2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-A Homozygous POU3F2 Polyproline Tract Expansion Is Associated with Severe Psychomotor Delay, Developmental and Epileptic Encephalopathy, and Ichthyosis

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Researchers have identified a homozygous POU3F2 polyproline tract expansion as a potential cause of severe developmental and epileptic encephalopathy (DEE) and ichthyosis. POU3F2 is a key neuronal transcription factor, and previous studies have shown that knockout of POU3F2 in animal models leads to abnormal neurogenesis and early mortality. In mice, the loss of its highly conserved homopolymeric amino acid repeats has been linked to behavioral and cognitive impairment, as well as reduced hippocampal neurogenesis. However, few cases of POU3F2-related diseases in humans have been reported.<br /><br />In this study, twins who were homozygous for a proline expansion in the polyproline tract of POU3F2 were found to have severe DEE and primary ichthyosis. The researchers also studied the transcriptional activity of the mutant POU3F2 and found that it was unable to regulate certain target genes involved in brain development, such as BMP4 and HOXB2. Additionally, the mutant POU3F2 overexpression led to the regulation of genes involved in the Wnt signaling pathway and synapse organization, suggesting a potential gain of function mechanism.<br /><br />The authors highlight the importance of this finding, as it represents the first biallelic POU3F2-related disorder and the first proline repeat expansion human disease reported to their knowledge. They emphasize the need for identifying additional cases to confirm their findings.<br /><br />Overall, this study provides insights into the role of POU3F2 in neuronal development and highlights its potential contribution to severe developmental and epileptic encephalopathy and ichthyosis.

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Presenting Author - Camille Tremblay-Laganière, MD, MSc; Co-Author - Sophie Ehresmann, Mrs, MSc; Co-Author - Alina Levtova, MD; Co-Author - Julie Gauthier, PhD; Co-Author - He Fu, MSc; Co-Author - Robert J. McEvilly, MD; Co-Author - Michael G. Rosenfeld, PhD; Co-Author - Elisabeth Simard-Tremblay, MD; Co-Author - Isabelle DeBie, MD; Co-Author - Jean-Francois Soucy, MD; Co-Author - Jacques L. Michaud, MD; Co-Author - Emmanuelle Lemyre, MD; Co-Author - Philippe M. Campeau;

Meta Tag

Brain/Nervous System

Identification of Disease Genes

Intellectual disability

Triplet and Other Repeats

Co-Author Sophie Ehresmann, Mrs, MSc

Co-Author Alina Levtova, MD

Co-Author Julie Gauthier, PhD

Co-Author He Fu, MSc

Co-Author Robert J. McEvilly, MD

Co-Author Michael G. Rosenfeld, PhD

Co-Author Elisabeth Simard-Tremblay, MD

Co-Author Isabelle DeBie, MD

Co-Author Jean-Francois Soucy, MD

Co-Author Jacques L. Michaud, MD

Co-Author Emmanuelle Lemyre, MD

Co-Author Philippe M. Campeau

Presenting Author Camille Tremblay-Laganière, MD, MSc

Keywords

POU3F2 polyproline tract expansion

severe developmental encephalopathy

ichthyosis

neuronal transcription factor

abnormal neurogenesis

cognitive impairment

hippocampal neurogenesis

proline expansion

brain development

Wnt signaling pathway