Relevance to Autism

A de novo likely gene-disruptive (LGD) variant in the ITSN1 gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017), while de novo damaging missense variants (defined by CADD score 25) in this gene were observed in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014) and in two ASD probands from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA in Feliciano et al., 2019 identified ITSN1 as an ASD candidate gene with a false discovery rate between 0.01 and 0.05 (0.01 < FDR 0.05). Rare singleton inherited LGD variants in the ITSN1 gene were also identified in ASD probands from the SPARK cohort and the Simons Simplex Collection (Krumm et al., 2015; Feliciano et al., 2019). Bruel et al., 2021 described the clinical presentation of 10 individuals from 8 families with heterozygous ITSN1 variants, all of whom presented with a neurodevelopmental disorder characterized by global developmental delay and delayed speech and language development; additional neurodevelopmental disorders such as autism spectrum disorders (90%), intellectual disability (86%), ADHD (50%), and epilepsy (30%) were also observed in this cohort. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified ITSN1 as a gene reaching exome-wide significance (P < 2.5E-06); association of ITSN1 with ASD risk was primarily driven by rare inherited loss-of-function variants.

Molecular Function

The protein encoded by this gene is a cytoplasmic membrane-associated protein that indirectly coordinates endocytic membrane traffic with the actin assembly machinery. In addition, the encoded protein may regulate the formation of clathrin-coated vesicles and could be involved in synaptic vesicle recycling.

External Links

References