Application of molecular methods of genetic counseling in inherited forms of renal tubular acidosis for preventive strategy

ABSTRACT

Renal tubular acidosis [RTA] results from failure of the kidney to acidify the urine resulting in a state of hyperchloraemic metabolic acidosis with a normal anion gap. Three main clinical types of RTA are now recognized [proximal, distal and hyperkalemic] but the number of possible causes is large. Inherited forms of distal RTA have three variants autosomal dominant and autosomal recessive with or without deafness, while the inherited forms of proximal RTA include many variants as autosomal recessive proximal RTAt cystinosis, Fanconi-Bickel syndrome [FBS] and Wilson's disease. Thus, we conducted a prospective study to screen all the documented cases of inherited RTA in pediatric nephrology outpatient clinic in MUCH for relevant gene mutation. This study was carried out in the period from November 2009 to February 2012. The study comprised 17 Egyptian families having documented cases of inherited RTA. We found three families compatible with the clinical diagnosis of FBS, two families compatible with the clinical diagnosis of cystinosis and 12 families of dRTA. All patients were subjected to a thorough history, full clinical examination and laboratory investigations. Pedigree construction was done for each family. Radiological investigations were done for some cases including plain x-ray for racketic findings, abdominal ultrasound and echocardiography done for those with clinical findings coping with congenital or acquired heart diseases. Liver biopsy was done for those with hepatomegaly. Molecular workup was done in the form of DNA extraction, agarose gel electrophoresis, polymerase chain reaction of the extracted DNA and sequencing for the specific gene according to each disease. We found two new mutations in GLUT2 gene and an old missense mutation [re-enumerated] in three families of FBS. We found a novel truncating mutation in CTNS gene associated with a severe clinical course and double heterozygosity for two known mutations in the other family. Two novel mutations were detected in two out of 12 families of dRTA in ATP6VOA4 gene. We concluded that although these diseases are not rare in the Egyptian population, evolving new mutations could add some allelic variants. Moreover, studying phenotype-genotype pattern of different mutations is crucial for linkage analysis: