NOG – Brachydactyly type B2

In a Japanese kindred with stapes ankylosis, broad thumbs and toes, and conductive hearing impairment (HP:0000381, HP:0000405), a heterozygous NOG c.682T>G (p.Cys228Gly) variant segregated with the brachydactyly type B2 phenotype in three affected individuals (PMID:26211601). The disorder follows an autosomal dominant inheritance with complete co-segregation in the family (2 additional affected relatives).

Functional studies of human NOG missense mutations demonstrate reduced secretion of functional noggin dimers (PMID:11562478) and impaired dimerization (PMID:25888563), consistent with a hypomorphic mechanism leading to haploinsufficiency. No studies have disputed the association of NOG with brachydactyly type B2. These data support the clinical utility of NOG sequencing in patients presenting with brachydactyly type B2 and related skeletal anomalies.

Key Take-home: Heterozygous hypomorphic NOG variants underlie autosomal dominant brachydactyly type B2 and should be included in diagnostic genetic testing.

References

• European journal of medical genetics • 2015 • Novel NOG mutation in Japanese patients with stapes ankylosis with broad thumbs and toes. PMID:26211601
• 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
• 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
• 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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