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

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. K E Y W O R D S fetal hypo-/akinesia, club foot/-feet, complicated spastic paraplegia/ spasticity, Xq11.2 microdeletion, ZC4H2, ZC4H2-Associated Rare Disorders (ZARD) DDD study presents independent

The Zinc-Finger Domain Containing Protein ZC4H2 Interacts with TRPV4, Enhancing Channel Activity and Turnover at the Plasma Membrane

“…At this point, the cellular function of ZC4H2 is not well understood, and, as for TRPV4, the link between specific mutations in the ZC4H2 gene and the resulting disease symptoms is elusive [16,21,23]. ZC4H2 contains a C-terminal zinc-finger domain characterized by four cysteine and two histidine residues.…”

“…Interestingly, patients with mutations in the X-linked gene encoding the zinc-finger domain-containing protein ZC4H2 exhibit a highly variable clinical presentation, originally described as Wieacker-Wolff or Miles-Carpenter syndrome but recently confined into ZC4H2 deficiency or ZC4H2-associated rare disorders (ZARDs) [16]. Generally, patients are diagnosed with intellectual disability accompanied by variable symptoms of central and peripheral nervous system involvement, including spasticity, hyperreflexia, muscle weakness, and arthrogryposis [16,20], symptoms that are also present to a variable extent in patients with mutations in the TRPV4 gene [14]. However, at this point, very little is known about the molecular expression, cellular function, and (patho)physiological roles of ZC4H2.…”

“…We identified the zinc-finger C4H2-type containing protein (ZC4H2) as a TRPV4 interaction partner, and provide evidence that it augments TRPV4-mediated Ca 2+ signals and enhances channel turnover at the plasma membrane. Interestingly, mutations in the X-linked ZC4H2 gene are the cause of so-called ZC4H2-associated rare disorders (ZARDs) [16]), formerly referred to as Wieacker-Wolff syndrome or Miles-Carpenter syndrome. ZARD patients suffer from a complex set of neurological problems, including several symptoms that overlap with typical features of TRPV4-pathies, such as arthrogryposis, distal muscle weakness, club foot, and camptodactyly.…”

A framework for the evaluation of patients with congenital facial weakness

“…ZC4H2 -associated rare disorders includes a spectrum of disease with arthrogryposis multiplex and peripheral and central nervous system involvement [ 47 ]. This spectrum includes Wieacker-Wolff syndrome (WRWF), an X-linked recessive condition caused by pathogenic variants in ZC4H2 .…”

Loss of ZC4H2 and RNF220 Inhibits Neural Stem Cell Proliferation and Promotes Neuronal Differentiation

“…In humans, mutations in ZC4H2, a zinc-finger nuclear factor, have been reported to cause various clinical phenotypes, including arthrogryposis multiplex congenita, intellectual disability, epilepsy, spasticity, hypotonia, etc., which are now referred to as ZC4H2-associated rare disorders (ZARD) [ 4 , 5 , 6 , 7 , 8 , 9 ]. Mechanistically, ZC4H2 has been suggested to be involved in neural development and dendritic spine density [ 4 , 9 ].…”