Supplementary Material for: DUAL-GENETIC ETIOLOGY IN AN ATYPICAL DENT DISEASE PHENOTYPE WHICH COMBINES FEATURES OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS AND ELLIS-VAN CREVELD-LIKE SYNDROME: A CASE REPORT

Introduction. Dent disease (DD) is an X-linked recessive renal disorder characterized by features of incomplete Fanconi syndrome. DD varies in clinical presentation, manifesting with proteinuria alone or in combination with nephrocalcinosis/nephrolithiasis, and with or without chronic kidney disease (CKD), posing a challenge to clinical diagnosis. The genetic basis of DD is not completely known; about 25-35% of DD cases lack mutations in the disease-causing CLCN5 and OCRL genes. This case report represents a rare example of a patient initially suspected of having DD, but through whole exome sequencing (WES) was found to harbor pathogenic variants in the WT1 and EVC2 genes, suggesting a dual genetic etiology mimicking DD.
Case presentation. We describe a young man with a renal phenotype resembling DD associated with nephrotic syndrome, focal segmental glomerulosclerosis (FSGS), tubular microcysts, and a significant family history of kidney disease. Also present was an extra-renal phenotype with short stature, narrow chest, recurrent upper respiratory tract infections, teeth anomalies and hypertension.
We identified in the WT1 gene the heterozygous ultrarare missense variant (NM_024426.6:c.1088C>T p.Thr363Met), classified as a variant of uncertain significance (VUS), and in the EVC2 gene the heterozygous nonsense variant (NM_147127.5:c.2833C>T p.Arg945Ter), classified as pathogenic. The clinical phenotype combines WT1-related focal segmental glomerulosclerosis (FSGS) with a rare tubular phenotype of Ellis-van Creveld-like syndrome (EVC).
Conclusions. This case report provides insights into the phenotypic complexity of hereditary nephropathies and the diagnostic challenge posed by overlapping glomerular and tubular presentations. WES enabled us to expand our knowledge of the genetics of kidney diseases in adults and to reclassify the patient’s nephropathy.