Fig. 2

Statistics of the mutation sites on the SMPD1 gene. A Distribution of the patients by onset age. F, female. M, male. B Country of origin of the patients: Mediterranean countries, including Italy, Algeria, Spain, Turkey, Maghreb, Jordan, and North Africa; Asian countries, such as China and Japan; European countries, such as Caucasian (documented by the research), Poland, Gypsy (documented by the research), and the Netherlands; Middle East countries including Iran and Palestine. C Amino acid mutation frequency in all collected cases. D SMPD1 mutation types (do not include all mutations). Severe mutations include deletions, insertions, and nonsense. E SMPD1 mutation distribution in domains of ASM domains in each subtype of NPD. A, NPA. AB, intermediate NPD subtype. B, NPB. F Distribution of missense mutations on the conserved domain of the human ASM protein. Each point represents one reported mutation in the collected cases. Points are coloured according to the domains. G The landscape of SMPD1 mutations and 21 novel pathogenic variants prediction based on the databases of ClinVar, ANNOVAR and the EVE model. Purple squares, novel predicted pathogenic variants. Orange triangles, pathogenic/likely pathogenic variants from the ClinVar. Domains were annotated by NCBI. Please note: in A, E panels, A, NPA. AB, intermediate. B, NPB. In D, F, and G, domains were retrieved from the NCBI (NP_000534.3), namely, saposin (B) (smart00741, Location: 89 → 161), metallophosphatase domain (cd00842, Location: 202 → 497) and Calcineurin-like phosphoesterase domain (Metallophos for short, pfam00149, Location: 255 → 462)