Functional and Molecular Characterization of New SPTLC1 Missense Variants in Patients with Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1)

Hereditary sensory and autonomic neuropathy type 1 is an autosomal dominant neuropathy caused by the or variants. These variants modify the preferred substrate of serine palmitoyl transferase, responsible for the first step of sphingolipids synthesis, leading to accumulation of cytotoxic deoxysphingolipids. Diagnosis of HSAN1 is based on clinical symptoms, mainly progressive loss of distal sensory keep, and genetic analysis. Identifying new or " " variants raises the question as to their pathogenicity. This work focused on characterizing six new variants using in silico prediction tools, new meta-scores, 3D modeling, and functional testing to establish their pathogenicity. Variants from six patients with HSAN1 were studied. , CADD and REVEL scores and the 3D modeling software MITZLI were used to characterize the pathogenic effect of the variants. Functional tests based on plasma sphingolipids quantification (total deoxysphinganine, ceramides, and dihydroceramides) were performed by tandem mass spectrometry. In silico predictors did not provide very contrasting results when functional tests discriminated the different variants according to their impact on deoxysphinganine level or canonical sphingolipids synthesis. Two variants were newly described as pathogenic: NM_006415.4:c.998A>G and NM_006415.4:c.1015G>A. The combination of the different tools provides arguments to establish the pathogenicity of these new variants. When available, functional testing remains the best option to establish the in vivo impact of a variant. Moreover, the comprehension of metabolic dysregulation offers opportunities to develop new therapeutic strategies for these genetic disorders.