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

TitleDeleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.
Publication TypeJournal Article
Year of Publication2019
AuthorsFrints, SGM, Hennig, F, Colombo, R, Jacquemont, S, Terhal, P, Zimmerman, HH, Hunt, D, Mendelsohn, BA, Kordaß, U, Webster, R, Sinnema, M, Abdul-Rahman, O, Suckow, V, Fernández-Jaén, A, van Roozendaal, K, Stevens, SJC, Macville, MVE, Al-Nasiry, S, van Gassen, K, Utzig, N, Koudijs, SM, McGregor, L, Maas, SM, Baralle, D, Dixit, A, Wieacker, P, Lee, M, Lee, AS, Engle, EC, Houge, G, Gradek, GA, Douglas, AGL, Longman, C, Joss, S, Velasco, D, Hennekam, RC, Hirata, H, Kalscheuer, VM
JournalHum Mutat
Date Published2019 12

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.

Alternate JournalHum. Mutat.
PubMed ID31206972
PubMed Central IDPMC6874899
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
OND1312421 / / Nederlandse Organisatie voor Wetenschappelijk Onderzoek / International
HICF-1009-003 / / Health Innovation Challenge Fund / International
X01HL132377 / HL / NHLBI NIH HHS / United States
R01EY027421 / EY / NEI NIH HHS / United States
R01 EY027421 / EY / NEI NIH HHS / United States
/ WT / Wellcome Trust / United Kingdom
WT098051 / / Wellcome and the Department of Health, and the Wellcome Sanger Institute / International