Through WES (Whole Exome Sequencing) analysis, a mutation in the HMBS gene (exon 10, c.651G>C, p.Gln217His) was detected in the patient. Sanger sequencing confirmed the presence of this mutation in the patient’s father and brother (as shown in Figure 2 for validation of the mutation and wild-type results), although both of them were asymptomatic. It is presumed that this variant originated from the patient’s father, as depicted in the pedigree chart (see Figure 2). This mutation was not found in normal population databases (1000Genome, MutIn Database, ESP6500, ExAC); it has not been cataloged in ClinVar database yet. The REVEL software assigned a score of 0.979 (>0.75 indicates predicted pathogenicity), while ClinPred gave a score of 0.9998 (>0.5 indicates predicted pathogenicity). According to MutationTaster prediction, this variant is considered pathogenic (score=1) and shows conservation characteristics (see Figure 2). Protein function predictions using SIFT and PolyPhen-2 software both suggest its pathogenicity. Structural modeling using the 3EQ1 model (https://www.rcsb.org/structure/3EQ1) successfully demonstrated changes in protein structure (Figure 2). Furthermore, reports on the association of this mutation with the Chinese population have also been found. According to ACMG guidelines, it is considered a likely pathogenic variant.
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