Novel de novo ZBTB20 mutations in three cases with Primrose syndrome and constant corpus callosum anomalies

Abstract

Corpus callosum (CC) is the major brain commissure connecting homologous areas of cerebral hemispheres. CC anomalies (CCAs) are the most frequent brain anomalies leading to variable neurodevelopmental outcomes making genetic counseling difficult in the absence of a known etiology that might inform the prognosis. Here, we used whole exome sequencing, and a targeted capture panel of syndromic CCA known causal and candidate genes to screen a cohort of 64 fetuses with CCA observed upon autopsy, and 34 children with CCA and intellectual disability. In one fetus and two patients, we identified three novel de novo mutations in ZBTB20, which was previously shown to be causal in Primrose syndrome. In addition to CCA, all cases presented with additional features of Primrose syndrome including facial dysmorphism and macrocephaly or megalencephaly. All three variations occurred within two out of the five zinc finger domains of the transcriptional repressor ZBTB20. Through homology modeling, these variants are predicted to result in local destabilization of each zinc finger domain suggesting subsequent abnormal repression of ZBTB20 target genes. Neurohistopathological analysis of the fetal case showed abnormal regionalization of the hippocampal formation as well as a reduced density of cortical upper layers where originate most callosal projections. Here, we report novel de novo ZBTB20 mutations in three independent cases with characteristic features of Primrose syndrome including constant CCA. Neurohistopathological findings in fetal case corroborate the observed key role of ZBTB20 during hippocampal and neocortical development. Finally, this study highlights the crucial role of ZBTB20 in CC development in human.

Expansion of the Primrose syndrome phenotype through the comparative analysis of two new case reports with ZBTB20 variants

“…PRIMS is a very rare genetic condition with variable but severe clinical presentations that include what appears to be a progressive form of muscle wasting, intellectual disability, brain calcification, calcified pinnae, and various dysmorphic features, some of which only occur later in life (Alby et al, ; Carvalho & Speck‐Martins, ; Cordeddu et al, ). PRIMS is caused by heterozygous missense variants in ZBTB20 .…”

“…PRIMS is caused by heterozygous missense variants in ZBTB20 . Over 60% of the variants reported are located in the ZnF domains of this gene, which are predicted to alter its binding affinity to DNA (Alby et al, ; Casertano et al, ; Cleaver et al, ; Cordeddu et al, ; Hersh et al, ; Mattioli et al, ). In agreement, both variants reported here affect the second ZnF domain of ZBTB20 , within which several other disease‐associated variants have been reported.…”

“…In 2014, Cordeddu and colleagues described heterozygous variants in ZBTB20 (most de novo) in eight patients previously diagnosed clinically with PRIMS. Thus far, there have been a total of 22 individuals with molecularly confirmed PRIMS reported in the literature (Alby et al, ; Casertano et al, ; Cleaver et al, ; Cordeddu et al, ; Grímsdóttir et al, ; Hersh et al, ; Mattioli et al, ; Stellacci et al, ).…”

Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation

“…Patient 4 underwent targeted sequencing of a panel of 423 genes that are associated with corpus callosum anomalies in France [22]. The approach to analysis and filtering of this panel has previously been described [24,25]. No other candidate variants were identified in the patient.…”

Primrose syndrome associated with unclassified immunodeficiency and a novel ZBTB20 mutation

“…A ZBTB20 disruption due to a de novo balanced translocation has also been identified in a patient with similar clinical features (Rasmussen et al, ). Finally, in 2014, de novo mutations in ZBTB20 were identified in patients presenting clinical features of Primrose syndrome (Cordeddu et al, ) and additional patients with ZBTB20 mutations have been reported to date (Alby et al, ; Casertano et al, ; Cleaver et al, ; Grimsdottir et al, ; Mattioli et al, ; Stellacci et al, ). Thus, ZBTB20 was established as a gene responsible for Primrose syndrome and 3q13.31 deletion syndrome.…”