HSPA6 – EAST Syndrome

This summary evaluates the association between HSPA6 (HGNC:5239) and EAST syndrome (MONDO_0013005). EAST syndrome is characterized by intellectual disability (HP:0001249) among other neurological features. In the available studies, a common homozygous variant in HSPA6 was identified in all four affected patients, supporting an autosomal recessive (AR) inheritance pattern (PMID:31640787).

The genetic evidence originates from case and multi‐patient studies where variant prioritization pipelines detected HSPA6 as a candidate gene in the context of EAST syndrome. Although the same study primarily highlighted mutations in KCNJ10 and PI4KB, a homozygous variant in HSPA6 was consistently observed across the cohort of four probands, indicating potential pathogenicity when inherited in an AR manner (PMID:31640787).

Further segregation analysis in the reported family supports the AR inheritance model; however, the evidence is limited by the small number of probands and the absence of additional extended family data. The segregation data indicate that no additional affected relatives beyond the four probands were documented, limiting broader genetic confidence.

Regarding the variant spectrum, while a precise HGVS-coded variant for HSPA6 was not explicitly provided in the study, the presence of a recurrent, common homozygous alteration is noted as a key finding. This variant, although not described by a detailed c. notation, is considered in the context of the disease but will require further molecular delineation in future studies.

Functional evidence directly linking HSPA6 alterations to EAST syndrome pathogenesis is currently lacking. Notably, the study’s functional assays were focused on KCNJ10 and PI4KB; hence, the pathogenic mechanism underlying HSPA6 remains inferential. As such, the putative role of HSPA6 in modifying disease phenotypes is supported indirectly by its segregation pattern rather than by targeted functional experiments.

In conclusion, while the evidence for the involvement of HSPA6 in EAST syndrome is promising—demonstrated by its identification as a common homozygous variant across affected individuals—the overall case for a pathogenic relationship is limited by both the modest sample size and the absence of direct functional validation. Key take‑home: The detection of a recurring homozygous HSPA6 variant in EAST syndrome patients underscores its potential clinical utility in diagnostics and warrants further research to clarify its mechanistic role.

References

• Human Genomics • 2019 • Identification and functional characterization of two novel mutations in KCNJ10 and PI4KB in SeSAME syndrome without electrolyte imbalance PMID:31640787

Evidence Based Scoring (AI generated)