女性中 X 连锁 ZC4H2 的有害从头变异导致神经源性多发性先天性关节弯曲的可变表型.

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 家庭和 14 affected males from nine
家庭. Of note, 这 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, 的
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 家庭. 这
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.