Open AccessA biallelic SNIP1 Amish founder variant causes a recognizable neurodevelopmental disorder
Author(s) -
Zineb Ammous,
Lettie E. Rawlins,
Hannah Jones,
Joseph S Leslie,
Olivia Wenger,
Ethan M. Scott,
Jim Deline,
Tom Herr,
R. J. Evans,
Angela Scheid,
Joanna Kennedy,
Barry A. Chioza,
Ryan M. Ames,
Harold E. Cross,
Erik G. Puffenberger,
Lorna W. Harries,
Emma L. Baple,
Andrew H. Crosby
Publication year - 2021
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1009803
Subject(s) - biology , hypotonia , neurodevelopmental disorder , genetics , intellectual disability , gene , medical genetics
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.