Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay

Arezoo Mohajeri; Guney Bademci; Maryam Vaseghi-Shanjani; Deborah Barbouth; Irman Forghani; Jill A Rosenfeld; Gui Xiang Yang; Rosario Isasi; Henry Lu; Xue Zhong Liu; Mehul Sharma; Jacob McCauley; Susan Lin; Mario Saporta; Areesha Salman; Mustafa Tekin; Meriam Waqas; Willa Thorson; Mahshid Sababi Azamian; Stephan Zuchner; Kim C Worley; Kate L Del Bel; Frederick K Kozak; Ronak Rahmanian; Catherine M Biggs; Kyla J Hildebrand; Seema R Lalani; Sarah K Nicholas; Daryl A Scott; Sara Mostafavi; Clara van Karnebeek; Erika Henkelman; Jessica Halparin; Connie L Yang; Linlea Armstrong; Stuart E Turvey; Anna Lehman; Maria T Acosta; Margaret Adam; David R Adams; Raquel L Alvarez; Justin Alvey; Laura Amendola; Ashley Andrews; Euan A Ashley; Carlos A Bacino; Ashok Balasubramanyam; Dustin Baldridge; Jim Bale; Michael Bamshad; Pinar Bayrak-Toydemir; Anita Beck; Alan H Beggs; Edward Behrens; Gill Bejerano; Hugo J Bellen; Jimmy Bennett; Beverly Berg-Rood; Jonathan A Bernstein; Gerard T Berry; Anna Bican; Stephanie Bivona; Elizabeth Blue; John Bohnsack; Devon Bonner; Lorenzo Botto; Brenna Boyd; Lauren C Briere; Elly Brokamp; Gabrielle Brown; Elizabeth A Burke; Lindsay C Burrage; Manish J Butte; Peter Byers; William E Byrd; John Carey; Olveen Carrasquillo; Thomas Cassini; TaChen Peter Chang; Sirisak Chanprasert; Hsiao-Tuan Chao; Gary D Clark; Terra R Coakley; Laurel A Cobban; Joy D Cogan; Matthew Coggins; F Sessions Cole; Heather A Colley; Cynthia M Cooper; Heidi Cope; Rosario Corona; William J Craigen; Andrew B Crouse; Michael Cunningham; Precilla D’Souza; Hongzheng Dai; Surendra Dasari; Joie Davis; Jyoti G Dayal; Esteban C Dell'Angelica; Katrina Dipple; Daniel Doherty; Naghmeh Dorrani; Argenia L Doss; Emilie D Douine; Laura Duncan; Dawn Earl; David J Eckstein; Lisa T Emrick; Christine M Eng; Marni Falk; Elizabeth L Fieg; Paul G Fisher; Brent L Fogel; William A Gahl; Ian Glass; Bernadette Gochuico; Page C Goddard; Rena A Godfrey; Katie Golden-Grant; Alana Grajewski; Sihoun Hahn Don Hadley; Meghan C. Halley; Rizwan Hamid; Kelly Hassey; Nichole Hayes; Frances High; Anne Hing; Fuki M Hisama; Ingrid A Holm; Jason Hom; Martha Horike-Pyne; Alden Huang; Sarah Hutchison; Wendy Introne; Kosuke Izumi; Fariha Jamal; Gail P Jarvik; Jeffrey Jarvik; Suman Jayadev; Orpa Jean-Marie; Vaidehi Jobanputra; Lefkothea Karaviti; Jennifer Kennedy; Shamika Ketkar; Dana Kiley; Gonench Kilich; Shilpa N Kobren; Isaac S Kohane; Jennefer N Kohler; Susan Korrick; Mary Kozuira; Deborah Krakow; Donna M Krasnewich; Elijah Kravets; Byron Lam; Christina Lam; Brendan C Lanpher; Ian R Lanza; Kimberly LeBlanc; Brendan H Lee; Roy Levitt; Richard A Lewis; Pengfei Liu; Nicola Longo; Sandra K Loo; Joseph Loscalzo; Richard L Maas; Ellen F Macnamara; Calum A MacRae; Valerie V Maduro; Rachel Mahoney; MayChristine V Malicdan; Laura A Mamounas; Teri A Manolio; Rong Mao; Kenneth Maravilla; Ronit Marom; Gabor Marth; Beth A Martin; Martin G Martin; Julian A Martínez-Agosto; Shruti Marwaha; Allyn McConkie-Rosell; Alexa T McCray; Elisabeth McGee; Heather Mefford; J Lawrence Merritt; Matthew Might; Ghayda Mirzaa; Eva Morava; Paolo Moretti; John Mulvihill; Mariko Nakano-Okuno; Stanley F Nelson; John H Newman; Deborah Nickerson; Shirley Nieves-Rodriguez; Donna Novacic; Devin Oglesbee; James P Orengo; Laura Pace; Stephen Pak; J Carl Pallais; Christina GS Palmer; Jeanette C Papp; Neil H Parker; John A PhillipsIII; Jennifer E Posey; Lorraine Potocki; Barbara N PuseySwerdzewski; Aaron Quinlan; Deepak A Rao; Anna Raper; Wendy Raskind; Genecee Renteria; Chloe M Reuter; Lynette Rives; Amy K Robertson; Lance H Rodan; Natalie Rosenwasser; Francis Rossignol; Maura Ruzhnikov; Ralph Sacco; Jacinda B Sampson; Judy Schaechter; Timothy Schedl; Kelly Schoch; C Ron Scott; Vandana Shashi; Jimann Shin; Edwin K Silverman; Janet S Sinsheimer; Kathy Sisco; Edward C Smith; Kevin S Smith; Emily Solem; Lilianna Solnica-Krezel; Ben Solomon; Rebecca C Spillmann; Joan M Stoler; Kathleen Sullivan; Jennifer A Sullivan; Angela Sun; Shirley Sutton; David A Sweetser; Virginia Sybert; Holly K Tabor; Queenie K-G Tan; Amelia LM Tan; Fred Telischi; Cynthia J Tifft; Camilo Toro; Alyssa A Tran; Rachel A Ungar; Tiina K Urv; Adeline Vanderver; Matt Velinder; Dave Viskochil; Tiphanie P Vogel; Colleen E Wahl; Melissa Walker; Stephanie Wallace; Nicole M Walley; Jennifer Wambach; Jijun Wan; Lee-kai Wang; Michael F Wangler; Patricia A Ward; Daniel Wegner; Monika Weisz Hubshman; Mark Wener; Tara Wenger; Monte Westerfield; Matthew T Wheeler; Jordan Whitlock; Lynne A Wolfe; Kim Worley; Changrui Xiao; Shinya Yamamoto; John Yang; Zhe Zhang; Undiagnosed diseases network

