Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population

Abstract

Osteochondrodysplasias represent a large group of developmental structural disorders that can be caused by mutations in a variety of genes responsible for chondrocyte development, differentiation, mineralization and early ossification. The application of whole-exome sequencing to disorders apparently segregating as Mendelian traits has proven to be an effective approach to disease gene identification for conditions with unknown molecular etiology. We identified a homozygous missense variant p.(Gly697Arg) in COL27A1, in a family with Steel syndrome and no consanguinity. Interestingly, the identified variant seems to have arisen as a founder mutation in the Puerto Rican population.

Figure 1

Photographs of index patient (a: patient II-1) and sister (b: patient II-2). Oval-shaped face with prominent forehead and mild frontal bossing and broad nasal bridge in both patients.

Figure 2

(a) Bilateral hip dysplasia in a sibling pair. Patient II-1 at 13 years of age (a1) and patient II-2 at 12 years of age (a2). (b) Bilateral capitate–hamate coalition in patient II-1 at 13 years of age (b1) and patient II-2 at 12 years of age (b2).

Figure 3

(a) Pedigree showing family with Steel syndrome. Affected individuals are denoted as black filled symbols and are homozygous for the p.(Gly69Arg) variant. All unaffected parents are heterozygous carriers for the variant. (b) Domain structure of the COL27A1 protein is shown. It is a 1860-amino-acid propeptide with an N-terminal cleavage site and overlapping laminin G and thrombospondin domains in the N-terminus, followed by the triple helical domain characteristic of collagen genes. (c) Alignment and conservation of amino-acid residues surrounding the identified p.(Gly697Arg) variant. The variant changes a highly conserved Glycine residue that is part of the Gly–Xaa–Yaa repeat motif characteristic of collagen proteins' triple helical domain.

Figure 4

View of complete chromosome 9 on high-resolution SNP arrays for all the family members. The red line indicates the chromosomal location of COL27A1. No large regions of homozygosity were observed in the three affected individuals besides the regions surrounding COL27A1.