Back
Polycystic kidney disease (PKD) is part of a genetically heterogeneous group of conditions called ciliopathies recognized as the most frequent inherited disorder leading to chronic kidney disease (CKD). The PKD1 and PKD2 genes are the main contributors to the autosomal dominant PKD (ADPKD) form typically observed in adults. In contrast, the PKHD1 gene is responsible for the autosomal recessive PKD form (ARPKD) that is generally diagnosed in utero or during the first months of life. Recently, mono-allelic, loss-of-function variants in IFT140, a core component required for retrograde transport in cilia, have been described as the third most common gene associated with the ADPKD spectrum with a mild phenotype. Notably, bi-allelic IFT140 variants are associated with another ciliopathy named Mainzer–Saldino Syndrome (MSS) characterized by skeletal abnormalities, ocular anomalies, kidney disease and additional findings such as hepatic fibrosis, intellectual disability, and short stature.
The clinical data were collected from both the patient's original hospital of admission and the referring hospital. The medical history, physical examination findings, laboratory test results, and radiological reports were thoroughly reviewed to compile a comprehensive clinical profile. Given the severe progression of CKD a targeted panel involving 400 genes associated with hereditary nephropathies was performed. ACMG guidelines were employed for preliminar variant classification, but Varsome, Internar, Missende 3d and mCSM were considered for variant re-analysis. Whole exome sequencing was performed to evaluate consanguinity.
A 21-month-old female patient born from a Native Amerindian couple, exhibited chronic kidney disease stage IV, with malnutrition, short stature, severe hypermetropia, and developmental delay. Echographies exhibited renal cysts and hepatic fibrosis suggestive of ARPKD. Targeted gene panel revealed a homozygous novel variant of uncertain significance (VUS) IFT140 c.240G>T (p.W80C), confirmed to be inherited from her parents (ages 35 and 43), who did not show echographic anomalies. PKD1 genetic analysis was negative. After re-analysis with diverse bioinformatic tools IFT140 W80C was reclassified as “likely pathogenic” with moderate and supporting evidence (PM1, PM2, PM3, and PP3) in an autosomal recessive inherited phenotype. The diagnosis of MSS was supported by the evidence of cone-shaped phalangeal epiphyses as well as short rib arches on an X-ray by the age of 2 years. During her last visit to the ophthalmologist, atypical retinitis was observed. The genetic data after a exome sequencing revealed a high rate of consanguinity in the patient.
This report highlights the role of genetic testing to elucidate diagnosis in severe phenotypes compromising kidney function that can be confused with PKD. Latin American populations are significantly underrepresented in genetic databases. As a result, variants from this population are often classified as VUS, but deserve re-analysis in benefit of the patient. MSS is an ultra-rare disease, with a frequency of less than 1 in 1,000,000. To the best of our knowledge, this is the first case of MSS diagnosed in Latin American. The content presented in this abstract was submitted for the Chilean Nephrological Meeting. Grant FICR 22-13.