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Hum Mutat. 2019 Jun 17. doi: 10.1002/humu.23841. [Epub ahead of print]

Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.

Author information

1
Department of Clinical Genetics, Maastricht University Medical Center+, azM, Maastricht, The Netherlands.
2
Department of Genetics and Cell Biology, Faculty of Health Medicine Life Sciences, Maastricht University Medical Center+, Maastricht University, Maastricht, The Netherlands.
3
Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
4
Catholic University of the Sacred Heart, Rome, Italy.
5
Center for the Study of Rare Inherited Diseases (CeSMER), Niguarda Ca' Granda Metropolitan Hospital, Milan, Italy.
6
Service de Génétique Médicale, CHUV, Lausanne, Switzerland.
7
Laboratories, Pharmacy and Biomedical Genetics Division, University Medical Centre Utrecht, Utrecht, The Netherlands.
8
Department of Pediatrics, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, Mississippi.
9
Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
10
Division of Genetics, Department of Pediatrics, University of California, San Francisco, California.
11
MVZ für Humangenetik und Molekularpathologie GmbH, Greifswald, Germany.
12
The Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, NSW, Australia.
13
Munroe-Meyer Institute for Genetics & Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska.
14
Hospital Universitario Quirónsalud, Universidad Europea de Madrid, Madrid, Spain.
15
Department of Obstetrics and Gynecology, Prenatal Diagnostics & Therapy, Maastricht University Medical Center+, Maastricht, The Netherlands.
16
Klinik für Kinder- und Jugendmedizin, Universitätsmedizin Greifswald, Greifswald, Germany.
17
Department of Neurology, Maastricht University Medical Center+, Maastricht, The Netherlands.
18
SA Clinical Genetics Service, Women's and Children's Hospital, North Adelaide, SA, Australia.
19
Department of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands.
20
Faculty of Medicine, University of Southampton, Southampton, UK.
21
City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK.
22
Institute of Human Genetics, Westfälische Wilhelms Universität Münster, Münster, Germany.
23
Department of Pediatrics, Division of Pediatric Neurology, University of Mississippi Medical Center, Jackson, Mississippi.
24
Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
25
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
26
Department of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
27
Howard Hughes Medical Institute, Chevy Chase, Maryland.
28
Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
29
Human Development and Health, Faculty of Medicine, University of Southampton, UK.
30
West of Scotland Regional Genetic Centre, Queen Elizabeth University Hospital, Glasgow, Scotland, UK.
31
Department of Pediatrics, Munroe-Meyer Institute for Genetics & Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska.
32
Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands.
33
Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University, Sagamihara, Japan.

Abstract

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.

KEYWORDS:

Xq11.2 microdeletion; ZC4H2; ZC4H2-Associated Rare Disorders (ZARD); club foot/-feet; complicated spastic paraplegia/ spasticity; fetal hypo-/akinesia

PMID:
31206972
DOI:
10.1002/humu.23841

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