Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.

TitleFunctional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.
Publication TypeJournal Article
Year of Publication2020
AuthorsGonzaga-Jauregui, C, Yesil, G, Nistala, H, Gezdirici, A, Bayram, Y, Nannuru, KC, Pehlivan, D, Yuan, B, Jimenez, J, Sahin, Y, Paine, IS, Akdemir, ZCoban, Rajamani, S, Staples, J, Dronzek, J, Howell, K, Fatih, JM, Smaldone, S, Schlesinger, AE, Ramírez, N, Cornier, AS, Kelly, MA, Haber, R, Chim, SMan, Nieman, K, Wu, N, Walls, J, Poueymirou, W, Siao, C-J, V Sutton, R, Williams, MS, Posey, JE, Gibbs, RA, Carlo, S, Tegay, DH, Economides, AN, Lupski, JR
Corporate AuthorsBaylor-Hopkins Center for Mendelian Genetics, Regeneron Genetics Center
JournalEur J Hum Genet
Date Published2020 Sep
KeywordsAbnormalities, Multiple, Adolescent, Animals, Bone Development, Child, Child, Preschool, Consanguinity, Extracellular Matrix, Female, Fibrillar Collagens, Founder Effect, Gene Frequency, Hip Dislocation, Homozygote, Humans, Male, Mice, Mice, Inbred C57BL, Mutation, Pedigree, Scoliosis, Syndrome

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

Alternate JournalEur J Hum Genet
PubMed ID32376988
PubMed Central IDPMC7608441
Grant ListK08 HG008986 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States

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