Wieacker-Wolff Syndrome via the ZC4H2 Gene

Wieacker-Wolff syndrome is a rare, X-linked recessive disorder affecting both the central and peripheral nervous system. Affected males may present muscle weakness in utero (fetal akinesia), severe joint contracture (arthrogryposis), muscle degeneration (atrophy), multiple dysmorphic features and mild intellectual disability. Carrier females may have mild clinical symptoms of the disorder due to skewed X inactivation (Hirata et al. 2013).

Wieacker-Wolff syndrome is inherited in an X-linked recessive manner and is caused by pathogenic variants in the ZC4H2 gene. The ZC4H2 gene is located on the X chromosome (Xq11.2) and encodes a member of the zinc finger domain-containing protein family. It expressed in the central and peripheral nervous systems and plays a critical role in nervous system development and neuromuscular junction formation (Hirata et al. 2013). Pathogenic variants in the ZC4H2 gene may affect the development of a subset of interneurons and therefore interfere with the connectivity throughout the brain and spinal cord (May et al. 2015). The majority of pathogenic ZC4H2 variants are missense. Two large deletions and one complex arrangement have also been reported (Human Gene Mutation Database).

Precise estimates of clinical sensitivity are not available because only a limited number of patients have been reported. The majority of pathogenic ZC4H2 variants are missense.

Precise estimates of clinical sensitivity are not available because only a limited number of patients have been reported. Two large deletions and one complex arrangement involving ZC4H2 have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the ZC4H2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).