Abstracts

Rationale: Chromosome 1q41-q42 deletion syndrome is a rare cause of cognitive impairment and seizures with distinct facial dysmorphology. Brain anomalies are common as are growth and dental abnormalities, nail hypoplasia, finger and toe anomalies and contractures. Cleft palate, congenital diaphragmatic hernia, club feet and cardiac anomalies have also been observed. Most 1q41-q42 deletions encompass FBXO28, encoding F-box family protein 28. Two patients have been reported with FBXO28 sequence variants, one with limited phenotypic data and the other with features in keeping with 1q41-q42 deletion syndrome. We aimed to describe the phenotypic and genotypic characteristics of patients with FBXO28 developmental and epileptic encephalopathy (DEE) and their associated FBXO28 pathogenic sequence variants. Methods: Patients were collected from research and diagnostic genetic testing laboratories where single nucleotide variants or small indels in FBXO28 had been identified. Detailed phenotypic analysis of their clinical data was performed. Results: Five patients were identified with pathogenic variants in FBXO28 including 3 nonsense, 1 frameshift and 1 missense variants. Three variants arose de novo in the proband and the remaining two were inherited from an unaffected mosaic parent (2.5% and 6% alternate allele frequencies). Patients were aged 11 months – 25 years (median 9 years) at study; 2 patients had died. All patients had a developmental and epileptic encephalopathy; 3 patients had infantile spasms, 1 evolving to Lennox-Gastaut syndrome, 1 patient had multifocal DEE and the last had a progressive DEE. Three patients had developmental delay prior to seizure onset. Median age at seizure onset was 15 months (range 8 months – 4 years) and all patients developed multiple seizure types: tonic (3), myoclonic (2), focal (2) and GTCS (1). All patients have refractory epilepsy and movement disorders; hyperkinetic movements (2), choreoathetosis (2), dyskinesia (1), non-epileptic myoclonus (1), dystonia (1), irregular arm and truncal movements (1) and stereotypies (1). Four of 5 patients had profound developmental impairment, 2 had drooling and dysphagia, 2 were gastrostomy-tube fed and two patients had apnoea. None of the 5 patients had the dysmorphic features characteristic of 1q41-q42 deletion syndrome.Albeit small numbers, there appears to be a genotype-phenotype correlation in patients with FBXO28 sequence variants. Three patients with nonsense variants had a strikingly similar phenotype with onset of infantile spasms at 8-9 months, profound developmental impairment and movement disorders. Our 1 patient with a frameshift variant has refractory seizures with profound impairment and stereotypies, however seizure onset was later at 21 months. This patient has dysmorphic features (low set ears, hypertelorism, short palpebral fissures, acquired microcephaly and scoliosis) but these are not the characteristic dysmorphic features seen in patients with 1q41-q42 deletion syndrome. Our single patient with a missense variant had a much later seizure onset at 4 years and developed a progressive DEE resulting in death at 25 years. Conclusions: Pathogenic variants in FBXO28 cause DEE with severe to profound impairment, infantile spasms, movement disorders, feeding issues, apnoea, hypotonia, scoliosis and kyphosis. Most patients do not have the characteristic dysmorphic features associated with 1q41-q42 deletion syndrome. Thus, FBXO28 sequence variants should still be considered in patients without dysmorphic features. Funding: No funding