ClinGen Dosage Sensitivity Curation Page

ZC4H2

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
31206972 Pathogenic variants of the ZC4H2 gene have been described in families with X-linked arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. Frintz et al.(2019), reported on the genetic and clinical findings of 23 families and simplex cases with inherited and de novo ZC4H2 variants identified in males and females. A total of 23 total variants were identified. Thirteen of the 23 variants were de novo LOF in affected females (7 variants were nonsense, splice site, frameshift; 5 variants intragenic deletions) and presented with a phenotype that ranged from mild to severe and clinically overlapped with those seen in affected males. The remaining 10 variants were missense variants identified in affected males and were inherited from their asymptomatic or mildly affected carrier mothers. X-inactivation studies in blood or skin in affected females varied from random to skewed and did not predict the phenotype. None of the variants reported in the study were seen in 1000 Genomes project database, gnomAD, or DGV. Most ZC4H2 variants in males were missense variants and except for two were inherited from carrier mothers that were asymptomatic or mildly affected. In contrast affected females had a spectrum of de novo pathogenic variants including missense, frame shift, splice site , early stop and microdeletions. The de novo variants in females are predicted to be loss of function alleles.
29254829 Okubo et al.(2018), described a Japanese female with arthrogryposis multiplex congenital (AMC) with severe intellectual disability, spastic quadriplegia with progressive brain atrophy. Microarray analysis identified a de novo 395 kb deletion of Xq11.2 including only the ZC4H2 gene.
23623388 Hirata et al. (2013) identified 5 familial missense mutations, 1 de novo disruptive inversion and 2 focal microdeletions in the X-linked ZC4H2 gene in several intellectually disabled patients with arthrogryposis multiplex congenital (AMC) or cerebral palsy (CP). Affected heterozygous females were also identified with milder features including intellectual disability, distal muscle weakness, camptodactyly, equinovarus foot deformity or contracture of the Achilles tendon. Of note, the two focal microdeletions were found in mildly affected female simplex cases. One of these deletions was found not to be inherited from the mother, though the father was unavailable. For the other, parental samples were unavailable for analysis. Functional studies in primary hippocampal mouse neurons and in zebrafish were shown in support for the pathogenicity of the missense mutations. The authors report "preferential inactivation of the mutated X chromosome in all females tested, except for the affected girl of family 4 and her unaffected mother (the only family with an initial diagnosis of cerebral palsy). The one inversion (observed in a male) appears to disrupt the gene. RT-PCR in the male inversion case demonstrated no expression of the ZC4H2 protein.

Haploinsufficiency phenotype comments:

Additional PMID 28345801 Zanzottera et al. (2017) described a female with a de novo 429 kb deletion including only the ZC4H2 gene. The female presented with a severe clinical phenotype similar to what is seen in males with pathogenic ZC4H2 variants. PMID 29150902 Godfrey et al. (2017) described a female with a heterozygous de novo nonsense mutation and a classic phenotype of Wieaker Wolf syndrome. Pathogenic variants seen in the ZC4H2 gene have been described in males with intellectual disability in variable association with spasticity, hyperflexia and/or pyramidal signs, seizures or CNS abnormalities, muscle weakness, and joint contractures (Arthrogryposis multiplex congenital). The clinical phenotype of heterozygous females with pathogenic ZC4H2 variants is variable and may be asymptomatic or variably affected. of note, ZC4H2 variants have been identified in families with Wieaker-Wolff syndrome and Miles Carpenter syndrome, which are considered allelic syndromes. Frintz et al. (2019) refers to these allelic syndromes as ZC4H2 associated rare disorders (ZARD). In general, affected females typically have loss of function variants; females with missense variants may be asymptomatic; affected males generally have missense variants.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.