A novel variant in NEUROD2 in a patient with Rett-like phenotype points to Glu130 codon as a mutational hotspot

• Published in: Brain & development (Tokyo. 1979) Vol. 45; no. 3; pp. 179 - 184
• Main Authors: POLITANO, Davide, GANA, Simone, PEZZOTTI, Elena, BERARDINELLI, Angela, PASCA, Ludovica, Carmen BARBERO, Veronica, PICHIECCHIO, Anna, Maria VALENTE, Enza, ERRICHIELLO, Edoardo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-03-2023
• Subjects: Autism Spectrum Disorder - genetics; Autism spectrum disorders (ASD); Basic Helix-Loop-Helix Transcription Factors - genetics; bHLH transcription factor; Codon; Developmental delay (DD); Dominant negative (DN); Epilepsy, Generalized - genetics; Exome sequencing (ES); Humans; Intellectual disability (ID); Intellectual Disability - genetics; Mutation - genetics; NEUROD2; Neuropeptides - genetics; Phenotype; Rett syndrome (RTT); Rett Syndrome - diagnosis; Rett Syndrome - genetics; NEUROD2; Intellectual disability (ID); bHLH transcription factor; Exome sequencing (ES); Rett syndrome (RTT); Autism spectrum disorders (ASD); Developmental delay (DD); Dominant negative (DN)
• ISSN: 0387-7604; 1872-7131
• DOI: 10.1016/j.braindev.2022.11.004

NEUROD2, encoding the neurogenic differentiation factor 2, is essential for neurodevelopment. To date, heterozygous missense variants in this gene have been identified in eight patients (from six unrelated families) with epileptic encephalopathy and developmental delay.
We describe a child with initial clinical suspicion of Rett/Rett-like syndrome, in whom exome sequencing detected a novel de novo variant (c.388G > A, p.Glu130Lys) in NEUROD2. Interestingly, a missense change affecting the same codon, c.388G > C (p.Glu130Gln), was previously identified in other two patients.
Our results suggest that Glu130 might represent a potential mutational hotspot of NEUROD2. Furthermore, the clinical findings (especially the absence of clinically overt seizures) strengthen the NEUROD2-phenotypic spectrum, implying that developmental delay may also manifest isolatedly. We suggest inclusion of NEUROD2-associated developmental and epileptic encephalopathies (DEEs) in the differential diagnosis of atypical Rett syndrome as well as gene panels related to autism spectrum disorder.