Phenotypic Heterogeneity of ADTKD-MUC1 Diagnosed Using VNtyper, a Novel Genetic Technique

Molecular diagnosis of autosomal dominant tubulointerstitial kidney disease (ADTKD) due to variants in the MUC1 gene has long been challenging because variants lie in a large variable number of tandem repeat (VNTR) region, making identification impossible using standard short-read techniques. Previously, we addressed this diagnostic limitation by developing a computational pipeline named VNtyper for easier reliable detection of MUC1 VNTR pathogenic variants from short-read sequences. This led to unexpected diagnoses of ADTKD-MUC1 among patients with kidney disease referred for genetic testing, which we report here.

Cross-sectional observational study.

4,040 patients referred to Necker Enfants-Malades Hospital from 2017 to 2023 for genetic testing for (1) glomerular disease, (2) ciliopathy, (3) congenital anomalies of the kidneys and urinary tracts (CAKUT), (4) ADTKD, or (5) chronic kidney disease (CKD) of unknown origin, in whom MUC1 had not been previously tested by SNaPshot minisequencing.

Clinical suspicion of ADTKD.

ADTKD-MUC1 diagnosed using VNtyper.

Data were collected from patients in whom ADTKD-MUC1 was newly diagnosed and patients in whom ADTKD was clinically suspected were compared with those in whom ADTKD was not.

We identified 40 patients with MUC1 variants by VNtyper, including 33 new index patients and 7 relatives. Of the 33 index cases, 20 had been suspected of having ADTKD based on clinical features, and in the other 13 ADTKD had not been considered. In patients in whom ADTKD had not been considered clinically, the detection rate was 0.05% (1 of 1,895) among patients with glomerular disease, 1.2% (4 of 329) among patients with ciliopathy, 0.09% (1 of 1,099) among patients with CAKUT and 2.5% (7 of 285) among patients with CKD of unknown origin. In 6 patients there was no family history of kidney disease, and we confirmed de novo presentation in 2 patients by segregation studies.

Observational study and selected referral population (may not represent the prevalence or phenotypes in the general kidney disease population).

With VNtyper, we were able to diagnose new cases of ADTKD-MUC1 in a large cohort of patients with various phenotypes. Some patients had atypical phenotypes due to a variant in another gene, and some had no family history of kidney disease, suggesting de novo disease, which was confirmed in 2 patients.

Molecular diagnosis of autosomal dominant tubulointerstitial kidney disease due to variants in the MUC1 gene (ADTKD-MUC1) has long been challenging. Recently, we developed a computational pipeline named VNtyper to allow easier, reliable detection of MUC1 variants. When applied to a large heterogenous cohort of patients, it allowed us to diagnose ADTKD in patients in whom it had not been suspected. In some cases, this was due to 2 concomitant genetic diagnoses, which affected the phenotype. In others, there was no family history of kidney disease suggestive of an autosomal dominant disorder, and we were able to confirm de novo ADTKD-MUC1 in 2 patients.