%0 Journal Article
%T Unexpected complexity in the molecular diagnosis of spastic paraplegia 11.
%A Mademont-Soler I
%A Esteba-Castillo S
%A Jiménez-Xifra A
%A Alemany B
%A Ribas-Vidal N
%A Cutillas M
%A Coll M
%A Pinsach ML
%A Pagans S
%A Alcalde M
%A Viñas-Jornet M
%A Montero-Vale M
%A de Castro-Miró M
%A Rodríguez J
%A Armengol L
%A Queralt X
%A Obón M
%J Mol Genet Genomic Med
%V 12
%N 6
%D 2024 Jun
%M 38938072
%F 2.473
%R 10.1002/mgg3.2475
%X <B>BACKGROUND: </B>Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844).<BR><B>METHODS: </B>The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing.<BR><B>RESULTS: </B>CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping.<BR><B>CONCLUSIONS: </B>We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.