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ESS2 (also known as DGSI) is located within the 22q11 minimal deletion region, which has been implicated in velocardiofacial syndrome (PMID:9063747). In a mutational analysis of 16 patients with features of 22q11 deletion syndromes, eight sequence variants in ESS2 were identified; however, seven of these variants were also observed in unaffected individuals, thereby limiting the strength of the genetic association. This observation suggests that while ESS2 is in a critical genomic interval, its individual contribution to disease pathology remains uncertain. No clearly pathogenic variant (e.g., a coding change validated by HGVS nomenclature) has been exclusively associated with the syndrome in the available evidence.
The inheritance pattern of velocardiofacial syndrome is autosomal dominant. Despite the identification of several sequence variants, segregation data is minimal with no additional affected relatives definitively showing co-segregation with disease-specific variants. This limits the weight of the genetic evidence despite the moderate sample size of unrelated probands (PMID:9063747).
Functional studies lend further insight into the biological role of ESS2. Experimental data demonstrate that ESS2 functions as a transcriptional co-regulator and a component of spliceosomal complexes. These studies, including those that dissect the domains responsible for interacting with transcription factors and spliceosomal RNAs, support a mechanistic link between ESS2 dysfunction and the clinical features observed in 22q11 deletion syndromes (PMID:29454968). Although these assays are not specific to velocardiofacial syndrome, they indicate that ESS2’s role in RNA processing and gene regulation might contribute to disease pathogenesis in the context of 22q11 deletions.
Furthermore, additional multi-patient studies have evaluated promoter polymorphisms and other regulatory elements across the deletion region, yet the data do not conclusively implicate ESS2 as the primary etiologic factor in velocardiofacial syndrome. The scarcity of robust segregation and variant-specific evidence thus tempers the overall confidence in a direct causal relationship.
Overall, the available evidence supports a Limited gene-disease association for ESS2 with velocardiofacial syndrome. The genetic data, although supported by relevant functional studies, do not yet reach the higher ClinGen thresholds required for a stronger classification. This caveat should be considered in diagnostic decision-making and future clinical validations.
Key Take‑home sentence: While ESS2 lies in a critical chromosomal region and shows functional relevance, current evidence supports only a limited association with velocardiofacial syndrome, emphasizing the need for further targeted studies.
Gene–Disease AssociationLimitedAlthough ESS2 (DGSI) is positioned within the 22q11 minimal deletion region associated with velocardiofacial syndrome, analysis in 16 patients revealed eight sequence variants—seven of which were also found in unaffected individuals (PMID:9063747). Genetic EvidenceLimitedEight sequence variants detected in a cohort of 16 patients lacked robust segregation, as the majority were present in controls, limiting the specific genetic evidence for a causal role in velocardiofacial syndrome (PMID:9063747). Functional EvidenceModerateIn vitro studies demonstrate that ESS2 is involved in transcriptional regulation and spliceosomal assembly, which could contribute to disease mechanisms underlying 22q11 deletion syndromes (PMID:29454968). |