doi:10.1136/jmg-2022-109127

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Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay

Journal article

Peer reviewed

Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay

Arezoo Mohajeri, Guney Bademci, Maryam Vaseghi-Shanjani, Deborah Barbouth, Irman Forghani, Jill A Rosenfeld, Gui Xiang Yang, Rosario Isasi, Henry Lu, Xue Zhong Liu, …

Journal of medical genetics, p.jmg-2022-109127

2023-06-14

DOI: https://doi.org/10.1136/jmg-2022-109127

PMID: 37316189

Appears in Miller School of Medicine - Latest Publications

Abstract

Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Developmental defects

Genetics, Medical

Immune System Diseases

Sequence Analysis, DNA

Genomics

BackgroundHelios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. Although predominantly recognised for its role in the development and function of T lymphocytes, particularly the CD4+ regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans.MethodsWe performed detailed phenotypic, genomic and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss and congenital abnormalities.ResultsGenome sequencing revealed de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZFs) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136_Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). Functional studies confirmed that both these variant proteins are expressed and that they interfere with the ability of the wild-type Helios protein to perform its canonical function—repressing IL2 transcription activity—in a dominant negative manner.ConclusionThis study is the first to describe dominant negative IKZF2 variants. These variants cause a novel genetic syndrome characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.189 Genome Studies; 1.189.310 Population Genetics
Web Of Science research areas: Genetics & Heredity
ESI research areas: Clinical Medicine

