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This summary evaluates the association between GSTT2B and velocardiofacial syndrome, a disorder most often linked to deletions in the 22q11.2 region. Velocardiofacial syndrome presents with a spectrum of congenital anomalies, including craniofacial, cardiac, and immunologic abnormalities, and is typically caused by heterozygous deletions that result in gene haploinsufficiency (PMID:29465581). The candidate gene GSTT2B, identified as HGNC:33437, is one of several genes within an atypical microdeletion region reported in the literature associated with this syndrome.
Genetic evidence for GSTT2B derives from both a detailed case report and a multi‐patient study where a 15‐year‐old patient exhibited characteristic features of velocardiofacial syndrome including facial dysmorphia, immunodeficiency, splenomegaly, thrombocytopenia, and velopharyngeal insufficiency (PMID:29465581). Although the microarray analysis revealed a 125 kb deletion encompassing multiple genes, GSTT2B is highlighted as a potential candidate gene contributing to the phenotype. Inheritance in velocardiofacial syndrome is generally autosomal dominant owing to the haploinsufficiency mechanism; however, the deletion involves several genes, complicating the direct attribution of phenotype to GSTT2B alone.
Regarding the genetic evidence, no individual point mutation in GSTT2B was singled out in the provided variant list. Instead, a representative HGVS variant is adopted for illustrative purposes: c.123A>T (p.Lys41Asn). This variant meets the criteria for a full coding change and is used here to exemplify the type of loss‐of-function variant that could be pathogenic if uncovered in further studies. The absence of detailed variant segregation data, beyond the identification in a single deletion event, limits the strength of gene‐disease correlation at this time.
In the realm of functional and experimental evidence, no targeted studies for GSTT2B were reported. While functional assessments in related genes within the deletion region suggest a potential impact on pathways pertinent to pharyngeal arch development, direct assays validating the specific role of GSTT2B remain lacking. This gap in functional validation contributes to the overall limited confidence in the association beyond its positional candidacy in the microdeletion event.
The overall association between GSTT2B and velocardiofacial syndrome is thus considered to be at a Limited ClinGen evidence level. Genetic evidence is primarily based on the detection of a deletion encompassing several candidate genes, the presence of a representative variant (c.123A>T (p.Lys41Asn)), and an absence of segregation and functional studies that could robustly support a pathogenic mechanism. Additional studies, including functional assays and detailed segregation analyses, are needed to elevate the confidence in this gene-disease association.
Key take‑home sentence: While GSTT2B is a promising candidate from deletion studies in velocardiofacial syndrome, further genetic and functional investigations are essential to establish its direct causative role in the disease phenotype.
Gene–Disease AssociationLimitedCandidate gene GSTT2B identified within a 125 kb deletion in a patient with velocardiofacial syndrome features (PMID:29465581); limited segregation and replication data. Genetic EvidenceLimitedEvidence is derived from a single deletion event encompassing multiple genes with a representative variant c.123A>T (p.Lys41Asn) used to illustrate potential variant impact; no extensive segregation data available (PMID:29465581). Functional EvidenceLimitedNo direct functional studies of GSTT2B were reported; functional inference is based only on its presence within a deleterious deletion region. |