Heterozygous variants in SPTBN1 cause intellectual disability and autism

Abstract

Spectrins are common components of cytoskeletons, binding to cytoskeletal elements and the plasma membrane, allowing proper localization of essential membrane proteins, signal transduction, and cellular scaffolding. Spectrins are assembled from α and β subunits, encoded by SPTA1 and SPTAN1 (α) and SPTB, SPTBN1, SPTBN2, SPTBN4, and SPTBN5 (β). Pathogenic variants in various spectrin genes are associated with erythroid cell disorders (SPTA1, SPTB) and neurologic disorders (SPTAN1, SPTBN2, and SPTBN4), but no phenotypes have been definitively associated with variants in SPTBN1 or SPTBN5. Through exome sequencing and case matching, we identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities). Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset. Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis. Our findings support the essential roles of SPTBN1 in human neurodevelopment and expand the knowledge of human spectrinopathy disorders.

Keywords: SPTBN1; neurodevelopmental disorder; spectrin; spectrinopathy.

Figure 1.. Location of identified variants within SPTBN1 protein domains.

(A) Schematic of βII spectrin illustrating location of protein domains and variants, with coding variants above the schematic and predicted splicing variants shown below. Red circles indicate predicted loss-of-function variants, while purple circles indicate missense variants. Two previously reported de novo variants indentified in males with autism spectrum disorder (Iossifov et al., 2014) are represented by gray, italicized text. CH = calponin homology domain; PH = plekstrin homology domain; aa = amino acids. (B) Residues affected by missense variants in individuals 1 and 2 are conserved across vertebrate species (obtained from UCSC Genome Browser, genome.ucsc.edu). (C-D) Visualization of wild-type aspartic acid at amino acid 1881 (light green, C) and its replacement by asparagine (light green, D). This residue is within the 15^th spectrin repeat, near the site of ankyrin binding. Visualization is from DynaMut (Rodrigues, Pires, & Ascher, 2018), based on the crystal structure of the 14^th-16^th spectrin repeats (3EDV from Protein Data Bank, rcsb.org). Crystal structure for the second calponin homology domain, where individual 1’s missense variant is located, was not available in Protein Data Bank.

Figure 2.. Physical features of individuals with SPTBN1 variants.

(A-B) Individual 1 at 25 years of age. Note broad forehead and tapered fingers. (C-D) Individual 5 at 4 years of age. Note flat nasal bridge, uplifted earlobes, and fetal finger pads. (E-G) Individual 6 at 10 years of age. Note suspected shortened fourth and fifth metacarpals, hypoplastic nails, and hypoplastic fifth toe. (H) Individual 7 at 4 years of age.