Child Neurology: Multiple Genetic Etiologies Causing Dandy-Walker Variant With Microcephaly, Epilepsy, and Global...

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Dandy-Walker syndrome and Dandy-Walker variant (DWv) are congenital brain malformations affecting the cerebellum and posterior fossa.
• DWv typically presents with milder features than Dandy-Walker syndrome, usually with normal or enlarged head circumference.

Purpose of the Study:

• To investigate the genetic etiology of a severe neurodevelopmental disorder with microcephaly and Dandy-Walker variant features in a 16-month-old girl.
• To explore the potential contribution of multiple genetic variants to a complex clinical phenotype.

Main Methods:

• Brain MRI for neuroimaging assessment.
• Chromosomal microarray analysis to detect copy number variations and homozygosity.
• Trio-based whole-exome sequencing to identify causative genetic variants.

Main Results:

• The patient presented with congenital microcephaly, seizures, and global developmental delay, with MRI findings consistent with DWv.
• Genetic analysis identified a heterozygous variant in CACNA1I (associated with neurodevelopmental disorders) and a homozygous variant in LRP5 (linked to microcephaly).
• These findings suggest a complex genetic etiology involving multiple pathogenic variants.

Conclusions:

• Atypical and severe presentations of DWv may result from combined genetic factors.
• The identified CACNA1I and LRP5 variants likely contributed to the patient's severe microcephaly and neurodevelopmental issues.
• Comprehensive genomic evaluation is crucial for diagnosing complex genetic disorders with unusual phenotypes.