Novel biallelic ZNF335 variant causing primary microcephaly: A case report and radiological review

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Biallelic pathogenic variants in ZNF335 are a recently identified genetic cause of microcephaly.
• ZNF335 plays a crucial role in regulating neural progenitor proliferation and neurogenesis via interaction with a H3K4 methyltransferase complex.
• Pathogenic ZNF335 variants can lead to neuronal cell death and aberrant differentiation, resulting in secondary microcephaly.

Observation:

• A novel homozygous ZNF335 splice site variant (c.3591+2dup) was identified in an individual of Nepalese ancestry.
• The patient presented with primary microcephaly, characterized by atrophic cerebral hemispheres, simplified gyri, basal ganglia abnormalities, and corpus callosal atrophy.
• RNA analysis confirmed the variant as a splice site mutation in intron 23.

Findings:

• The identified ZNF335 variant contributes to primary microcephaly and significant neurodevelopmental anomalies.
• The patient's phenotype includes severe brain abnormalities affecting the cortex, posterior fossa, and basal ganglia.
• This case expands the known spectrum of ZNF335-associated microcephaly.

Implications:

• Understanding ZNF335's role in neurodevelopment is critical for diagnosing and potentially treating microcephaly.
• Identification of novel variants like the one reported here refines genotype-phenotype correlations in ZNF335-related disorders.
• Further research into ZNF335 function may reveal therapeutic targets for neurodevelopmental disorders.