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

Xueyang Pan; Alice M Tao; Shenzhao Lu; Mengqi Ma; Shabab B Hannan; Rachel Slaugh; Sarah Drewes Williams; Lauren O'Grady; Oguz Kanca; Richard Person; Melissa T Carter; Konrad Platzer; Franziska Schnabel; Rami Abou Jamra; Amy E Roberts; Jane W Newburger; Anya Revah-Politi; Jorge L Granadillo; Alexander P A Stegmann; Margje Sinnema; Andrea Accogli; Vincenzo Salpietro; Valeria Capra; Lina Ghaloul-Gonzalez; Martina Brueckner; Marleen E H Simon; David A Sweetser; Kevin E Glinton; Susan E Kirk; Baylor College of Medicine Center for Precision Medicine Models; Michael F Wangler; Shinya Yamamoto; Wendy K Chung; Hugo J Bellen

doi:10.1016/j.ajhg.2024.02.007

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

Am J Hum Genet. 2024 Apr 4;111(4):742-760. doi: 10.1016/j.ajhg.2024.02.007. Epub 2024 Mar 12.

Authors

Xueyang Pan¹, Alice M Tao², Shenzhao Lu¹, Mengqi Ma¹, Shabab B Hannan¹, Rachel Slaugh³, Sarah Drewes Williams⁴, Lauren O'Grady⁵, Oguz Kanca¹, Richard Person⁶, Melissa T Carter⁷, Konrad Platzer⁸, Franziska Schnabel⁸, Rami Abou Jamra⁸, Amy E Roberts⁹, Jane W Newburger¹⁰, Anya Revah-Politi¹¹, Jorge L Granadillo³, Alexander P A Stegmann¹², Margje Sinnema¹², Andrea Accogli¹³, Vincenzo Salpietro¹⁴, Valeria Capra¹⁵, Lina Ghaloul-Gonzalez¹⁶, Martina Brueckner¹⁷, Marleen E H Simon¹⁸, David A Sweetser¹⁹, Kevin E Glinton²⁰, Susan E Kirk²¹; Baylor College of Medicine Center for Precision Medicine Models; Michael F Wangler¹, Shinya Yamamoto²², Wendy K Chung²³, Hugo J Bellen²⁴

Collaborators

Baylor College of Medicine Center for Precision Medicine Models:
Lindsay C Burrage, Jason D Heaney, Seon-Young Kim, Denise G Lanza, Zhandong Liu, Dongxue Mao, Aleksander Milosavljevic, Sandesh C S Nagamani, Jennifer E Posey, Uma Ramamurthy, Vivek Ramanathan, Jeffrey Rogers, Jill A Rosenfeld, Matthew Roth, Ramin Zahedi Darshoori

Affiliations

¹ 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.
² Vagelos School of Physicians and Surgeons, Columbia University, New York, NY, USA.
³ Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
⁴ Division of Genetic and Genomic Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
⁵ Division of Medical Genetics & Metabolism, Massachusetts General for Children, Boston, MA, USA; MGH Institute of Health Professions, Charlestown, MA, USA.
⁶ GeneDx, LLC, Gaithersburg, MD, USA.
⁷ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁸ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
⁹ Department of Cardiology, Boston Children's Hospital, Boston, MA, USA; Department of Medicine, Division of Genetics, Boston Children's Hospital, Boston, MA, USA.
¹⁰ Department of Cardiology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
¹¹ Institute for Genomic Medicine and Precision Genomics Laboratory, Columbia University Irving Medical Center, New York, NY, USA.
¹² Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
¹³ Division of Medical Genetics, Department of Medicine, McGill University Health Center, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.
¹⁴ Department of Neuromuscular Disorders, University College London Institute of Neurology, Queen Square, London, UK.
¹⁵ Unit of Medical Genetics and Genomics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
¹⁶ 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.
¹⁷ Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
¹⁸ Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁹ Division of Medical Genetics & Metabolism, Massachusetts General for Children, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
²⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Genetics, Texas Children's Hospital, Houston, TX, USA.
²¹ Section of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Cancer and Hematology Center, Houston, TX, USA.
²² 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.
²³ Departments of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].
²⁴ 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: [email protected].

Abstract

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.

Keywords: Drosophila; FRYL; developmental delay; furry; intellectual disability; rare disease.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Child
Developmental Disabilities / diagnosis
Developmental Disabilities / genetics
Drosophila
Humans
Intellectual Disability* / genetics
Mammals
Musculoskeletal Abnormalities* / genetics
Mutation, Missense
Transcription Factors / genetics

Substances

Transcription Factors
fry protein, Drosophila

Abstract

Publication types

MeSH terms

Substances

Grants and funding