A biallelic SNIP1 Amish founder variant causes a recognizable neurodevelopmental disorder

Abstract

SNIP1 (Smad nuclear interacting protein 1) is a widely expressed transcriptional suppressor of the TGF-β signal-transduction pathway which plays a key role in human spliceosome function. Here, we describe extensive genetic studies and clinical findings of a complex inherited neurodevelopmental disorder in 35 individuals associated with a SNIP1 NM_024700.4:c.1097A>G, p.(Glu366Gly) variant, present at high frequency in the Amish community. The cardinal clinical features of the condition include hypotonia, global developmental delay, intellectual disability, seizures, and a characteristic craniofacial appearance. Our gene transcript studies in affected individuals define altered gene expression profiles of a number of molecules with well-defined neurodevelopmental and neuropathological roles, potentially explaining clinical outcomes. Together these data confirm this SNIP1 gene variant as a cause of an autosomal recessive complex neurodevelopmental disorder and provide important insight into the molecular roles of SNIP1, which likely explain the cardinal clinical outcomes in affected individuals, defining potential therapeutic avenues for future research.

Development of the correlation between mitophagy-related genes and epilepsy

“…In the present study, we constructed a diagnostic model of epilepsy using 23 MRGs obtained from the peripheral blood of patients with epilepsy. The model showed good diagnostic performance, as evaluated by ROC analysis (AUC = 0.8912), which was superior to that of many other epilepsy diagnosis models [41][42][43][44] .…”

Snip1 and PRC2 coordinate intrinsic apoptosis, cell division, and neurogenesis in the developing brain

“…We previously showed that PRC2 maintains the self-renewal of NPCs by suppressing neurogenesis 60 . This study uncovered that Snip1 and PRC2 transcriptionally regulate cell cycle progression; this may be clinically relevant to developmental defects including skull dysplasia, global developmental delay, and intellectual disability and seizure that are associated with 1097A>G (Glu366Gly) variant of SNIP1 61,62 . Our findings about the Snip1–PRC2 interactions in NPC survival and functions improves our understanding about the neurodevelopmental disorders caused by SNIP1 mutations and PRC2 dysfunction.…”

“…Clinical relevance of the SNIP1 gene has been recently documented. Homozygous 1097A>G (Glu366Gly) variant on human SNIP1 has been linked to a neurodevelopmental disorder having clinical features including skull dysplasia, global developmental delay, and intellectual disability and seizure (Ammous et al, 2021; Puffenberger et al, 2012). Our findings on the Snip1-PRC2 interaction in suppressing apoptosis and promoting neural development in the developing brain hold promise for better understanding of the neurodevelopmental disorders caused by SNIP1 mutations and PRC2 dysregulation.…”

The clinical utilization of SNIP1 and its pathophysiological mechanisms in disease

“…Despite the prevalence of programmed cell death in development, the underlying mechanisms governing this process are not fully understood. Recent studies have highlighted the significance of SNIP1 in the viability of neural precursor cells and the generation of new neurons, underscoring its essential role in brain maturation [ 41 ]. Dysplasia and caspase 9-dependent apoptosis were significantly upregulated in the brain lacking SNIP1.…”