Radial Microbrain (Micrencephaly) Is Caused by a Recurrent Variant in the RTTN Gene.

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Primary microcephaly (PM) is a genetic brain development disorder causing congenital microcephaly and intellectual disability.
• Radial microbrain, the most severe PM form, leads to early lethality or severe intellectual handicap and lacks a molecular diagnosis.
• Previous studies elucidated PM genetics using exome and genome sequencing.

Purpose of the Study:

• To identify the genetic cause of radial microbrain.
• To analyze the genotype of individuals with extremely small brains.

Main Methods:

• Recruited individuals with the smallest head circumference from PM studies.
• Performed neurodevelopmental, brain imaging, and next-generation sequencing analyses.
• Conducted neuropathologic and immunohistologic analyses on fetal brains.

Main Results:

• Identified 5 individuals with a homozygous c.2953A>G variant in the RTTN gene.
• Found the same variant in 2 fetuses with severe brain abnormalities.
• Observed a 70% reduction in cortical plate thickness and a 50% loss of radial glial columns.

Conclusions:

• The homozygous c.2953A>G substitution in RTTN is a recurrent cause of radial microbrain.
• This finding provides a molecular diagnosis for the most severe form of primary microcephaly.
• The study enhances understanding of radial microbrain's severity and prognosis.