Triple-A Syndrome in Morocco: Founder Effect, Age Estimation of the <i>AAAS</i> c.1331+1G>A Variant, and Implications for Genetic Diagnosis

Abstract

<b><i>Introduction:</i></b> Triple-A syndrome (Triple-A) is an autosomal recessive disorder characterized by alacrimia, achalasia, and adrenal insufficiency. Several variants on the <i>AAAS</i> gene have been described, and some variants are clustered in particular geographical areas, such as the c.1331+1G>A variant which is very frequent in North Africa. Here, we describe the genetic features of Triple-A in a series of unrelated families from Morocco. <b><i>Methods:</i></b> Screening for the <i>AAAS</i> c.1331+1G>A variant was performed by direct sequencing or by PCR-RFLP. Haplotype analysis using Single Tandem Repeat (STR) markers flanking <i>AAAS</i> gene was performed in order to evaluate the founder effect and estimate the age of the c.1331+1G>A variant. <b><i>Results:</i></b> Seven unrelated families with ten individuals clinically diagnosed with Triple-A were evaluated for sequence variations in the <i>AAAS</i> gene. The median age at diagnosis was 3 years, with a range between 2 and 11 years. Molecular analysis revealed that all patients were homozygous for the c.1331+1G>A variant. This variant was not found in 200 healthy controls, indicating that carriers are very rare in the general Moroccan population. Subsequently, STR marker analysis revealed a founder effect and that the most recent common ancestor of Triple-A patients in Morocco would have lived 125 years ago. <b><i>Conclusion:</i></b> This is the largest series of Triple-A in Morocco. The same <i>AAAS</i> c.1331+1G>A variant was found in all patients, suggesting a founder effect in Morocco which was subsequently confirmed by microsatellite marker analysis. Therefore, this variant should be systematically investigated to diagnose Triple-A in Morocco.