Variants in LRRC7 lead to intellectual disability, autism, aggression and abnormal eating behaviors.

Researchers found that changes in a specific gene called LRRC7 cause intellectual disability, autism, ADHD, aggression, and eating problems in children. They studied 33 people with these gene changes and found they all had similar symptoms. The gene makes a protein that helps brain cells communicate properly. When the gene doesn't work correctly, it affects learning, behavior, and sometimes leads to overeating and weight gain.

This study identified 33 individuals with neurodevelopmental disorders caused by genetic variants in the LRRC7 gene, which encodes Densin-180, a protein crucial for brain cell communication. The research demonstrated that these genetic changes lead to intellectual disability, autism, ADHD, aggressive behaviors, and eating problems including obesity in some cases. Laboratory studies revealed that the genetic variants disrupt the protein's normal function at brain synapses and interfere with its interactions with other important proteins. This represents the largest cohort described for LRRC7-related disorders and establishes it as a significant genetic cause of neurodevelopmental conditions with specific behavioral presentations.

LRRC7 genetic testing should be considered for individuals with intellectual disability, autism, and aggressive behaviors, particularly when accompanied by eating problems. Results support genetic counseling for families and may inform targeted behavioral interventions for hyperphagia and aggression management.

Study does not specify exact sample size methodology or control groups. Functional studies were conducted in laboratory systems rather than human tissue. Long-term outcomes and detailed behavioral assessments are not described in the abstract.

Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca/calmodulin-dependent protein kinase II. We have previously observed an association between high impact variants in LRRC7 and Intellectual Disability; also three individual cases with variants in LRRC7 had been described.

We identify here 33 individuals (one of them previously described) with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in LRRC7. The clinical spectrum involves intellectual disability, autism, ADHD, aggression and, in several cases, hyperphagia-associated obesity. A PDZ domain variant interferes with synaptic targeting of Densin-180 in primary cultured neurons. Using in vitro systems (two hybrid, BioID, coimmunoprecipitation of tagged proteins from 293T cells) we identified new candidate interaction partners for the LRR domain, including protein phosphatase 1 (PP1), and observed that variants in the LRR reduced binding to these proteins.

We conclude that LRRC7 encodes a major determinant of intellectual development and behaviour.