Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.
The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.
The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit–hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.
The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
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We thank all the affected individuals and families for their collaboration. Several authors of this publication are members of the European Reference Network for Developmental Anomalies and Intellectual Disability (ERN-ITHACA) ITHACA (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01–2016/739516). We thank Jette Rasmussen for graphical assistance and Cristina Guilera and Juanjo Martínez for technical assistance.
Funding information can be found in Supplementary text 2.
Informed written consent for genetic testing and publication of the clinical information including clinical pictures was obtained from the parents or the legal guardians of each individual according to the Declaration of Helsinki. The work carried out at the corresponding author’s (Z.T.) institution has been approved by the Regional Ethical Committee, Capital Region of Denmark (H15007871).
The authors declare no competing interests.
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Rodríguez-Palmero, A., Boerrigter, M.M., Gómez-Andrés, D. et al. DLG4-related synaptopathy: a new rare brain disorder. Genet Med (2021). https://doi.org/10.1038/s41436-020-01075-9