# A low frequency damaging SORCS2 variant identified in a family with ADHD compromises receptor stability and quenches activity

## TL;DR

A rare SORCS2 gene variant found in a family with ADHD disrupts receptor function and signaling, potentially contributing to ADHD risk.

## Contribution

Identification of a low-frequency SORCS2 variant that compromises receptor stability and BDNF signaling in ADHD.

## Key findings

- The SORCS2 variant causes abnormal receptor processing and localization.
- The variant disrupts BDNF signaling in a dominant negative manner.
- Rare missense variants in the Vps10p domain affect SorCS2 stability and function.

## Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder affecting 5% of children and 2.5% of adults worldwide. ADHD is considered a polygenic disorder caused by a combination of both common and rare risk variants, each with low individual effect size. The Vps10p domain receptor SorCS2 is involved in neuronal development and synaptic plasticity by modulating brain-derived neurotrophic factor (BDNF) signaling. We here describe the identification and characterization of a heterozygous damaging variant in the SORCS2 gene found in two members of a family with persistent ADHD. The SORCS2 variant results in an arginine to tryptophan substitution in the 10CC region of the extracellular Vps10p domain, leading to aberrant posttranslational receptor processing, subcellular localization and ligand binding. Furthermore, the variant abrogates BDNF signaling in a dominant negative manner. Biochemical analysis of additional rare missense variants from ADHD cohorts suggested that SorCS2 structural stability and function is susceptible to such variation in the Vps10p domain. Our findings provide insights into how low frequency damaging variants in SORCS2 may contribute to the risk of ADHD.