Clinical and molecular characterization of 1q43q44 deletion and corpus callosum malformations: 2 new cases and literature review

Abstract

Background Corpus callosum malformations (CCM) represent one of the most common congenital cerebral malformations with a prevalence of around one for 4000 births. There have been at least 230 reports in the literature concerning 1q43q44 deletions of varying sizes discovered using chromosomal microarrays. This disorder is distinguished by global developmental delay, seizures, hypotonia, corpus callosum defects, and significant craniofacial dysmorphism. In this study, we present a molecular cytogenetic analysis of 2 Tunisian patients with corpus callosum malformations. Patient 1 was a boy of 3 years old who presented psychomotor retardation, microcephaly, behavioral problems, interventricular septal defect, moderate pulmonary stenosis, hypospadias, and total CCA associated with delayed encephalic myelination. Patient 2 was a boy of 9 months. He presented a facial dysmorphia, a psychomotor retardation, an axial hypotonia, a quadri pyramidal syndrome, a micropenis, and HCC associated with decreased volume of the periventricular white matter. Both the array comparative genomic hybridization and fluorescence in situ hybridization techniques were used. Results Array CGH analysis reveals that patient 1 had the greater deletion size (11,7 Mb) at 1q43. The same region harbors a 2,7 Mb deletion in patient 2. Here, we notice that the larger the deletion, the more genes are likely to be involved, and the more severe the phenotype is likely to be. In both patients, the commonly deleted region includes six genes: PLD5, AKT3, ZNF238, HNRNPU, SDCCAG8 and CEP170. Based on the role of the ZNF238 gene in neuronal proliferation, migration, and cortex development, we hypothesized that the common deletion of ZNF238 in both patients seems to be the most responsible for corpus callosum malformations. Its absence may directly cause CCM. In addition, due to their high expression in the brain, PLD5 and FMN2 could modulate in the CCM phenotype. Conclusion Our findings support and improve the complex genotype–phenotype correlations previously reported in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of several genes related to this pathology.

HNRNPU's multi‐tasking is essential for proper cortical development

“…[3] Subsequent studies, including recent ones, identified over 200 additional patients displaying a broad phenotypic spectrum. [4][5][6][7][8][9] Typical clinical features, including developmental delay, intellectual disability, growth retardation, microcephaly, facial dysmorphisms, and congenital heart defects, have been noted.…”

Transcription factors in microcephaly

“…ZNF238 , also known as RP58 encodes a highly conserved (95% homology in the amino acid sequences between humans and mice) transcription factor containing four zinc finger domains (responsible for DNA binding) and a BTB/POZ domain (multifaceted protein–protein interaction motif) (Aoki et al, 1998 ; Tatard et al, 2010 ). Deletion of the distal arm of human chromosome-1q, termed “1qter deletion,” “1q4 deletion,” or “terminal 1q deletion”, is linked to microcephaly with agenesis of the corpus callosum (Boland et al, 2007 ; Hill et al, 2007 ; Bon et al, 2008 ), and the patients carrying this deletion have severe intellectual disability and short stature with profound growth defects (Khadija et al, 2022 ). A critical region contains a handful of genes, including ZNF238 (Boland et al, 2007 ; Hill et al, 2007 ; Bon et al, 2008 ; Orellana et al, 2010 ).…”

“…2p25.2 Congenital (Tsurusaki et al, 2014;Hempel et al, 2016;Wakim et al, 2020) Growth deficiency, intellectual disability, characteristic facial features, and hypoplastic nails of the fifth fingers and/or toes Coffin-Siris syndrome Zinc finger ZNF238 * 1q44 Congenital and postnatal (Boland et al, 2007;Hill et al, 2007;Bon et al, 2008;Orellana et al, 2010;Khadija et al, 2022) Severe intellectual disability, profound growth defects, short stature, agenesis of corpus callosum, dysmorphic facial features 1qter deletion syndrome…”