PLXNA2 and LRRC40 as candidate genes in autism spectrum disorder.
Two new recessive genes—PLXNA2 and LRRC40—show disrupted expression and interaction in an ASD patient, warranting inclusion in genetic panels.
01Research in Context
What this study did
Doctors looked at one child with autism. They checked every gene in the child’s cells.
They found two broken genes, PLXNA2 and LRRC40. Both copies were bad, one from mom and one from dad.
What they found
The broken genes made warped proteins. The proteins did not talk to each other the right way.
This single case shows the genes could be new autism markers.
How this fits with other research
Arcebido et al. (2025) found only 3 in 10 kids with autism ever get any gene test. Adding PLXNA2 and LRRC40 to lab panels could catch more cases.
Szoko et al. (2017) warned that most protein studies are small and use blood, not brain. The new study keeps the same limit—one patient—so we need bigger checks.
Duan et al. (2020) sifted mouse brains and picked 15 other genes. Human PLXNA2 and LRRC40 now join that growing list.
Why it matters
You can ask the medical team if the child’s gene panel includes PLXNA2 and LRRC40. If it does not, request an update. One note in the chart could push the lab to add these two genes and help families get clearer answers.
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02At a glance
03Original abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD.
Autism research : official journal of the International Society for Autism Research, 2021 · doi:10.1002/aur.2502