# MPDZ Pathogenic Variants Cause Obstructive Ventriculomegaly Related to Diencephalosynapsis and Third Ventricle Atresia

## TL;DR

MPDZ gene variants cause obstructive ventriculomegaly in fetuses, linked to brain structure abnormalities like diencephalosynapsis and third ventricle atresia.

## Contribution

This study identifies MPDZ pathogenic variants as a cause of obstructive ventriculomegaly with specific anatomical features.

## Key findings

- MPDZ variants are associated with obstructive ventriculomegaly due to partial thalamic fusion and third ventricle atresia.
- MRI and neuropathological analysis confirmed the obstructive pattern in six cases with MPDZ mutations.
- Immunostaining showed MPDZ expression in fetal brain tissue, supporting its role in brain development.

## Abstract

Objective: Ventriculomegaly is the main prenatal imaging feature for diagnosing fetal central nervous system anomalies in humans. Many ventriculomegalies can be related to genetic causes, regardless of their imaging presentations. Among these, MPDZ variants have been reported to cause severe ventriculomegaly inherited in an autosomal recessive manner (OMIM#615219). Several hypotheses have been put forward linking MPDZ variants to ventriculomegaly, but the precise underlying mechanisms, in particular whether its origin is obstructive or non-obstructive, are yet to be elucidated. Methods: To address this question, we retrospectively analyzed pre- and postnatal neuro-imaging and neuropathological data for cases of ventriculomegaly in which MPDZ variants were found through exome or genome sequencing. We performed anti-MPDZ immunostaining on fetal brain samples. Results: We analyzed six cases (four fetuses and two children) of ventriculomegaly of variable severities with MPDZ variants. The precise analysis of brain MRI data, corroborated by fetopathological examinations, demonstrated an obstructive pattern of ventriculomegaly upstream from partial fusion of the thalami, also called diencephalosynapsis, with partial atresia of the third ventricle, which could extend to Sylvius’s aqueduct. Conclusions: The morphological analysis using targeted brain magnetic resonance imaging (MRI) and neuropathological data allowed us to unravel the underlying mechanisms of congenital ventriculomegaly related to MDPZ variants.