The MGP gene (OMIM: 154870) is located on chromosome 12 at 12p12.3 and encodes Matrix Gla protein, a vitamin-K dependent protein that is secreted by chondrocytes and cardiovascular cells and inhibits ectopic tissue calcification. Variants in MGP were first reported in relation to autosomal recessive Keutel syndrome in 1999 (Munroe et al., PMID: 9916809). Keutel syndrome is a rare disorder characterized by abnormal cartilage calcification, brachytelephalangy, dysmorphic facial features including midface hypoplasia, and peripheral pulmonary artery stenosis. Other reported features include mixed hearing loss, congenital heart defects, pulmonary hypoplasia, respiratory distress, mild short stature, and mild intellectual disability. Evidence supporting this GDR includes case-level data, segregation data and experimental evidence.
8 unique variants including nonsense and splice variants from 7 publications have been included in this curation. All reported variants are homozygous in the affected individuals and all families were consanguineous. Variants in this gene segregate with disease in at least one family. The suggested mechanism of pathogenicity is loss of function. The gene disease relationship is also supported by a knockout mouse model and phenotype rescue (Luo et al., 1997, PMID: 9052783, Marulanda et al., 2017, PMID: 28487368).
In summary, there is definitive evidence supporting the relationship between MGP and autosomal recessive Keutel syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date May 16th, 2025 (SOP Version 11).
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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