Background The neurodevelopmental prognosis of anomalies of the corpus callosum (ACC), one of the most frequent brain malformations, varies extremely, ranging from normal development to profound intellectual disability (ID). Numerous genes are known to cause syndromic ACC with ID, whereas the genetics of ACC without ID remains poorly deciphered.
Methods Through a collaborative work, we describe here ZEB1, a gene previously involved in an ophthalmological condition called type 3 posterior polymorphous corneal dystrophy, as a new dominant gene of ACC. We report a series of nine individuals with ACC (including three fetuses terminated due to ACC) carrying a ZEB1 heterozygous loss-of-function (LoF) variant, identified by exome sequencing.
Results In five cases, the variant was inherited from a parent with a normal corpus callosum, which illustrates the incomplete penetrance of ACC in individuals with an LoF in ZEB1. All patients reported normal schooling and none of them had ID. Neuropsychological assessment in six patients showed either normal functioning or heterogeneous cognition. Moreover, two patients had a bicornuate uterus, three had a cardiovascular anomaly and four had macrocephaly at birth, which suggests a larger spectrum of malformations related to ZEB1.
Conclusion This study shows ZEB1 LoF variants cause dominantly inherited ACC without ID and extends the extraocular phenotype related to this gene.
- Genetics, Medical
- Nervous System Malformations
Data availability statement
Data are available upon reasonable request.
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SH and EA contributed equally.
Contributors SH and EA contributed equally. SH is the guarantor of this study. Analysis and interpretation of data and drafting/revising the manuscript—SH, EA, DH and CD. Study concept and design, acquisition, analysis and interpretation of data, study supervision and coordination, and revising the manuscript—DH, CD and ES. Acquisition of data and revising the manuscript—SV, LB, NR, CM, CN, BK, KG, AF, AG, CG, EB, AR, DG, LM, LR, TA-B and CL.
Funding This work was supported by an NIH grant (R01NS058721).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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