De Novo Pathogenic Variant in FBRSL1, Non OMIM Gene Paralogue AUTS2, Causes a Novel Recognizable Syndromic Manifestation with Intellectual Disability; An Additional Patient and Review of the Literature

Abstract

FBRSL1, together with FBRS and AUTS2 (Activator of Transcription and Developmental Regulator; OMIM 607270), constitutes a tripartite AUTS2 gene family. AUTS2 and FBRSL1 are evolutionarily more closely related to each other than to FBRS (Fibrosin 1; OMIM 608601). Despite its paralogous relation to AUTS2, FBRSL1's precise role remains unclear, though it likely shares functions in neurogenesis and transcriptional regulation. Herein, we report the clinical presentation with therapeutic approaches and the molecular etiology of a patient harboring a de novo truncating variant (c.371dupC) in FBRSL1, leading to a premature stop codon (p.Cys125Leufs*7). Our study extends previous knowledge by highlighting potential interactions and implications of this variant, alongside maternal and paternal duplications, for the patient's phenotype. Using sequence conservation data and in silico analysis of the truncated protein, we generated a predicted domain structure. Furthermore, our in silico analysis was extended by taking into account SNP array results. The extension of in silico analysis was performed due to the possibility that the coexistence of FBRSL1 truncating variant contemporary with maternal and paternal duplication could be a modifier of proband's phenotype and/or influence the novel syndrome clinical characteristics. FBRSL1 protein may be involved in neurodevelopment due to its homology with AUTS2, together with distinctive neuronal expression profiles, and thus should be considered as a potential modulation of clinical characteristics in a novel syndrome. Finally, considering that FBRSL1 is apparently involved in neurogenesis and in transcriptional regulatory networks that orchestrate gene expression, together with the observation that different genetic syndromes are associated with distinct genomic DNA methylation patterns, the specific episignature has been explored.

Keywords: FBRSL1 and AUTS2; neurodevelopment; polycomb complex.

Figure 1

“Pedigree” of index patient (III₁₁).

Figure 2

Patient at different periods of life: ~1 month (A), ~6 months (B) and ~48 months (C–L).

Figure 3

EEG (A) Awake polygraphic (bilateral deltoid muscles) video EEG, recorded with the internationally standardized 10–20 system: ictal EEG underlined in red shows diffuse high-voltage slow-wave complex followed by short voltage attenuation prevalent on both anterior regions. No real change in deltoids muscle tone. (B) Sleep polygraphic (bilateral deltoid muscles) interictal EEG, recorded with the internationally standardized 10–20 system, showed 2 Hz burst of spikes and spike-and-wave complexes prevalent on the bilateral fronto-central regions and midline.

Figure 4

Confirmation of the de novo variant in the proband by Sanger sequencing, and comparison of electropherograms between father, mother, and proband.

Figure 5

Predicted three-dimensional structures of FBRSL1, wild-type (panel A) and truncated proteins p.Cys125Leufs*7 (panel B). Highlighted in light blue space-filling mode is the predicted protein domain, which extends from the amino acid residues 81 to 93 capable of binding the amino acid residues of FBRSL1 in the same position. Highlighted in blue ball-and-stick mode are the specific amino acid residues (at the top right, 85, 86, 87, 90, 91, 92, 93 aa; on the bottom left, 81, 82, 83, 84, 87, 88, 89 aa) able to bind the light blue domain.

Figure 6

STITCH in silico analysis. Emphasized in yellow are the proteins involved in paternal duplication, while in red, the proteins involved in maternal duplication. Only a possible relationship between paternal protein NMD3 and maternal protein RPL15 was detected, as highlighted in the dotted rectangle.

Figure 7

EpiSign (DNA methylation) analysis of peripheral blood from a patient with a truncating FBRSL1 variant. (A) Hierarchical clustering and (B) multidimensional scaling plots indicate the patient (red) has a DNA methylation signature similar to controls (green) and distinct from cases with the PRC2 episignature (blue). (C) MVP score, a multi-class supervised classification system capable of discerning between multiple episignatures by generating a probability score for each episignature. The lack of elevated scores indicated the patient was similar to controls for all episignatures evaluated.