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| Item Type: | Article |
|---|---|
| Title: | LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions |
| Creators Name: | Lybaek, H., Robson, M., de Leeuw, N., Hehir-Kwa, J.Y., Jeffries, A., Haukanes, B.I., Berland, S., de Bruijn, D., Mundlos, S., Spielmann, M. and Houge, G. |
| Abstract: | LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism-susceptibility haplotype had a specific TAD pattern. We also found a male/female quantitative difference in the amount histone-3-lysine-9-associated chromatin around the LRFN5 gene itself (p < 0.01), possibly related to the male-restricted autism susceptibility. To better understand locus behavior, the prevalence of a 60 kb deletion polymorphism was investigated. Surprisingly, in three cohorts of individuals with DD (n = 8757), the number of deletion heterozygotes was 20%-26% lower than expected from Hardy-Weinberg equilibrium. This suggests allelic interaction, also because the conversions from heterozygosity to wild-type or deletion homozygosity were of equal magnitudes. Remarkably, in a control group of medical students (n = 1416), such conversions were three times more common (p = 0.00001), suggesting a regulatory role of this allelic interaction. Taken together, LRFN5 regulation appears unusually complex, and LRFN5 dysregulation could be an epigenetic cause of autism. LAY SUMMARY: LRFN5 is involved with communication between brain cells. The gene sits alone in a huge genomic niche, called the LRFN5 locus, of complex structure and high mammalian conservation. We have found that a specific locus structure increases autism susceptibility in males, but we do not yet know how common this epigenetic cause of autism is. It is, however, a cause that potentially could explain why higher-functioning autism is more common in males than females. |
| Keywords: | Allelic Interaction, Autism, Chromatin Structure, Epigenetics, Epigenomics, LRFN5, SALM5, TAD Structure, Animals, Mammals |
| Source: | Autism research |
| ISSN: | 1939-3792 |
| Publisher: | Wiley |
| Volume: | 15 |
| Number: | 3 |
| Page Range: | 421-433 |
| Date: | 16 March 2022 |
| Official Publication: | https://doi.org/10.1002/aur.2677 |
| PubMed: | View item in PubMed |
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