Figure 1.

WES Analysis Reveals GIIα p.Arg422Leu (c.1265G>T) in Family M263 as the Likely Pathogenic Variant

(A) Pedigree of family M263 shows that the two affected individuals (I-1 and II-1, shaded in black) have the GIIα p.Arg422Leu (p.R422L) missense variant resulting from c.1256G>T in exon 12, but the unaffected daughter (II-2, for whom no cysts were detected on ultrasound at 30 years of age) does not.

(B) GenomeBrowse (SVS, Golden Helix) view of the WES results from II-1 show GANAB variant c.1265G>T (reverse strand), and details of the reads are tabulated below.

(C) Sanger sequencing confirmation of heterozygous GIIα variant p.Arg422Leu (p.R422L) (c.1256G>T) in II-1. The WT is shown for comparison.

(D) MSA of GIIα orthologous proteins shows invariance of Arg422 from humans to yeast. In silico analysis of the likely pathogenicity of GIIα p.Arg422Leu (p.R422L) shows variant scores (SIFT = 0.00, Align GVGD = C65) characteristic of a highly likely pathogenic mutation.

(E) MSA of related glucosidases GANC (neutral alpha-glucosidase C) and GAA (lysosomal alpha-glucosidase) of various eukaryotic species and prokaryotic GH31 (glycosyl hydrolase family 31) shows invariant conservation of GIIα Arg422.

(F) CT scan with contrast of kidneys and liver of individual I-1 at 66 years shows a few large kidney cysts (red arrows) and multiple scattered liver cysts (green arrows).

(G) T2-weighted MRI of II-1 at 41 years shows a few kidney (red arrows) and liver (green arrows) cysts.