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Dominant and recessive forms of fibrochondrogenesis resulting from mutations at a second locus, COL11A2
Author(s) -
Tompson Stuart W.,
Faqeih Eissa Ali,
AlaKokko Leena,
Hecht Jacqueline T.,
Miki Rika,
Funari Tara,
Funari Vincent A.,
Nevarez Lisette,
Krakow Deborah,
Cohn Daniel H.
Publication year - 2012
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.34406
Subject(s) - genetics , locus (genetics) , biology , exon , disease gene identification , loss of heterozygosity , exon trapping , gene , mutation , allele , exome sequencing , alternative splicing
Fibrochondrogenesis is a severe, recessively inherited skeletal dysplasia shown to result from mutations in the gene encoding the proα1(XI) chain of type XI collagen, COL11A1 . The first of two cases reported here was the affected offspring of first cousins and sequence analysis excluded mutations in COL11A1 . Consequently, whole‐genome SNP genotyping was performed to identify blocks of homozygosity, identical‐by‐descent, wherein the disease locus would reside. COL11A1 was not within a region of homozygosity, further excluding it as the disease locus, but the gene encoding the proα2(XI) chain of type XI collagen, COL11A2 , was located within a large region of homozygosity. Sequence analysis identified homozygosity for a splice donor mutation in intron 18. Exon trapping demonstrated that the mutation resulted in skipping of exon 18 and predicted deletion of 18 amino acids from the triple helical domain of the protein. In the second case, heterozygosity for a de novo 9 bp deletion in exon 40 of COL11A2 was identified, indicating that there are autosomal dominant forms of fibrochondrogenesis. These findings thus demonstrate that fibrochondrogenesis can result from either recessively or dominantly inherited mutations in COL11A2 . © 2012 Wiley Periodicals, Inc.