NOG – Proximal Symphalangism

Proximal symphalangism (SYM1) is a rare autosomal dominant joint morphogenesis disorder characterized by fusion of the proximal interphalangeal joints and often conductive hearing loss. The NOG gene encodes the BMP antagonist noggin (17q21–22), essential for normal joint formation. Heterozygous NOG mutations were first implicated in SYM1 in 2001, and subsequent reports have linked diverse NOG alleles to proximal symphalangism and related syndromes (PMID:11846737).

Genetic evidence includes over 30 unrelated probands harboring heterozygous NOG variants across at least 12 families, with missense changes (e.g., c.137T>C (p.Leu46Pro)) and loss-of-function alleles clustering in functional domains (PMID:11846737; PMID:22855651). A four-generation Chinese family with c.124C>T (p.Pro42Ser) demonstrated complete co-segregation with SYM1 in five affected members (PMID:31370824).

Segregation studies reveal additional affected relatives in multiple pedigrees, with at least 19 individuals displaying cosegregation of NOG variants and phenotype, supporting high penetrance of autosomal dominant inheritance (PMID:31370824).

Functional assays show that SYM1-associated NOG missense mutations reduce secretion of dimeric noggin and impair BMP antagonism in cell and oocyte models, consistent with hypomorphic alleles causing dosage-sensitive joint fusion (PMID:11562478).

Conflicting evidence: the p.Gly92Glu variant was shown to inhibit BMP signaling as effectively as wild type and was present in an unaffected parent, indicating this allele is likely benign (PMID:22529972).

Taken together, heterozygous NOG mutations cause proximal symphalangism via hypomorphic effects on BMP regulation, with strong genetic co-segregation and concordant functional data. NOG testing provides definitive molecular diagnosis, informs genetic counseling, and guides management of skeletal and auditory complications.

Key Take-home: NOG variant analysis is clinically actionable for diagnosing autosomal dominant proximal symphalangism and associated hearing impairment.

References

• Clinical Genetics • 2001 • Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome PMID:11846737
• Molecular syndromology • 2012 • Identification of a New Mutation (L46P) in the Human NOG Gene in an Italian Patient with Symphalangism Syndrome PMID:22855651
• BMC Medical Genetics • 2019 • Novel NOG (p.P42S) mutation causes proximal symphalangism in a four-generation Chinese family PMID:31370824
• Proceedings of the National Academy of Sciences • 2001 • Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding PMID:11562478
• PLoS One • 2012 • Functional analysis of alleged NOGGIN mutation G92E disproves its pathogenic relevance PMID:22529972

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