Variants in ZFX are associated with an X-linked neurodevelopmental disorder with recurrent facial gestalt

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

  • James L. Shepherdson
  • Katie Hutchison
  • Dilan Wellalage Don
  • George McGillivray
  • Tae Ik Choi
  • Carolyn A. Allan
  • David J. Amor
  • Siddharth Banka
  • Donald G. Basel
  • Laura D. Buch
  • Deanna Alexis Carere
  • Renée Carroll
  • Jill Clayton-Smith
  • Ali Crawford
  • Morten Dunø
  • Laurence Faivre
  • Christopher P. Gilfillan
  • Nina B. Gold
  • Karen W. Gripp
  • Emma Hobson
  • Alexander M. Holtz
  • A. Micheil Innes
  • Bertrand Isidor
  • Adam Jackson
  • Panagiotis Katsonis
  • Leila Amel Riazat Kesh
  • Sébastien Küry
  • François Lecoquierre
  • Paul Lockhart
  • Julien Maraval
  • Naomichi Matsumoto
  • Julie McCarrier
  • Josephine McCarthy
  • Noriko Miyake
  • Lip Hen Moey
  • Andrea H. Németh
  • Østergaard, Elsebet
  • Rushina Patel
  • Kate Pope
  • Jennifer E. Posey
  • Rhonda E. Schnur
  • Marie Shaw
  • Elliot Stolerman
  • Julie P. Taylor
  • Erin Wadman
  • Emma Wakeling
  • Susan M. White
  • Lawrence C. Wong
  • James R. Lupski
  • Olivier Lichtarge
  • Mark Corbett
  • Jozef Gècz
  • Charles M. Nicolet
  • Peggy J Farnham
  • Cheol-Hee Kim
  • Marwan Shinawi
  • Genomics England Research Consortium
Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.
OriginalsprogEngelsk
TidsskriftAmerican Journal of Human Genetics
Vol/bind111
Udgave nummer3
Sider (fra-til)487-508
Antal sider22
ISSN0002-9297
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
We thank the cohort members and their families for participating in this study. For additional acknowledgments, including detailed funding information, please see the supplemental acknowledgments. Investigation: J.L.S. K.H. D.W.D. G.M. T.-I.C. C.A.A. D.J.A. S.B. D.G.B. L.D.B. D.A.C. R.C. J.C.-S. A.C. M.D. L.F. C.P.G. N.B.G. K.W.G. E.H. A.M.H. A.M.I. B.I. A.J. P.K. L.A.R.K. S.K. F.L. P.L. J. Maraval, N. Matsumoto, J. McCarrier, J. McCarthy, N. Miyake, L.H.M. A.H.N. E.Ø. R.P. K.P. J.E.P. R.E.S. M. Shaw, E.S. J.P.T. E. Wadman, E. Wakeling, S.M.W. L.C.W. J.R.L. O.L. M.A.C. J.G. C.M.N. P.J.F. C.-H.K. M. Shinawi; writing—original draft: J.L.S. D.W.D. P.K. C.M.N. M. Shinawi; writing—review & editing: J.L.S. K.H. D.W.D. G.M. C.A.A. D.J.A. S.B. D.G.B. L.D.B. D.A.C. J.C.-S. A.C. M.D. L.F. C.P.G. N.B.G. K.W.G. E.H. A.M.H. A.M.I. B.I. A.J. P.K. L.A.R.K. S.K. F.L. P.L. J. Maraval, N. Matsumoto, J. McCarrier, J. McCarthy, N. Miyake, L.H.M. A.H.N. E.Ø. R.P. K.P. J.E.P. R.E.S. E.S. J.P.T. E. Wadman, E. Wakeling, S.M.W. L.C.W. J.R.L. O.L. M.A.C. J.G. C.M.N. P.J.F. C.-H.K. M. Shinawi; resources: G.M. C.A.A. D.J.A. S.B. D.G.B. L.D.B. D.A.C. R.C. J.C.-S. M.D. L.F. C.P.G. N.B.G. K.W.G. E.H. A.M.H. A.M.I. B.I. A.J. L.A.R.K. G.E.R.C. S.K. F.L. P.L. J. Maraval, N. Matsumoto, J. McCarrier, J. McCarthy, N. Miyake, L.H.M. A.H.N. E.Ø. R.P. K.P. R.E.S. M. Shaw, E.S. E. Wadman, E. Wakeling, S.M.W. L.C.W. M.A.C. P.J.F. C.-H.K. M. Shinawi; supervision: O.L. J.G. P.J.F. C.-H.K. M. Shinawi; funding acquisition: J.G. P.J.F. C.-H.K. M. Shinawi; conceptualization: M. Shinawi; project administration: M. Shinawi. D.A.C. and R.E.S. are employees of GeneDx, LLC. A.C. and J.P.T. are employees and shareholders of Illumina, Inc. L.D.B. performs advisory board, consulting, and speaking arrangement work unrelated to the present study for Sanofi S.A. Horizon Therapeutics, Amicus Therapeutics, and Chiesi Farmaceutici S.p.A. N.B.G. has received personal fees from Pfizer Inc. and RCG Consulting for work unrelated to the present study. J.R.L. has stock ownership in 23andMe and is a paid consultant to Genome International.

Publisher Copyright:
© 2024 American Society of Human Genetics

ID: 386527627