NOG – Tarsal-Carpal Coalition Syndrome

NOG-associated tarsal-carpal coalition syndrome is an autosomal dominant skeletal disorder characterized by congenital fusion of carpal and tarsal bones leading to hindfoot varus, forefoot supination, pain, and gait disturbances. Initial descriptions include a sporadic 10-year-old female with bilateral foot varus requiring tailored surgical management (PMID:25799911) and a multigenerational Indian family (mother and two children) with similar phenotypes in which Sanger sequencing identified a novel heterozygous missense variant c.611G>A (p.Arg204Gln) in NOG (PMID:29159868). Only six NOG mutations have been reported in TCC to date, underscoring the rarity of this condition.

Genetic evidence for NOG in TCC is limited, comprising three affected members segregating the c.611G>A (p.Arg204Gln) allele in a single kindred (PMID:29159868). Functional studies demonstrate that NOG missense mutations act as hypomorphic alleles, reducing the secretion of noggin dimers and diminishing BMP antagonism in vitro, consistent with a dosage-dependent mechanism of joint fusion (PMID:11562478). Additional segregation and functional data are needed to reach higher ClinGen validity. Key take-home: Heterozygous NOG variants should be considered in the genetic evaluation of individuals with tarsal-carpal coalition syndrome for accurate diagnosis and management.

References

• The Journal of Foot and Ankle Surgery • 2015 • Surgical Considerations for Massive Tarsal Coalitions in Multiple Synostosis Syndrome: A Case Report PMID:25799911
• American Journal of Medical Genetics. Part A • 2018 • Tarsal-carpal coalition syndrome: Report of a novel missense mutation in NOG gene and phenotypic delineation PMID:29159868
• Proceedings of the National Academy of Sciences of the United States of America • 2001 • Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding PMID:11562478

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