TY - JOUR
T1 - Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita
AU - Frints, Suzanna G.M.
AU - Hennig, Friederike
AU - Colombo, Roberto
AU - Jacquemont, Sebastien
AU - Terhal, Paulien
AU - Zimmerman, Holly H.
AU - Hunt, David
AU - Mendelsohn, Bryce A.
AU - Kordaß, Ulrike
AU - Webster, Richard
AU - Sinnema, Margje
AU - Abdul-Rahman, Omar
AU - Suckow, Vanessa
AU - Fernández-Jaén, Alberto
AU - van Roozendaal, Kees
AU - Stevens, Servi J.C.
AU - Macville, Merryn V.E.
AU - Al-Nasiry, Salwan
AU - van Gassen, Koen
AU - Utzig, Norbert
AU - Koudijs, Suzanne M.
AU - McGregor, Lesley
AU - Maas, Saskia M.
AU - Baralle, Diana
AU - Dixit, Abhijit
AU - Wieacker, Peter
AU - Lee, Marcus
AU - Lee, Arthur S.
AU - Engle, Elizabeth C.
AU - Houge, Gunnar
AU - Gradek, Gyri A.
AU - Douglas, Andrew G.L.
AU - Longman, Cheryl
AU - Joss, Shelagh
AU - Velasco, Danita
AU - Hennekam, Raoul C.
AU - Hirata, Hiromi
AU - Kalscheuer, Vera M.
N1 - Funding Information:
The authors would like to thank the individuals and their families who participated in this study. We also thank Andrew Green, Christina Fagerberg, and Melissa Lees for giving permission to include publicly available DECIPHER entries on their patients. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for the project was provided by the Wellcome Trust. For one of the families this study was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. Part of this study was supported by a Dutch NWO VENI grant (OND1312421 to S.F.), NEI grant R01EY027421, and NHLBI grant X01HL132377 (to ECE). The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute.
Publisher Copyright:
© 2019 Wiley Periodicals, Inc.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC.
AB - Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC.
KW - Xq11.2 microdeletion
KW - ZC4H2
KW - ZC4H2-Associated Rare Disorders (ZARD)
KW - club foot/-feet
KW - complicated spastic paraplegia/ spasticity
KW - fetal hypo-/akinesia
UR - http://www.scopus.com/inward/record.url?scp=85070930315&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070930315&partnerID=8YFLogxK
U2 - 10.1002/humu.23841
DO - 10.1002/humu.23841
M3 - Article
C2 - 31206972
AN - SCOPUS:85070930315
VL - 40
SP - 2270
EP - 2285
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 12
ER -