To date, FBRSL1-related disorder has been reported in five individuals with congenital abnormalities and severe postnatal impairment with or without epilepsy; however, the full extent of the phenotypic and genotypic spectrum remains unclear. Previously reported cases involved small truncating variants apparently escaping nonsense-mediated decay, suggesting either a haploinsufficiency or a dominant-negative mechanism. We report the first case of a complex structural variant at the FBRSL1 locus, resulting in an additional, partially truncated copy of the gene, providing strong evidence for a dominant-negative mechanism. RNA-Seq supported the expression of the additional truncated gene copy.

The patient is an infant girl with a profound developmental and epileptic encephalopathy (DEE). The child presented at birth with intrauterine growth restriction, respiratory insufficiency, severe swallowing dysfunction, spasticity, contractures, optic nerve hypoplasia, facial dysmorphism, and atrial septal defect. She developed severe postnatal growth restriction with microcephaly and profound developmental impairment. She has a DEE with frequent neonatal focal seizures evolving to infantile epileptic spasms syndrome (IESS). Our patient has congenital abnormalities in common with previously reported cases, along with a profound DEE, not associated previously with FBRSL1. Our case expands both the phenotypic and genotypic spectrum of FBRSL1-related disorder.

IES has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Takeda Pharmaceuticals, UCB, Xenon Pharmaceuticals, Longboard Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova, Nutricia, Zuellig Pharma, Stoke Therapeutics, Eisai, Akumentis, Praxis; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin, Encoded Therapeutics, Stoke Therapeutics, Eisai, Longboard Pharmaceuticals; has served as an investigator for Anavex Life Sciences, Biohaven Ltd, Bright Minds Biosciences, Cerebral Therapeutics, Cerecin Inc, Cereval Therapeutics, Encoded Therapeutics, EpiMinder Inc, Epygenix, ES-Therapeutics, GW Pharma, Longboard Pharmaceuticals, Marinus, Neuren Pharmaceuticals, Neurocrine BioSciences, Ovid Therapeutics, Praxis Precision Medicines, Shanghai Zhimeng Biopharma, SK Life Science, Supernus Pharmaceuticals, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix, Zynerba; and has consulted for Care Beyond Diagnosis, Epilepsy Consortium, Atheneum Partners, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, BioMarin, Encoded Therapeutics, Biohaven Pharmaceuticals, Stoke Therapeutics, Praxis; and is a Non-Executive Director of Bellberry Ltd and a Director of the Australian Academy of Health and Medical Sciences. She may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc and licensed to various diagnostic companies; has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 & 2012900190 and PCT/AU2012/001321 (TECH ID:2012-009). The other authors have no relevant financial or non-financial interests to disclose.

LCV has received research support through an AUSiMED Lowy Paediatric Fellowship scholarship, and a Sima Weissman foundation scholarship. MFB, IES, MSH and SFB were supported by an MRFF Genomics Health Futures Mission Grant (2007707). IES was also supported by funding from the National Health and Medical Research Council of Australia (GNT1172897, GNT2010562, GNT2006841, GNT2033247) and Medical Research Future Foundation (GHFM76728). MB was supported by an NHMRC Investigator grant (1195236). This research was supported by the Commonwealth through an Australian Government Research Training Program Scholarship [DOI: https://doi.org/10.82133/C42F-K220]".

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

THis work was approved by the Austin Health Human Research Ethics Committee, Austin Health, Melbourne, Australia (study ID H2007/02961) and the Walter and Eliza Hall Human Research Ethics Committee (project G20/01)

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The raw data that support the findings of this study are not publicly available due to ethical restrictions and participant consent limitations. The dataset contains sensitive genomic information from an individual with a rare disease and their unaffected parents, for which informed consent was obtained only for use within the scope of this study. Requests for access to de-identified data will be considered on a case-by-case basis, subject to institutional ethics approval and a formal data sharing agreement. Enquiries should be directed to the corresponding author.