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

Lybaek, H., Robson, M., de Leeuw, N., Hehir-Kwa, J. Y., Jeffries, A., Haukanes, B. I., et al. (2022). LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions. Autism Research, 15(3), 421-433. doi:10.1002/aur.2677.

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Autism Res_Lybæk et al_2022.pdf (Publisher version), 2MB
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Lybaek, Helle , Author
Robson, Michael , Author
de Leeuw, Nicole , Author
Hehir-Kwa, Jayne Y. , Author
Jeffries, Aaron , Author
Haukanes, Bjørn Ivar , Author
Berland, Siren , Author
de Bruijn, Diederik , Author
Mundlos, Stefan1, Author              
Spielmann, Malte, Author
Houge, Gunnar , Author
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Free keywords: allelic interaction, autism, chromatin structure, epigenetics, epigenomics,LRFN5, SALM5, TADstructure
 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.

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Language(s): eng - English
 Dates: 2022-01-112022-01-282022-03
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1002/aur.2677
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Title: Autism Research
Source Genre: Journal
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Publ. Info: Hoboken, NJ, USA : Wiley
Pages: - Volume / Issue: 15 (3) Sequence Number: - Start / End Page: 421 - 433 Identifier: ISSN: 1939-3792
CoNE: https://pure.mpg.de/cone/journals/resource/1939-3792