A novel variant in GATM causes idiopathic renal Fanconi syndrome and predicts progression to end-stage kidney disease

Abstract

Renal Fanconi syndrome (RFS) is a generalised disorder of the proximal convoluted tubule. Many genes have been associated with RFS including those that cause systemic disorders such as cystinosis, as well as isolated RFS. We discuss the case of a 10-year-old female who presented with leg pain and raised creatinine on a screening blood test. Her mother has RFS and required a kidney transplant in her thirties. Further investigations confirmed RFS in the daughter. Exome sequencing was performed on the affected mother, child, and unaffected father. We identified a novel variant in GATM; c.965G>C p.(Arg322Pro) segregating dominantly in the mother and daughter. We validated our finding with molecular dynamics simulations and demonstrated a dynamic signature that differentiates our variant and two previously identified pathogenic variants in GATM from wildtype. Genetic testing has uncovered a novel pathogenic variant that predicts progression to end stage kidney failure and has important implications for family planning and cascade testing. We recommend that GATM is screened for in children presenting with RFS, in addition to adults, particularly with kidney failure, who may have had previous negative gene testing.

Keywords: end-stage kidney disease; exome sequencing; genetics; molecular dynamics; renal Fanconi syndrome.

FIGURE 1

Molecular dynamics results of GATM B4‐B4 dimer mutants. (A) Graphical representation of GATM wild‐type (WT) homodimer, each monomer coloured blue and orange, dimerized at the B4–B4 interface. (B) Representative cartoon structures of 316–324 loop for WT (blue/orange) and R322P (purple/brown) global minima with respect to residue 320 distances, proline 320 residues are overlaid as a stick representation. (C) Free‐energy values for all mutants and WT across residue 320 CB atom distances, averaged across all three repeats. (D, E) Free‐energy values for WT and p.(Arg322Pro) for each simulation replica for WT and p.(Arg322Pro) simulations across residue 320 CB atom distances [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Heterozygous variants in GATM causing renal Fanconi syndrome with kidney failure. All known pathogenic variants in GATM, including our variant Arg322Pro (bold and with asterisk). All variants are highly conserved across species. Amino acids discordant with the human reference are shown in red. All variants span a small region of exons 6 and 7 [Colour figure can be viewed at wileyonlinelibrary.com]