LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions

Helle Lybæk, Michael Robson, Nicole de Leeuw, Jayne Y. Hehir-Kwa, Aaron Jeffries, Bjørn Ivar Haukanes, Siren Berland, Diederik de Bruijn, Stefan Mundlos, Malte Spielmann, Gunnar Houge

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

7 Citaten (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)421-433
Aantal pagina's13
TijdschriftAutism Research
Nummer van het tijdschrift3
StatusGepubliceerd - mrt. 2022


  • LRFN5
  • SALM5
  • TAD structure
  • allelic interaction
  • autism
  • chromatin structure
  • epigenetics
  • epigenomics


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