Fig. 1

Majority of SPOUT1/CENP-32 variants identified in affected individuals are located in the RNA methyltransferase domain of the protein and at amino acid residues intolerant to variation.

A Schematic of SPOUT1/CENP-32 at the exon level (NM_016390.4) and protein level (NP_057474.2) with positions of the variants identified in our cohort and the number of alleles in unrelated families identified for each variant. Missense variants are displayed in green, loss-function variants in black and the in-frame deletion in red. The single annotated domain in green is from Pfam and reflects the RNA methyltransferase domain. B Overlay of SPOUT1/CENP-32 variants identified in this cohort with the protein intolerance landscape of SPOUT1/CENP-32 from MetaDome. MetaDome analyses shows the mutation tolerance at each position of the protein, with red being intolerant, yellow is neutral and blue is tolerant¹⁰⁰. C–J Variable dysmorphic features were seen in 50% (14/28) individuals including high arched palate, prominent ears, upturned nostrils, tented upper lip and high forehead. C Subject: family G-II-1 at 1 year. D Subject: family G-II-1 at 9 years. E Subject: family G-II-2 at 6 years. F Subject: family L-II-1 at 8 years. G Subject: family L-II-2 at 1 year 4 months. H Subject: family M-V-2 at 4 years. I Subject: family N-IV-2 at 18 months. J Subject: family Q-II-1 at 9 years. Created in BioRender¹⁰¹.