The NOG gene is located on chromosome 17 at 17q22 and encodes a secreted homodimeric glycoprotein called noggin that is essential for normal bone and joint development. NOG was first reported in relation to autosomal dominant NOG-related Symphalangism Spectrum Disorder in 1999 (Gong et al., 1999, PMID: 10080184). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, phenotypic variability, and inheritance pattern of the five disease assertions. For these reasons, the following diseases have been lumped into one entity; proximal symphalangism (MIM 185800), multiple synostoses syndrome 1 (MIM 186500), tarsal-carpal coalition syndrome (MIM 186570), stapes ankylosis with broad thumbs and toes (MIM 184460), and brachydactyly type B2 (MIM 611377). The new term encompassing these five overlapping clinical syndromes is NOG-related Symphalangism Spectrum Disorder (NOG-SSD) (MONDO: 0100521, Potti et al., 2011, PMID: 21538686). NOG-SSD is characterized by proximal symphalangism, conductive deafness caused by stapes ankylosis, ocular abnormality such as hyperopia and strabismus, and characteristic facial features including a broad, tubular-shaped nose and a thin upper vermilion (PMID: 21538686). The term NOG-SSD aids in the clinical diagnosis and evaluation of affected individuals.Two missense, five frameshift, and three nonsense variants reported in ten probands in four publications (PMID: 12089654, 15699718, 21358557, 25241334) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function which leads to misfolding, decreased stability, decreased affinity to bone morphogenic proteins (BMPs), or reduced/undetectable secretion of noggin. This gene-disease relationship is also supported by biochemical data, functional alteration assay, and mouse animal models (PMID: 9603738, 12478285, 1156247, 18096605). In summary, there is definitive evidence supporting the relationship between NOG and autosomal dominant NOG-related Symphalangism Spectrum Disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date July 5, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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