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Introduction: Triple-A syndrome (Triple-A) is an autosomal recessive disorder characterized by alacrimia, achalasia, and adrenal insufficiency. Several variants on the AAAS 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. Methods: Screening for the AAAS c.1331+1G>A variant was performed by direct sequencing or by PCR-RFLP. Haplotype analysis using Single Tandem Repeat (STR) markers flanking AAAS gene was performed in order to evaluate the founder effect and estimate the age of the c.1331+1G>A variant. Results: Seven unrelated families with ten individuals clinically diagnosed with Triple-A were evaluated for sequence variations in the AAAS 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. Conclusion: This is the largest series of Triple-A in Morocco. The same AAAS 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.
RESUMO
BACKGROUND: Chromosomal abnormalities are the main cause of birth defects, intellectual disability, and miscarriages. They contribute to significant human morbidity and infant mortality. Here we report for the first time the chromosomal abnormalities encountered in the population of Eastern Morocco. Furthermore, we describe a new case of a de novo partial trisomy 13q combined with a terminal deletion in an 11-day-old girl. METHODS: From November 2015 to March 2022, 195 patients from the BRO Biobank who were clinically suspected of having chromosomal abnormalities were referred to the cytogenetics laboratory of the Genetics Unit of the Faculty of Medicine and Pharmacy of Oujda for cytogenetic study. Karyotyping analysis was performed on peripheral blood samples using standard R banding techniques. To identify single-nucleotide polymorphism (SNP) and copy number variants (CNVs), Illumina SNP array was used. RESULTS: Among 195 studied cases, 32 (16.4 %) had abnormal karyotypes, of which 12 cases had numerical aberrations while 20 cases had structural aberrations. The most common numerical aberrations were Turner syndrome and Down syndrome followed by Edward, Patau, and Klinefelter syndromes. For structural aberrations, translocations were the most common, followed by derivative chromosomes, inversions, deletions, and an addition on chromosome 13 identified in an 11-day-old girl. To further characterize this addition, SNP array was carried out and revealed a 58.8-Mb duplication in region 13q14.3q34 associated with a 1-Mb deletion in region 13q34. Follow-up parental chromosomes analysis showed normal karyotypes for the parents, confirming that this partial trisomy 13q was de novo. Comparison of the phenotype associated with this novel duplication on chromosome 13q with those previously reported confirmed the considerable variability in the phenotype of the patients with partial trisomy 13q. CONCLUSION: This study provided the first report on chromosomal abnormalities in Eastern Morocco and it enriched the phenotype spectrum of partial trisomy 13q and further confirmed the genotype-phenotype correlations. Furthermore, these findings justify the need to set up microarray comparative genomic hybridization techniques in Morocco for better genetic diagnosis.