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

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.

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