Recessive loss-of-function and dominant gain-of-function variants in FBXO31 are associated with distinct neurodevelopmental disorders
- 1Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
Abstract
FBXO31 encodes the substrate receptor of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that recognizes C-terminal amide-bearing proteins (CTAPs) and targets them for proteasomal degradation, a function of particular importance in neurons. A recurrent de novo missense variant, c.1000G>A p.(Asp334Asn), reprograms FBXO31 substrate specificity and causes an autosomal-dominant neurodevelopmental disorder with spastic cerebral palsy through a neomorphic gain-of-function mechanism. By contrast, biallelic loss of function has tentatively been linked to a recessive disorder. Here we report a female patient, born to consanguineous parents, with moderate intellectual disability, developmental delay and dysmorphic features, who carries a homozygous ~54 kb deletion removing exons 2-8 and the coding part of exon 9 of FBXO31. The deletion retains only the exon 1-encoded F-box domain, while removing the coding sequence for the entire C-terminal substrate-recognition region. It is predicted to result in loss of function. Segregation is consistent with autosomal-recessive inheritance, with both parents and three of five unaffected siblings being heterozygous carriers. Together with two previously reported recessive families and the experimentally established neomorphic action of p.(Asp334Asn), the homozygous deletion supports an FBXO31 allelic series comprising dominant gain of function and recessive biallelic loss of function.
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BibTeX
@misc{boehnlein2026recessive,
title = {{Recessive loss-of-function and dominant gain-of-function variants in FBXO31 are associated with distinct neurodevelopmental disorders}},
author = {J. Boehnlein and B. Weiss and S. Hirsch and J. G. Maass and K. Obeid and K. Hinderhofer and S. Schroeder and B. Saemann and M. Hempel and S. Sailer},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.26363382},
url = {https://www.medrxiv.org/content/10.64898/2026.09.24.26363382v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Recessive loss-of-function and dominant gain-of-function variants in FBXO31 are associated with distinct neurodevelopmental disorders
AU - J. Boehnlein
AU - B. Weiss
AU - S. Hirsch
AU - J. G. Maass
AU - K. Obeid
AU - K. Hinderhofer
AU - S. Schroeder
AU - B. Saemann
AU - M. Hempel
AU - S. Sailer
PY - 2026
DA - 2026/09/24
PB - medRxiv
DO - 10.64898/2026.09.24.26363382
UR - https://www.medrxiv.org/content/10.64898/2026.09.24.26363382v1
AB - FBXO31 encodes the substrate receptor of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that recognizes C-terminal amide-bearing proteins (CTAPs) and targets them for proteasomal degradation, a function of particular importance in neurons. A recurrent de novo missense variant, c.1000G>A p.(Asp334Asn), reprograms FBXO31 substrate specificity and causes an autosomal-dominant neurodevelopmental disorder with spastic cerebral palsy through a neomorphic gain-of-function mechanism. By contrast, biallelic loss of function has tentatively been linked to a recessive disorder. Here we report a female patient, born to consanguineous parents, with moderate intellectual disability, developmental delay and dysmorphic features, who carries a homozygous ~54 kb deletion removing exons 2-8 and the coding part of exon 9 of FBXO31. The deletion retains only the exon 1-encoded F-box domain, while removing the coding sequence for the entire C-terminal substrate-recognition region. It is predicted to result in loss of function. Segregation is consistent with autosomal-recessive inheritance, with both parents and three of five unaffected siblings being heterozygous carriers. Together with two previously reported recessive families and the experimentally established neomorphic action of p.(Asp334Asn), the homozygous deletion supports an FBXO31 allelic series comprising dominant gain of function and recessive biallelic loss of function.
ER -