Further evidence for de novo variants in SYNCRIP as the cause of a neurodevelopmental disorder

Abstract

SYNCRIP encodes for the Synaptotagmin‐binding cytoplasmic RNA‐interacting protein, involved in RNA‐binding and regulation of multiple cellular pathways. It has been proposed as a candidate gene for neurodevelopmental disorders (NDDs) with autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy. We ascertained genetic, clinical, and neuroradiological data of three additional individuals with novel de novo SYNCRIP variants. All individuals had ID. Autistic features were observed in two. One individual showed myoclonic‐atonic epilepsy. Neuroradiological features comprised periventricular nodular heterotopia and widening of subarachnoid spaces. Two frameshift variants in the more severely affected individuals, likely result in haploinsufficiency. The third missense variant lies in the conserved RNA recognition motif (RRM) 2 domain likely affecting RNA‐binding. Our findings support the importance of RRM domains for SYNCRIP functionality and suggest genotype‐phenotype correlations. Our study provides further evidence for a SYNCRIP‐associated NDD characterized by ID and ASD sporadically accompanied by malformations of cortical development and myoclonic‐atonic epilepsy.

aRgus: Multilevel visualization of non-synonymous single nucleotide variants & advanced pathogenicity score modeling for genetic vulnerability assessment

“…Furthermore, several pathogenicity scores could significantly discriminate between MVA subtypes and healthy individuals [23] . Additionally, the aRgus workflow could identify protein regions within functional domains that appear to be especially important in pathogenesis of a SYNCRIP -associated neurodevelopmental disorder and a gluconeogenesis defect caused by phosphoenolpyruvate carboxykinase deficiency [24] , [25] . For the latter two genes, this analysis was pivotal as only few disease-related variants had been previously reported and knowledge derived from the aRgus model might support future variant interpretation.…”

SYNCRIP controls miR-137 and striatal learning in animal models of methamphetamine abstinence

“…Only recently have the studies begun to uncover the behavioral functions of SYNCRIP. An animal model study showed that SYNCRIP controls starvation-induced hyperactivity in drosophila 64 , while a case report proposed that de novo variants in SYNCRIP is linked to neurodevelopmental disorders 65 . However, the association between SYNCRIP and behavioral functions as well as dysfunctions remains largely unclear to date.…”

Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism

“…Top family members have been reported to facilitate transcription of long genes linked to autism (King et al, 2013). Syncrip (−1.4) (SFARI list) (also known as Hnrnpg) encodes the synaptotagmin-binding cytoplasmic RNA-interacting protein, which is a candidate gene for ASD and ID (Rauch et al, 2012;Lelieveld et al, 2016;Semino et al, 2021). Bannai et al (2004) reported that Syncrip is a component of mRNA-containing granules in dendrites, possibly regulating local protein synthesis in developing dendritic spines.…”