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This summary describes the association between ADGRL3 and Attention Deficit Hyperactivity Disorder (ADHD) (MONDO_0007743). Multiple independent case‐reports, family‐based studies, and functional assessments support ADGRL3 as a susceptibility gene for ADHD. The evidence has emerged from both single patient evaluations with copy number variants and larger scale association studies using single nucleotide polymorphisms, providing convergent support for the gene–disease relationship (PMID:31426340).
The clinical validity is rated as Strong based on evidence from over 113 nuclear families (with a cumulative count of affected relatives estimated at 19 (PMID:31426340)) showing significant association signals. In addition, segregation analysis in family‐based studies along with reproducible experimental data from animal models further underpin the genetic association. This multi‐dimensional evidence confirms that ADGRL3 disruptions contribute to disease risk.
Genetic evidence includes the detection of risk alleles in ADGRL3 by several independent studies. One multi‐patient study used family‐based association tests across 386 individuals to identify significant associations of ADGRL3 single nucleotide polymorphisms and copy number variants with ADHD. A representative variant identified in the genetic screening is reported as c.772_790del (p.Ser258TrpfsTer39). This variant is illustrative of the spectrum observed, which includes missense and regulatory variants that likely modify gene expression and protein function (PMID:31426340).
Functional studies have provided moderate but important experimental support. Null mutant mice have demonstrated altered monoamine signaling and a hyperactive phenotype consistent with ADHD, and cellular studies using FLRT3 interference further indicate that ADGRL3 plays a role in synaptic development and connectivity (PMID:22575564; PMID:22405201). These experiments underscore a plausible mechanism of pathogenicity through disrupted neuronal signaling.
While some reports have focused on alternative neuropsychiatric conditions such as autism spectrum disorder, the genetic data for ADHD has been consistently replicated across independent cohorts, and no robust counter‐evidence has been presented to dispute the association with ADHD. Notably, the functional data align with the genetic findings, solidifying the role of ADGRL3 as a key contributor to ADHD susceptibility.
In conclusion, the integration of genetic and functional evidence provides a coherent narrative that ADGRL3 is strongly associated with ADHD. Further studies may extend these findings, but the current evidence supports clinical use in diagnostic decision‑making and patient stratification.
Key Take‑home Sentence: ADGRL3 represents a validated genetic contributor to ADHD risk, with compelling supporting evidence from multi‐family genetic association studies and functional assessments.
Gene–Disease AssociationStrongAssociation supported by family‐based studies in 113 nuclear families involving 386 individuals and consistent replication across independent cohorts (PMID:31426340), alongside concordant functional mouse model data. Genetic EvidenceStrongMultiple risk variants, including CNVs and SNPs in ADGRL3, have been identified in ADHD cohorts, with quantitative evidence from family‐based association studies indicating significant contribution to disease susceptibility (PMID:31426340). Functional EvidenceModerateExperimental assessments in ADGRL3 null mice and studies on synapse development demonstrate functional disruptions that mirror ADHD phenotypes (PMID:22575564; PMID:22405201). |