Molecular characteristics

The ZFHX4 gene encodes a 3567 amino acid protein located within the cell nucleus. This protein has shown to be a DNA binding protein that plays a role in DNA transcription and transcription regulation. It is present in the brain and is integral in normal brain development. It is believed that haploinsufficiency is responsible for the phenotype. ZFHX4-associated syndrome is caused by heterozygous deletion at chromosome 8q21.11 that includes ZFHX4 or a heterozygous intragenic pathogenic variant in ZFHX4. Pathogenic variants in ZFHX4 (NM_024721.4) are scattered throughout the gene and are predicted protein truncation, including nonsense variants, frameshift variants, and canonical splice site variants. Intragenic duplications and balanced inversions disrupting ZFHX4 have been found in some individuals with ZFHX4-associated syndrome. Almost all CNVs and pathogenic variants are due to a de novo change and inheritance is consistent with an autosomal dominant inheritance pattern. However, some inherited deletions encompassing ZFHX4 have been found in mildly affected individuals.

Deletions of ZFHX4 can be detected by a chromosomal microarray analysis (CMA) using oligonucleotide arrays or single nucleotide polymorphism (SNP) arrays that target the 8q21.11 region. Most pathogenic variants in ZFHX4 to date have been identified by whole exome/genome sequencing. However, when the relationship between alterations in ZFHX4 and developmental delay and intellectual disability is recognized, this gene may be included in intellectual disability multigene panels.

If the pathogenic ZFHX4 variant or CNV is not found in the parents, then this is most likely a de novo change. In this case, the risk to future pregnancies is presumed to be low. However, couples may wish to consider prenatal testing as risk may be greater than in the general population because of the possibility of parental germline mosaicism.