TFAP2B – Char syndrome

TFAP2B encodes a neural-crest-expressed transcription factor whose heterozygous variants cause autosomal dominant Char syndrome, characterized by patent ductus arteriosus (PDA), facial dysmorphism, and hand anomalies. Initial mapping and mutation screening in two families established linkage and recurrent deleterious alleles in the basic DNA-binding domain, with evidence of variable expressivity and tissue-specific coactivator interactions (PMID:10802654; PMID:11505339).

Inheritance is autosomal dominant with high penetrance of PDA and dysmorphic features. Segregation analyses include 27 affected individuals in two kindreds (PMID:15684060) and a multigeneration pedigree of 20 affected members across six generations (PMID:29683802). Case series report eight unrelated probands in an American Journal of Human Genetics cohort (PMID:11505339) and additional single-family and sporadic cases (PMID:18752453; PMID:31012281; PMID:30579973).

The variant spectrum encompasses 7 missense mutations (e.g., c.830C>G (p.Ser277Trp))[PMID:10802654], 4 frameshifts (e.g., c.650delG (p.Gly217AlafsTer32))[PMID:30579973], and 5 canonical splice-site changes (e.g., c.601+1G>A)[PMID:15684060]. Recurrent variants include c.917C>T (p.Thr306Met)[PMID:31012281], underscoring mutation hotspots in the DNA-binding and transactivation domains.

Functional assays demonstrate that missense mutants fail to bind target DNA and exert dominant-negative effects on transactivation (PMID:10802654; PMID:11505339), while splice variants produce aberrant transcripts subject to nonsense-mediated decay, indicating haploinsufficiency (PMID:15684060; PMID:18752453).

In vivo, Tfap2b−/− mice exhibit persistent PDA and accessory digits due to dysregulated Bmp2/Bmp4 expression in ductus and limb buds, faithfully modeling human Char syndrome (PMID:21829553). Rescue experiments with coactivator CITED2 fail to restore transactivation in vitro, reinforcing a loss-of-function mechanism.

Although isolated PDA without facial or limb anomalies can occur (e.g., c.541-2A>T)[PMID:18752453], no studies to date dispute the TFAP2B–Char syndrome relationship. The breadth of segregation data, diverse pathogenic variants, and concordant functional and animal models provide definitive clinical validity.

Key take-home: Heterozygous TFAP2B variants are a definitive cause of autosomal dominant Char syndrome; targeted genetic testing and functional characterization of novel alleles are critical for accurate diagnosis and genetic counseling.

References

• Nature genetics • 2000 • Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus. PMID:10802654
• American journal of human genetics • 2001 • Novel TFAP2B mutations that cause Char syndrome provide a genotype-phenotype correlation. PMID:11505339
• Proceedings of the National Academy of Sciences of the United States of America • 2005 • Syndromic patent ductus arteriosus: evidence for haploinsufficient TFAP2B mutations and identification of a linked sleep disorder. PMID:15684060
• Genetic testing • 2008 • Novel TFAP2B mutation in nonsyndromic patent ductus arteriosus. PMID:18752453
• Clinical dysmorphology • 2018 • A study of familial Char syndrome involving the TFAP2B gene with a focus on facial shape characteristics. PMID:29683802
• American journal of medical genetics. Part A • 2019 • A novel missense mutation in TFAP2B associated with Char syndrome and central diabetes insipidus. PMID:31012281
• European journal of medical genetics • 2019 • Char Syndrome a novel mutation and new insights: A clinical report. PMID:30579973
• Journal of human genetics • 2017 • TFAP2B mutation and dental anomalies. PMID:28381879

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