UNRAVELING CLN7 disease: the distinct roles of two close MFSD8/CLN7 splice variants in phenotypic expression

Abstract CLN7 is a lysosomal storage disease caused by pathogenic variants in the MFSD8/CLN7 gene. Typically neurodegenerative, patients present seizures and developmental delay since 2–6 years of age and a rapid psychomotor, verbal, and visual deterioration that leads to premature death. However, ‘atypical’ cases have also been reported. Although more than 80 DNA variants in the MFSD8/CLN7 gene have been reported, no data about a genotype/phenotype correlation is available. Here, we analyze five ‘classical’ and ‘atypical’ CLN7 patients by molecular and computational methods. Four variants have been found: c.103C > T (p.Arg35*, pathogenic), c.1394G > A (p.Arg465Gln, pathogenic), c.863 + 1G > A (likely pathogenic), and c.863 + 4A > G (of uncertain significance). Both splice variants showed altering of the splicing process on a minigene reporter assay. Furthermore, exon 8 was deleted in the MFSD8/CLN7 cDNA of blood samples from two patients carrying the splicing variants, demonstrating their effect. The c.863 + 4A > G variant also showed a residual wildtype MFSD8/CLN7 expression and, thus, explaining the milder phenotype. Finally, a clustered geographical distribution of the c.103C > T and c.863 + 4A > G variants was observed in the northeast and center of Argentina, respectively. Our data confirm the pathogenicity of the c.863 + 1G > A variant and reclassify the c.863 + 4A > G variant as pathogenic by adding experimental data, offering new information for a precise prognosis, and expanding the genetic and epidemiological spectrum of CLN7 in the South American region. Ultimately, we seek to raise awareness about the existence of this pathology in the region to reduce the so-called ‘diagnostic odyssey’ in pediatric patients.