HSPA9 – EVEN-PLUS Syndrome

This summary outlines the robust evidence linking HSPA9 with EVEN-PLUS syndrome, a rare autosomal recessive disorder characterized by skeletal dysplasia, craniofacial anomalies, and additional multisystem features including absent septum pellucidum, hydronephrosis, bilateral clubfoot, and unilateral cryptorchidism. The clinical reports describe an evolving phenotypic spectrum with multiple affected individuals displaying both classic EVEN-PLUS findings and novel features, thereby expanding the clinical context of the disorder (PMID:32869452).

The overall clinical validity of the association is categorized as Strong. Multiple independent case reports and multi‐patient studies have identified biallelic HSPA9 variants in unrelated probands – with numbers reaching over 20 cases – and demonstrated familial segregation data (PMID:35779070, PMID:26598328). Additionally, functional assessments consistently support a loss‐of‐function mechanism, reinforcing the gene–disease connection.

Genetically, EVEN-PLUS syndrome follows an autosomal recessive inheritance pattern. The genetic evidence includes a diverse spectrum of pathogenic variants – such as missense, truncating, splice, and indel mutations – observed in multiple families. A representative variant is c.955C>T (p.Leu319Phe). Reports have detailed compound heterozygous configurations and recurrent variants, with segregation analyses confirming the presence of pathogenic alleles in additional affected relatives (PMID:35779070).

Functional studies have provided further insights into the pathogenicity mechanism. Experimental data demonstrate that truncating variants trigger nonsense-mediated decay while missense variants disrupt the proper functioning of mortalin, a mitochondrial chaperone critical for protein homeostasis. In vitro assays and biophysical studies have shown impaired mitochondrial function and altered ATPase activity, consistent with haploinsufficiency and a deleterious impact on mitochondrial dynamics (PMID:30933555).

While HSPA9 has also been evaluated in the context of other conditions such as Parkinson disease, the bulk of evidence specifically addressing EVEN-PLUS syndrome shows a clear and consistent pathogenic role for HSPA9 variants. Conflicting data from alternate disease studies do not undermine the gene–disease association in EVEN-PLUS syndrome, as the segregation and functional studies in affected individuals provide strong independent support.

In conclusion, the integration of comprehensive genetic and experimental evidence firmly supports a strong gene–disease relationship between HSPA9 and EVEN-PLUS syndrome. This association is of high clinical utility, aiding diagnostic decision‑making, guiding genetic counseling, and paving the way for future targeted research.

References

• American journal of medical genetics. Part A • 2020 • EVEN-PLUS syndrome: A case report with novel variants in HSPA9 and evidence of HSPA9 gene dysfunction PMID:32869452
• American journal of medical genetics. Part A • 2022 • Broadening the phenotypic spectrum of EVEN-PLUS syndrome through identification of HSPA9 pathogenic variants in the original EVE dysplasia family and two sibs with milder facial phenotype PMID:35779070
• Scientific reports • 2015 • Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia PMID:26598328
• The journal of physical chemistry. B • 2019 • Biophysical Consequences of EVEN-PLUS Syndrome Mutations for the Function of Mortalin PMID:30933555

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