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Title: Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay
Creators: Arezoo Mohajeri - University of British Columbia
Guney Bademci
Maryam Vaseghi-Shanjani - British Columbia Children's Hospital
Deborah Barbouth
Irman Forghani
Jill A Rosenfeld - Baylor College of Medicine
Gui Xiang Yang - University of British Columbia
Rosario Isasi
Henry Lu - British Columbia Children's Hospital
Xue Zhong Liu
Mehul Sharma - British Columbia Children's Hospital
Jacob McCauley
Susan Lin - British Columbia Children's Hospital
Mario Saporta
Areesha Salman - University of British Columbia
Mustafa Tekin
Meriam Waqas - British Columbia Children's Hospital
Willa Thorson
Mahshid Sababi Azamian - Baylor College of Medicine
Stephan Zuchner
Kim C Worley - Baylor College of Medicine
Kate L Del Bel - British Columbia Children's Hospital
Frederick K Kozak - University of British Columbia
Ronak Rahmanian - University of British Columbia
Catherine M Biggs - University of British Columbia
Kyla J Hildebrand - British Columbia Children's Hospital
Seema R Lalani - Baylor College of Medicine
Sarah K Nicholas - Texas Children's Hospital
Daryl A Scott - Baylor College of Medicine
Sara Mostafavi - University of British Columbia
Clara van Karnebeek - British Columbia Children's Hospital
Erika Henkelman - University of British Columbia
Jessica Halparin - British Columbia Children's Hospital
Connie L Yang - British Columbia Children's Hospital
Linlea Armstrong - University of British Columbia
Stuart E Turvey - University of British Columbia
Anna Lehman - University of British Columbia
Maria T Acosta
Margaret Adam
David R Adams
Raquel L Alvarez
Justin Alvey
Laura Amendola
Ashley Andrews
Euan A Ashley
Carlos A Bacino
Ashok Balasubramanyam
Dustin Baldridge
Jim Bale
Michael Bamshad
Pinar Bayrak-Toydemir
Anita Beck
Alan H Beggs
Edward Behrens
Gill Bejerano
Hugo J Bellen
Jimmy Bennett
Beverly Berg-Rood
Jonathan A Bernstein
Gerard T Berry
Anna Bican
Stephanie Bivona
Elizabeth Blue
John Bohnsack
Devon Bonner
Lorenzo Botto
Brenna Boyd
Lauren C Briere
Elly Brokamp
Gabrielle Brown
Elizabeth A Burke
Lindsay C Burrage
Manish J Butte
Peter Byers
William E Byrd
John Carey
Olveen Carrasquillo
Thomas Cassini
TaChen Peter Chang
Sirisak Chanprasert
Hsiao-Tuan Chao
Gary D Clark
Terra R Coakley
Laurel A Cobban
Joy D Cogan
Matthew Coggins
F Sessions Cole
Heather A Colley
Cynthia M Cooper
Heidi Cope
Rosario Corona
William J Craigen
Andrew B Crouse
Michael Cunningham
Precilla D’Souza
Hongzheng Dai
Surendra Dasari
Joie Davis
Jyoti G Dayal
Esteban C Dell'Angelica
Katrina Dipple
Daniel Doherty
Naghmeh Dorrani
Argenia L Doss
Emilie D Douine
Laura Duncan
Dawn Earl
David J Eckstein
Lisa T Emrick
Christine M Eng
Marni Falk
Elizabeth L Fieg
Paul G Fisher
Brent L Fogel
William A Gahl
Ian Glass
Bernadette Gochuico
Page C Goddard
Rena A Godfrey
Katie Golden-Grant
Alana Grajewski
Sihoun Hahn Don Hadley
Meghan C. Halley
Rizwan Hamid
Kelly Hassey
Nichole Hayes
Frances High
Anne Hing
Fuki M Hisama
Ingrid A Holm
Jason Hom
Martha Horike-Pyne
Alden Huang
Sarah Hutchison
Wendy Introne
Kosuke Izumi
Fariha Jamal
Gail P Jarvik
Jeffrey Jarvik
Suman Jayadev
Orpa Jean-Marie
Vaidehi Jobanputra
Lefkothea Karaviti
Jennifer Kennedy
Shamika Ketkar
Dana Kiley
Gonench Kilich
Shilpa N Kobren
Isaac S Kohane
Jennefer N Kohler
Susan Korrick
Mary Kozuira
Deborah Krakow
Donna M Krasnewich
Elijah Kravets
Seema R Lalani - Baylor College of Medicine
Byron Lam
Christina Lam
Brendan C Lanpher
Ian R Lanza
