Skip to main content
. 2026 Jul 9;6(5):100507. doi: 10.1016/j.xjidi.2026.100507

Figure 2.

Figure 2

Genomic identification of familial MYH9 variants. (a) The human MYH9 gene (chromosome 22) transcribes a 7451 bp full-length mRNA (NM_002473), comprising 41 exons, 40 of which encode a canonical protein of 1960 amino acids known as NMHC IIA (nonmuscle myosin heavy chain II A), also referred to as Myosin-9 (UniProt P35579). The domain architecture of Myosin-9 includes an ATP-binding motif (residues 174–181); a myosin N-terminal SH3-like domain (residues 27–77, shown in green); a myosin motor domain (residues 83–764, shown in maroon); an IQ (Ile/Gln) motif (residues 783–799, shown in blue), typically found in proteins regulated by calcium/calmodulin signaling; and a myosin tail domain (residues 1067–1923, shown in cyan). Previously reported pathogenic variants (missense, deletions/insertions, and frameshifts) linked to MALTA are shown in green lollipops; red lollipops indicate newly identified variants identified in the proband. Below, a schematic of the 41 MYH9 exons aligned with the corresponding protein regions. (b) Representative sequencing chromatograms of gDNA from tumor and saliva samples from the proband and immediate family members. Detected variants are shown: c.1363G>A (p.Gly455Ser; exon 12), c.4490G>A (pArg1497Gln; exon 32), and c.4876A>G (pIle1626Val; exon 34). Black boxes highlight the variant positions, red arrows denote altered peak in the chromatogram, and blue arrow indicates a synonymous variant in exon 34 (c.4872G>T; p.Ala1624=). Codon positions are marked with solid black lines. Double peaks indicate heterozygosity. The MYH9 c.1363G>A (p.Gly455Ser), c.4490G>A (p.Arg1497Gln), and c.4876A>G (p.Ile1626Val) pathogenic variants were confirmed as heterozygous in both normal tissue and saliva, indicating that these are constitutional (germline) variants rather than somatic changes confined to the tumor. (c) Table summarizing the MYH9 variants identified in gDNA from saliva samples of all individuals in the pedigree, including corresponding protein changes, exon locations, and ClinVar accession numbers (if available). For each variant, the genotype (eg, G/A, G/G, G/A, G/T, A/G) is provided for the proband and first-degree relatives. (d) Pedigree chart illustrating inheritance patterns of 3 MYH9 variants across 2 generations (I and II). gDNA from saliva samples revealed that the father (I-1) carries the Gly455Ser and Ile1626Val pathogenic variants on the same allele, whereas the mother (I-2) carries the Arg1497Gln variant. The chart shows a Mendelian segregation pattern, with paternal inheritance of Gly455Ser and Ile1626Val and maternal inheritance of Arg1497Gln in both male offspring (II-1 and II-2). The proband (II-1) is indicated by an arrow. Variant distribution is shown using patterned fills: solid black for Gly455Ser and Ile1696Val and diagonal stripes for Arg1497Gln. Squares represent males; circles denote females. (e) Summary of MYH9 variants associated with MALTA (MYH9-associated elastin aggregation), MATINS (macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss), and DFNA (deafness, autosomal dominant 17) phenotypes, including those located in the coding region and reported in this work. References: (a) this work, (b) Fewings et al (2019), (c) Fostier et al (2023), (d) only included 6 hotspot pathogenic variants of 107 MATINS variants reported (Shen et al, 2024), and (e) Lalwani et al (2000). ATP, adenosine triphosphate; gDNA, genomic DNA.