26 (10), pp. 101222. Date of Electronic Publication: 2024 Jul 20.
DOI:	10.1016/j.gim.2024.101222
Abstrakt:	Purpose: Hardikar syndrome (HS, MIM #301068) is a female-specific multiple congenital anomaly syndrome characterized by retinopathy, orofacial clefting, aortic coarctation, biliary dysgenesis, genitourinary malformations, and intestinal malrotation. We previously showed that heterozygous nonsense and frameshift variants in MED12 cause HS. The phenotypic spectrum of disease and the mechanism by which MED12 variants cause disease is unknown. We aim to expand the phenotypic and molecular landscape of HS and elucidate the mechanism by which MED12 variants cause disease. Methods: We clinically assembled and molecularly characterized a cohort of 11 previously unreported individuals with HS. Additionally, we studied the effect of MED12 deficiency on ciliary biology, hedgehog, and yes-associated protein (YAP) signaling; pathways implicated in diseases with phenotypic overlap with HS. Results: We report novel phenotypes associated with HS, including cardiomyopathy, arrhythmia, and vascular anomalies, and expand the molecular landscape of HS to include splice site variants. We additionally demonstrate that MED12 deficiency causes decreased cell ciliation, and impairs hedgehog and YAP signaling. Conclusion: Our data support updating HS standard-of-care to include regular cardiac imaging, arrhythmia screening, and vascular imaging. We further propose that dysregulation of ciliogenesis and YAP and hedgehog signaling contributes to the pathogenesis of HS. Competing Interests: Conflict of Interest The authors declare no conflicts of interest. (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu