Loss-of-function variants in cause dominant anomalies of the corpus callosum with favourable cognitive prognosis.

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 , 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 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 . 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 .

CONCLUSION

This study shows LoF variants cause dominantly inherited ACC without ID and extends the extraocular phenotype related to this gene.