Table 2

Variants identified in additional genes

Patient no.GeneDNA changeProtein effectPolyPhen-2SIFTClassgnomAD allele frequencyMolecular functionRNA expression in human β-cells (RPKM)*
43CASP10c.104delp.Asp35Valfs*104Protease0.2
44DACH1c.454_456dupp.Ser152dup4DNA binding6.9
45GCKRc.1484T>Gp.Val495Gly0.9604Carbohydrate binding0.1
6HGFACc.711C>Gp.Cys237Trp1040.00026Protease0
46HGFACc.711C>Gp.Cys237Trp1040.00026Protease0
18KCNQ1c.498C>Ap.Phe166Leu0.9670.054Potassium channel0.3
47MC4Rc.230C>Tp.Ser77Leu0.85504G-protein–coupled receptor0
48RFX2c.1894G>Ap.Ala632Thr0.99904DNA binding3.9
49RREB1c.3218C>Tp.Ser1073Leu0.9880.024DNA binding9
50SLC5A1c.932A>Tp.Lys311Met0.99904Glucose:sodium symporter3.5
51SLC5A1c.1415T>Cp.Leu472Pro0.89204Glucose:sodium symporter3.5
52SLC5A1c.1415T>Cp.Leu472Pro0.89204Glucose:sodium symporter3.5
53TMPRSS6c.2263A>Gp.Lys755Glu0.9980.014Peptidase4.4
54ZBED3c.211C>Gp.Leu71Val0.97704DNA binding8.3
  • Summary of all class 4 (likely pathogenic) variants identified in genes not yet associated with MD. Classification of the variants according to the methodology of Richards et al. (12). PolyPhen-2 score considered pathogenic if >0.47 and SIFT <0.05. gnomAD, Genome Aggregation Database; RPKM, reads per kilobase per million mapped reads.

  • * Nica et al. (13).

  • †The variants in the HGFAC and KCNQ1 genes are not likely to be causative for diabetes because the two identified carriers also had a GCK variant and a classical GCK diabetes phenotype. The HGFAC variant may also be considered to be too frequent in the gnomAD database to be an MD variant (26).