De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features.

Autor:	Pan X; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan & Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Tao AM; Vagelos School of Physicians and Surgeons, Columbia University, New York, NY, USA., Lu S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan & Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Ma M; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan & Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Hannan SB; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan & Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Slaugh R; Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Drewes Williams S; Division of Genetic and Genomic Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA., O'Grady L; Division of Medical Genetics & Metabolism, Massachusetts General for Children, Boston, MA, USA; MGH Institute of Health Professions, Charlestown, MA, USA., Kanca O; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan & Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Person R; GeneDx, LLC, Gaithersburg, MD, USA., Carter MT; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada., Platzer K; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Schnabel F; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Abou Jamra R; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Roberts AE; Department of Cardiology, Boston Children's Hospital, Boston, MA, USA; Department of Medicine, Division of Genetics, Boston Children's Hospital, Boston, MA, USA., Newburger JW; Department of Cardiology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA., Revah-Politi A; Institute for Genomic Medicine and Precision Genomics Laboratory, Columbia University Irving Medical Center, New York, NY, USA., Granadillo JL; Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA., Stegmann APA; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands., Sinnema M; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands., Accogli A; Division of Medical Genetics, Department of Medicine, McGill University Health Center, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada., Salpietro V; Department of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London, UK., Capra V; Unit of Medical Genetics and Genomics, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Ghaloul-Gonzalez L; Division of Genetic and Genomic Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA., Brueckner M; Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA., Simon MEH; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., Sweetser DA; Division of Medical Genetics & Metabolism, Massachusetts General for Children, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Glinton KE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Genetics, Texas Children's Hospital, Houston, TX, USA., Kirk SE; Section of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Cancer and Hematology Center, Houston, TX, USA., Wangler MF; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan & Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA., Yamamoto S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan & Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA., Chung WK; Departments of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: wendy.chung@childrens.harvard.edu., Bellen HJ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA. Electronic address: hbellen@bcm.edu.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2024 Apr 04; Vol. 111 (4), pp. 742-760. Date of Electronic Publication: 2024 Mar 12.
DOI:	10.1016/j.ajhg.2024.02.007
Abstrakt:	FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is expressed in multiple tissues, including the central nervous system where it is present in neurons but not in glia. Homozygous fry LoF mutation is lethal at various developmental stages, and loss of fry in mutant clones causes defects in wings and compound eyes. We next modeled four out of the five missense variants found in affected individuals using fry knockin alleles. One variant behaves as a severe LoF variant, whereas two others behave as partial LoF variants. One variant does not cause any observable defect in flies, and the corresponding human variant is not confirmed to be de novo, suggesting that this is a variant of uncertain significance. In summary, our findings support that fry is required for proper development in flies and that the LoF variants in FRYL cause a dominant disorder with developmental and neurological symptoms due to haploinsufficiency. Competing Interests: Declaration of interests W.K.C. is a member of the Board of Directors of Prime Medicine and RallyBio. R.P. is an employee of GeneDx, LLC. (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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