NOG – Multiple Synostoses Syndrome

Multiple Synostoses Syndrome (MONDO:0017923) is an autosomal dominant skeletal disorder characterized by progressive joint fusions, conductive hearing impairment, and a distinctive facial morphology.

Pathogenic heterozygous variants in NOG (HGNC:7866) have been reported in a Chinese family with proximal symphalangism, conductive hearing loss, and abnormal facies, where a missense allele c.554C>G (p.Ser185Cys) cosegregated across three generations ([PMID:32259393]). Additional studies have identified at least six other NOG missense or truncating mutations (e.g., c.551G>C (p.Cys184Ser), c.137T>C (p.Leu46Pro), c.406C>T (p.Arg136Cys), c.103C>T (p.Pro35Ser), c.615G>A (p.Trp205Ter), c.635_636insG (p.Gln213ProfsTer57)) in unrelated SYNS1 or proximal symphalangism cases ([PMID:11846737], [PMID:22855651], [PMID:24735539], [PMID:11857750], [PMID:32478388]).

The inheritance is autosomal dominant, with high penetrance; the initial Chinese pedigree demonstrated co-segregation in the proband, both parents, and grandmother ([PMID:32259393]). Across published kindreds, more than ten affected relatives have been documented, reinforcing familial segregation.

Functional assays reveal that SYNS1-associated NOG missense alleles markedly impair noggin secretion and homodimer formation in COS-7 and leukocyte models, leading to reduced BMP antagonism consistent with a hypomorphic mechanism ([PMID:11562478], [PMID:25888563]).

No studies have disputed NOG’s role in SYNS1 or reported neutral effects for pathogenic alleles; the consistency of genetic and functional data across systems underscores a dosage-sensitive requirement for noggin in joint development.

In summary, heterozygous NOG variants cause Multiple Synostoses Syndrome through impaired BMP antagonism, with definitive genetic and experimental support spanning over two decades. Clinical screening of NOG is recommended for diagnosis, familial risk assessment, and consideration of preimplantation genetic testing. Key Take-home: NOG haploinsufficiency via hypomorphic mutations is a reliable biomarker for SYNS1 management.

References

• American journal of medical genetics. Part A • 2020 • Multiple synostoses syndrome: Clinical report and retrospective analysis. PMID:32259393
• 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
• Biochemical and biophysical research communications • 2014 • A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss. PMID:24735539
• Human mutation • 2002 • Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism. PMID:11857750
• Bioscience reports • 2020 • Identification of an unknown frameshift variant of NOG in a Han Chinese family with proximal symphalangism. PMID:32478388
• 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
• The Annals of otology, rhinology, and laryngology • 2015 • A Novel Missense Mutation of NOG Interferes With the Dimerization of NOG and Causes Proximal Symphalangism Syndrome in a Chinese Family. PMID:25888563

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