SPNS2 and Hearing Loss Disorder

This summary examines the association between SPNS2 and hearing loss disorder. SPNS2 (HGNC:26992) has been implicated in sensorineural hearing loss through the identification of novel compound heterozygous variants. The patient, an eight-year-old female, presents with bilateral sensorineural hearing impairment and congenital hypothyroidism, features that are consistent with the clinical presentation of hearing loss disorder (MONDO_0005365) (PMID:36494063). Detailed clinical assessment and molecular testing revealed damaging variants in SPNS2, which underscore its role in auditory function and related phenotypes.

In the case report evidence, two novel damaging variants were identified in SPNS2. The patient was found to be a compound heterozygote for these variants, with Sanger sequencing confirming the genetic findings. One of the reported variants is c.487G>A (p.Asp163Asn), which meets HGVS standards and has been predicted to be deleterious by in silico tools (PMID:36494063). The identification of these variants in a single, well‐phenotyped proband supports an autosomal recessive inheritance pattern for this hearing loss disorder.

The genetic evidence is bolstered by segregation data even though additional affected relatives were not documented. Compound heterozygous inheritance in this patient aligns with the recessive transmission model. The reported variants, including c.487G>A (p.Asp163Asn), have not been previously encountered in public databases, adding to their novelty and potential pathogenicity. This singular case, reported in two separate evidentiary sources, provides meaningful insight into the genotype–phenotype correlation for SPNS2-associated hearing loss.

A key variant from the mutation list, c.487G>A (p.Asp163Asn), is used as a representative example in this report. The detailed variant description follows HGVS guidelines, ensuring clarity and consistency across all reports. In this context, the variant's damaging impact is further supported by in silico predictions, which reinforce its clinical relevance. Such rigorous characterization of the variant contributes to the overall genetic evidence supporting the association.

Functional studies provide additional insight into the molecular mechanism underlying SPNS2’s role in hearing. In a separate experimental assessment, cryo-electron microscopy and S1P transport assays have demonstrated that pathogenic mutations in SPNS2 disrupt its ability to export sphingosine-1-phosphate, a critical lysolipid in auditory development and function (PMID:39820269). These findings elucidate the biological mechanism whereby impaired SPNS2 activity may contribute to the hearing loss phenotype, thereby reinforcing its causative role. The experimental results are concordant with the clinical data, offering a cohesive narrative that spans both genetic and functional domains.

In summary, the integration of clinical, genetic, and functional evidence supports a moderate association between SPNS2 and hearing loss disorder. Although the current evidence is derived from a single proband with compound heterozygous variants, robust experimental demonstrations of disrupted S1P export strengthen the claim. This convergence of data positions SPNS2 as a clinically meaningful gene in the context of sensorineural hearing impairment, meriting consideration in diagnostic panels.

Key Take‑home Sentence: SPNS2 testing should be incorporated into diagnostic assays for hearing loss disorders as both genetic and functional data support its role in disease pathogenesis.

References

• European journal of medical genetics • 2023 • Compound heterozygous variants in SPNS2 cause sensorineural hearing loss PMID:36494063
• Nature communications • 2025 • Transport and inhibition of the sphingosine-1-phosphate exporter SPNS2 PMID:39820269

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