Novel Frameshift Variant in SORL1 Gene Identified in a EOAD Family Causes APP Sorting Dysfunction and Endolysosomal Swelling.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Rare, truncating variants in the sortilin-related receptor 1 (SORL1) gene are well established as high-risk factors for early-onset AD, although with incomplete penetrance. In this study, we identified a novel heterozygous frameshift variant in SORL1 (c.6152delA) in a Chinese family presenting with early-onset dementia characterized by progressive memory impairment and neuropsychiatric symptoms. The variant is extremely rare in gnomAD v4 and is predicted to introduce a premature termination codon. To investigate whether the truncated SORL1 transcript escapes nonsense-mediated mRNA decay (NMD) and to explore the potential cellular effects of residual truncated SORL1, the mutant SORL1 construct was expressed in SH-SY5Y cells and APPswe-expressing HEK293 cells. Additionally, SORL1 mRNA levels in the serum of the proband and her families were assessed by qRT-PCR. Confocal microscopy was used to examine amyloid precursor protein (APP) trafficking within early endosomes, late endosomes, and the trans-Golgi network, marked by EEA1, Rab7, and TGN46, respectively. Amyloid-β (Aβ40 and Aβ42) levels were quantified by ELISA. The results showed that SORL1 mRNA levels in the proband were reduced. And the SORL1 c.6152delA variant impaired the ability of SORL1 to retain APP within the Golgi-endosomal transport network, resulting in increased Aβ production. Overall, these findings indicate that the SORL1 c.6152delA frameshift variant is a significant risk factor for AD pathogenesis.