SNX14 – Autosomal recessive spinocerebellar ataxia 20

Autosomal recessive spinocerebellar ataxia 20 (SCAR20) is a syndromic cerebellar ataxia characterized by early-onset progressive ataxia, intellectual disability, coarse facial features, hearing impairment and skeletal anomalies. SCAR20 is caused by biallelic pathogenic variants in SNX14, a gene encoding an endoplasmic reticulum–associated sorting nexin involved in autophagy and lipid homeostasis ([PMID:27913285]). The characteristic facial coarsening and progressive Purkinje cell loss render SNX14-related SCAR20 clinically recognizable within the heterogeneous inherited ataxias.

Genetic evidence includes homozygous missense and loss-of-function variants in ≥15 unrelated families ([PMID:27913285]), with case series describing compound heterozygous nonsense and complex rearrangements in siblings ([PMID:33193593]) and a deep intronic variant causing pseudo-exon inclusion in consanguineous sisters ([PMID:37485342]). Variants span missense, nonsense, splice site, deep intronic and structural classes, exemplified by c.1108G>A (p.Glu370Lys) which disrupts protein conformation and function. Segregation analysis in compound heterozygous families confirmed co-segregation in four additional affected relatives ([PMID:33193593], [PMID:37485342]). Carrier frequencies are low, consistent with autosomal recessive inheritance.

Functional studies in patient-derived fibroblasts reveal disrupted autophagic flux and aberrant neutral lipid droplet accumulation, indicating impaired ER-lysosome crosstalk ([PMID:29635513]). SNX14 knockout HEK293 cells recapitulate lipid metabolism defects, with cholesterol accumulation in LAMP1-positive structures and decreased cholesterol esters. In vivo, SNX14-deficient zebrafish are viable with lipid abnormalities, whereas mouse models exhibit mid-gestation embryonic lethality due to placental syncytiotrophoblast disruption ([PMID:32792680]). A targeted SNX14 mouse model shows selective Purkinje cell vulnerability, lipid storage defects and progressive cerebellar degeneration ([PMID:38625743]).

No conflicting evidence has been reported. Collectively, genetic and experimental data support a Strong gene–disease association, with Strong genetic evidence and Moderate functional evidence. Additional unpublished cohort data likely exist but exceed the current ClinGen scoring cap.

Key Take-home: Biallelic SNX14 variant analysis is clinically useful for diagnosing SCAR20 and informing prognosis and genetic counseling.

References

• European Journal of Medical Genetics • 2017 • Autosomal recessive spinocerebellar ataxia 20: Report of a new patient and review of literature. [PMID:27913285]
• Frontiers in Genetics • 2020 • Two Compound Heterozygous Variants in SNX14 Cause Stereotypies and Dystonia in Autosomal Recessive Spinocerebellar Ataxia 20. [PMID:33193593]
• Frontiers in Genetics • 2023 • Homozygous deep intronic variant in SNX14 cause autosomal recessive Spinocerebellar ataxia 20: a case report. [PMID:37485342]
• Human Molecular Genetics • 2018 • SNX14 mutations affect endoplasmic reticulum-associated neutral lipid metabolism in autosomal recessive spinocerebellar ataxia 20. [PMID:29635513]
• Scientific Reports • 2020 • Diverse species-specific phenotypic consequences of loss of function sorting nexin 14 mutations. [PMID:32792680]
• JCI Insight • 2024 • Altered lipid homeostasis is associated with cerebellar neurodegeneration in SNX14 deficiency. [PMID:38625743]

Evidence Based Scoring (AI generated)