TBX1 – Velocardiofacial Syndrome

Velocardiofacial syndrome (VCFS; MONDO:0008644) is a developmental disorder characterized by cleft palate, cardiac outflow tract anomalies, thymic hypoplasia, and hypoparathyroidism. Heterozygous mutations and hemizygous deletions of TBX1 (HGNC:11592) underlie the autosomal‐dominant inheritance of VCFS. Diagnostic evaluation includes fluorescence in situ hybridization or array analysis to detect 22q11.2 deletions and targeted sequencing of TBX1 in deletion‐negative cases.

Genetic evidence for TBX1 involvement in VCFS comprises three unrelated deletion‐negative probands with novel heterozygous TBX1 variants (PMID:30083032; PMID:31428446; PMID:17273972). These include nonsense, frameshift, and gain‐of‐function missense mutations consistent with autosomal‐dominant haploinsufficiency or altered protein activity. A familial gain‐of‐function missense mutation (H194Q) segregated with VCFS features within a multigenerational pedigree (PMID:17273972).

The variant spectrum in TBX1 includes multiple loss‐of‐function alleles such as c.1063C>T (p.Gln355Ter) (PMID:15703190), c.1117del (p.Leu373fs), and c.1250del (p.Ser417fs), as well as in‐frame deletions (c.173_229del (p.Arg58_Pro76del)) and missense changes affecting DNA‐binding or dimerization. No recurrent founder alleles have been described, and population allele frequencies remain extremely low, supporting pathogenicity in affected individuals.

Segregation data include one additional affected relative carrying the familial H194Q variant (PMID:17273972). Although incomplete penetrance and variable expressivity are recognized, heterozygous TBX1 mutations consistently co‐segregate with core VCFS phenotypes in families.

Functional studies demonstrate that TBX1 haploinsufficiency in mouse models recapitulates the cardinal craniofacial, thymic, and cardiac malformations of VCFS (PMID:9268629; PMID:12223416). Genetic interaction with Fgf8 and Crkl modifies phenotype penetrance, and rescue experiments with retinoic acid pathway modulation ameliorate cardiovascular defects. Gain‐ and loss‐of‐function assays in vitro confirm that disease‐associated missense mutations alter transcriptional activity.

Conflicting evidence arises from a large cohort of 446 patients with non‐syndromic psychiatric disorders, where TBX1 tag SNPs showed no significant association with schizophrenia or mood disorders (PMID:17622328). This suggests that TBX1 variation is not a major contributor to nonsyndromic psychiatric phenotypes.

Integrating genetic and experimental data supports a Strong association between TBX1 and velocardiofacial syndrome. Mouse and cellular models elucidate a haploinsufficiency mechanism, while human case series confirm variant pathogenicity. Additional evidence, including modifier gene studies, exceeds the scope of this summary. Key take‐home: TBX1 sequencing is clinically valuable for diagnosing deletion‐negative VCFS and guiding genetic counseling.

References

• Genomics • 1997 • Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Tbx1 gene. PMID:9268629
• Development • 2002 • A genetic link between Tbx1 and fibroblast growth factor signaling. PMID:12223416
• Human molecular genetics • 2005 • Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation. PMID:15703190
• American journal of human genetics • 2007 • Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions. PMID:17273972
• Molecular medicine • 2007 • Analysis of TBX1 variation in patients with psychotic and affective disorders. PMID:17622328
• Clinical pediatric endocrinology • 2018 • Novel heterozygous mutation in TBX1 in an infant with hypocalcemic seizures. PMID:30083032
• Clinical diabetes and endocrinology • 2019 • A case report of T-box 1 mutation causing phenotypic features of chromosome 22q11.2 deletion syndrome. PMID:31428446

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