Novel biallelic ZNF335 variant causing primary microcephaly: A case report and radiological review
Dhrumil Deveshkumar Patel1, Karen W Gripp2, Erin Wadman2
1Department of Radiology, Nemours Children's Health, Wilmington, Delaware, USA.
Abstract:
Biallelic pathogenic variants in ZNF335 are one of the genetic causes of microcephaly, reported only in the past decade. It regulates neural progenitor proliferation and neurogenesis by interacting with a H3K4 methyltransferase complex. Biallelic pathogenic ZNF335 variants predispose to neuronal cell death and aberrant differentiation, thus causing secondary microcephaly. These neurodevelopmental anomalies lead to imaging findings in the cortex, posterior fossa, and basal ganglia. We report an individual of Nepalese ancestry with a novel homozygous ZNF335 variant (c.3591 + 2dup) (p.?) (NM_022095.3) which on further RNA analysis confirmed a splice site variant in intron 23. The patient presented with primary microcephaly with atrophic cerebral hemispheres, oversimplification of gyri, basal ganglia, and corpus callosal atrophy. Literature review on the topic revealed a spectrum of brain abnormalities, which can present either with a primary or secondary microcephaly depending upon the underlying genetic variant.
Insights
Genetic variants in ZNF335 cause microcephaly by affecting neural development. This study identifies a novel ZNF335 variant linked to primary microcephaly and brain abnormalities in a Nepalese patient.
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.
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