Kimberly LeBlanc
Brendan H Lee
Roy Levitt
Richard A Lewis
Pengfei Liu
Nicola Longo
Sandra K Loo
Joseph Loscalzo
Richard L Maas
Ellen F Macnamara
Calum A MacRae
Valerie V Maduro
Rachel Mahoney
MayChristine V Malicdan
Laura A Mamounas
Teri A Manolio
Rong Mao
Kenneth Maravilla
Ronit Marom
Gabor Marth
Beth A Martin
Martin G Martin
Julian A Martínez-Agosto
Shruti Marwaha
Allyn McConkie-Rosell
Alexa T McCray
Elisabeth McGee
Heather Mefford
J Lawrence Merritt
Matthew Might
Ghayda Mirzaa
Eva Morava
Paolo Moretti
John Mulvihill
Mariko Nakano-Okuno
Stanley F Nelson
John H Newman
Sarah K Nicholas - Texas Children's Hospital
Deborah Nickerson
Shirley Nieves-Rodriguez
Donna Novacic
Devin Oglesbee
James P Orengo
Laura Pace
Stephen Pak
J Carl Pallais
Christina GS Palmer
Jeanette C Papp
Neil H Parker
John A PhillipsIII
Jennifer E Posey
Lorraine Potocki
Barbara N PuseySwerdzewski
Aaron Quinlan
Deepak A Rao
Anna Raper
Wendy Raskind
Genecee Renteria
Chloe M Reuter
Lynette Rives
Amy K Robertson
Lance H Rodan
Jill A Rosenfeld - Baylor College of Medicine
Natalie Rosenwasser
Francis Rossignol
Maura Ruzhnikov
Ralph Sacco
Jacinda B Sampson
Judy Schaechter
Timothy Schedl
Kelly Schoch
Daryl A Scott - Baylor College of Medicine
C Ron Scott
Vandana Shashi
Jimann Shin
Edwin K Silverman
Janet S Sinsheimer
Kathy Sisco
Edward C Smith
Kevin S Smith
Emily Solem
Lilianna Solnica-Krezel
Ben Solomon
Rebecca C Spillmann
Joan M Stoler
Kathleen Sullivan
Jennifer A Sullivan
Angela Sun
Shirley Sutton
David A Sweetser
Virginia Sybert
Holly K Tabor
Queenie K-G Tan
Amelia LM Tan
Fred Telischi
Cynthia J Tifft
Camilo Toro
Alyssa A Tran
Rachel A Ungar
Tiina K Urv
Adeline Vanderver
Matt Velinder
Dave Viskochil
Tiphanie P Vogel
Colleen E Wahl
Melissa Walker
Stephanie Wallace
Nicole M Walley
Jennifer Wambach
Jijun Wan
Lee-kai Wang
Michael F Wangler
Patricia A Ward
Daniel Wegner
Monika Weisz Hubshman
Mark Wener
Tara Wenger
Monte Westerfield
Matthew T Wheeler
Jordan Whitlock
Lynne A Wolfe
Kim Worley - Baylor College of Medicine
Changrui Xiao
Shinya Yamamoto
John Yang
Zhe Zhang
Undiagnosed diseases network (Contributor)
Publication Details: Journal of medical genetics, p.jmg-2022-109127
Publisher: BMJ Publishing Group Ltd
Grant note: Jeffrey Modell Foundation (http://dx.doi.org/10.13039/100001245) U01HG007709 / Office of Strategic Coordination/Office of the NIH Director under Award Aubrey J. Tingle Professor of Pediatric Immunology Tier 1 Canada Research Chair in Pediatric Precision Health Genome Canada (http://dx.doi.org/10.13039/100008762) Health Professional-Investigator award from Michael Smith Health Research BC Genome British Columbia (http://dx.doi.org/10.13039/501100000233) Providence Healthcare Research Institute Early Career Investigator award Vanier Canada Graduate Scholarship The University of British Columbia Four Year Doctoral Fellowship National Institutes of Health (http://dx.doi.org/10.13039/100000002) F17-04161 / BC Children’s Hospital Research Institute PJT 178054 / Canadian Institutes of Health Research (http://dx.doi.org/10.13039/501100000024)
Academic Unit: Leadership Department; UMMG Dept of Human Genetics - Clinical and Translational Genetics; UMMG Department of Neurology; UMMG Department of Otolaryngology; UMMG Dept of Neurology - Neuromuscular Disorders Div; Miller School of Medicine; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation); John P. Hussman Institute for Human Genomics
Language: English
Resource Type: Journal article
PMID: 37316189
Record Identifier: 991031811220502976