Combined deletions of GALNS and PIEZO1 genes in two patients affected by MorquioA syndrome

Mucopolysaccharidosis IVA (Morquio A syndrome) is an autosomal recessive lysosomal storage disorder, caused by the deficiency of the enzyme N-Acetylgalactosamine-6 sulfate sulfatase (GALNS). The disease, albeit multisystemic, is characterized by prevalent skeletal involvement, short stature, and cardiorespiratory complications. Here we report two new large genetic rearrangements detected at the heterozygous level in two patients (Pt1 and Pt2) affected by Morquio A. The deletions include part of the PIEZO1 gene (piezo-type mechanosensitive ion channel component 1) whose mutations were found in the dehydrated hereditary stomatocitosis, a dominant autosomal recessive syndrome. This syndrome is typically associated with silent to mild hemolysis, perinatal edema, splenomegaly, elevated bilirubin levels and iron overload. Pt1 was found to be seemingly homozygous for the c.1485C>G (p.Asn495Lys) missense mutation in the exon 14 of the GALNS gene. Parents’ genetic analysis, haplotyping some loci in exon 14 of the GALNS gene (in the context of a prenatal diagnosis of a patient’s relative), and CGH-array revealed that Pt1 has a large deletion encompassing exons 10-14 of the GALNS gene and three upstream genes, including a part of the PIEZO1 gene. In Pt2, heterozygous for the c.346G>A (p.Gly116Ser) missense mutation, a large deletion ablating exons 9-14 of the GALNS gene and exon 1 of the PIEZO1 gene was also identified. The breakpoint regions were characterised in both patients and the eventual contribution of the partial deletion of the PIEZO1 gene on such patients’ phenotype was considered at a biochemical and clinical point of view