Constraints of carrier screening in spinal muscular atrophy: Co-existence of deletion and duplication in SMN1 gene and false negative MLPA result

Abstract

Spinal Muscular Atrophy (SMA) is the second most common autosomal recessive genetic disorder. Deletion/duplication changes in SMN1 gene are common features in SMA patients. MLPA (Multiplex Ligation-dependent Probe Amplification) is a robust method for investigation of copy number changes because it not only deals with investigating the SMN1 gene but also adjacent genes such as NAIPE, GTFH2 and SMN2. This study was carried out by MLPA and STR markers to SMA carrier screening on people were referred to Dr. Zeinali's Medical Genetics laboratory. Analysis of 150 unrelated families with at least one affected child suspected of having SMA identified causative mutations in 106 families. Among the nighty-nine patients with a homozygous deletion of SMN1 gene (93.3%), there were ten patients with only one parent showing this deletion as heterozygote, and the other parent had two copies of the gene with normal MLPA result. The results were unexpected findings in an autosomal recessive disorder. Paternity and maternity were tested and confirmed.Further analysis of the grandparents showed that the parents inherited both deletion and duplication from one of their parents. So they have two copies of SMN1 genes in a chromosome and no copy on the other one.Due to high carrier frequency of SMA in highly consanguineous population as Iran, co-existence of deletion and duplication must be highly considered. It seems that performing genetic testing only in patients and parents is not sufficient and investigation of the grandparents or autozygosity mapping is also necessary to have reliable results especially for next pregnancies.