Identification of rare variants shared by two or more siblings with ASD following integration of whole genome sequencing data of 866 multiplex families from the iHART and MSSNG cohorts in Lee et al., 2025 identified shared rare variants in the FRRS1L gene in two families; CRISPR/Cas9 experiments demonstrated downregulation of FRRS1L expression by the chr9:111924882C>T family variant. Furthermore, behavioral tests of Frrs1l heterozygous knockout mice (Frrs1l+/-) in Lee et al., 2025 showed specific impairment of social novetly recognition without altering other behavioral phenotypes. A maternally-inherited loss-of-function variant in FRRS1L had previously been identified in one of two ASD-affected siblings from a multiplex family from the AGRE cohort in Cirnigliaro et al., 2023.
Molecular Function
This gene encodes a component of the outer-core of an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor protein in the brain. The encoded protein is thought to interact with inner-core components of the receptor, and play a role in the modulation of glutamate signaling. Homozygous variants in this gene are responsible for an autosomal recessive form of early infantile epileptic encephalopathy (DEE37; OMIM 616981).
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Shared rare genetic variants in multiplex autism families suggest a social memory gene under selection
The heterozygous Frrs1l mouse model shows a deficit in discrimination for social novelty. This heterozygote model show no phenotype in sociability, novel object discrimination, contextual fear memory. The model also shows typical locomotor activity in a novel environment.
References
Type
Title
Author, Year
Primary
Shared rare genetic variants in multiplex autism families suggest a social memory gene under selection
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Exon 3 of Frrs1l was deleted by insertion of the LacZ reporter gene, resulting in a frameshift (MRC stock EM:07313).
Allele Type: Knockout
Strain of Origin: Not specified
Genetic Background: C57BL/6N
ES Cell Line: Not specified
Mutant ES Cell Line: Model Source: Medical Research Council Harwell
Description: Frrs1l heterozygous knockout mice show no preference for novel conspecific, measured by interaction time and number of interactions, resulting in a lower discrimination index compared to wildtype mice.
