Molecular genetics and long-term outcomes of primary distal renal tubular acidosis in Asia.

BACKGROUND AND HYPOTHESIS: Primary distal renal tubular acidosis (dRTA) is a rare inherited renal tubular disorder having a significant impact on growth and kidney function. Data on molecular genetics and long-term outcomes of primary dRTA, especially for newer genotypes, are limited.

METHODS

63 probands with a clinical diagnosis of dRTA underwent molecular genetic testing, specifically including SLC4A1, ATP6V1B1, ATP6V0A4, WDR72, and FOXI1. Genotype-phenotype characteristics and long-term outcomes were studied in this observational cohort study.

RESULTS

Diagnostic yield of genetic testing was 58.7%. Genotype positivity was associated with severe clinical and biochemical disease. SLC4A1 (38.5%) was the most common genotype, followed by WDR72 (13.5%) and ATP6V1B1 (11.5%). SLC4A1: p.Ala858Asp (32.7%) was the exclusive biallelic variant detected (likely founder variant in the region). Five (9.6%) had variants of unknown significance. Notable features at initial presentation were delayed diagnosis (median 17 months), frequent failure to thrive [44 (78.6%)], rickets [40 (71.4%)], and hypokalaemic paralysis [11 (19.6%)]. Mean [(standard deviation (SD)] follow-up duration was 14.8 (11.7) years. 30 (53.6%) were >18 years of age at last clinical visit. Long-term follow-up was characterized by poor final height [mean (SD score): -3.0 (2.2)], persistent bone deformities [19 (33.9%)], and decreased eGFR [mean (SD): 89.4 (26.1) ml/min/1.73 m2]. The biallelic SLC4A1: p.Ala858Asp variant was characteristically associated with increased osmotic fragility of red blood cells, manifesting as haemolytic anaemia. ATP6V1B1, ATP6V0A4, and FOXI1 variants were associated with sensorineural hearing deficit. All probands with WDR72 variants manifested amelogenesis imperfecta. We report 13 novel genetic variants in primary dRTA and the fourth proband with a rare FOXI1 variant.

CONCLUSIONS

Primary dRTA in Asian Indians is a genetically diverse disease, and is characterized by delayed diagnosis, severe growth failure, bone deformities, and decreased kidney function in the long term. Findings from this study highlight the regional diversity and expand genotype-phenotype correlations in primary dRTA.