Radial Microbrain (Micrencephaly) Is Caused by a Recurrent Variant in the RTTN Gene
Clarisse Gins1, Fabien Guimiot2,3, Séverine Drunat2,4
1Service de Neurologie Pédiatrique, DMU INOV-RDB, APHP, Hôpital Robert Debré, Paris, France.
Background And Objectives:
Genetic primary microcephaly (PM) is a defect in early brain development leading to congenital microcephaly, mostly recessively inherited, and mild-to-moderate intellectual disability. PM has been largely elucidated, thanks to exome and genome sequencing. However, radial microbrain, the most severe form of genetic PM or micrencephaly described in the 1980s, which leads to early lethality or very severe intellectual handicap, remains without a molecular diagnosis. We sought to identify the cause of radial microbrain by analyzing the genotype of children/adults and fetuses with an extremely small brain.
Methods:
We searched for individuals with the smallest head circumference among patients with a confirmed diagnosis of PM included in 2 French and European observational studies coordinated at the Robert Debré Children's Hospital in Paris. Their neurodevelopment and brain imaging were analyzed, as well as next-generation sequencing for a panel of microcephaly genes or exome sequencing. Neuropathologic and immunohistologic analyses of extremely severe microcephalic fetal brains and stage-matched controls were performed. A nonparametric test and Mann-Whitney post-test were used to compare the cortical thickness between groups.
Results:
We identified 5 individuals (4 female patients, 7 years 10 months-19 years) with a particularly small brain among a series of 50, all suffering from a severe neurodevelopmental disorder with no ability to communicate verbally and, in 3 of them, no ability to walk. Genetic analysis revealed in all individuals the presence of the same homozygous variant c.2953A>G (p.R985G) in the RTTN gene (ROTATIN). The same variant was found in 2 fetuses whose neuropathologic evaluation showed a major reduction in the thickness of the ventricular zone and neuronal heterotopias. The cortical plate was reduced by 70% compared with controls, irrespective of the region considered. Immunostaining with vimentin showed a 50% loss of radial glial columns, characteristic of radial microbrain.
Discussion:
Our data show that the homozygous c.2953A>G substitution in RTTN is a recurrent variant responsible for radial microbrain, the most severe form of primary microcephaly. Our combined neurologic, imaging, and histopathologic approaches provide a better understanding of the severity of this condition and its prognosis.
Trial Registration Information:
ClinicalTrials.gov number: NCT01565005.
Insights
A genetic variant in the RTTN gene causes radial microbrain, the most severe form of primary microcephaly. This discovery provides a molecular diagnosis for this rare brain development disorder.
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.
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