Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene

Yu Sun, Rowida Almomani, Emmelien Aten, Jacopo Celli, Jaap Van Der Heijden, Hanka Venselaar, Stephen P. Robertson, Anna Baroncini, Brunella Franco, Lina Basel-Vanagaite, Emiko Horii, Ricardo Drut, Yavuz Ariyurek, Johan T. Den Dunnen, Martijn H. Breuning

Research output: Contribution to journalArticlepeer-review


Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma with onset in female infancy. After performing X-exome capture and sequencing, we identified a mutation at the last nucleotide of exon 31 of the FLNA gene as the most likely cause of the disease. The variant c.5217G>A was found in six unrelated cases (three families and three sporadic cases) and was not found in 400 control X chromosomes, pilot data from the 1000 Genomes Project, or the FLNA gene variant database. In the families, the variant segregated with the disease, and it was transmitted four times from a mildly affected mother to a more seriously affected daughter. We show that, because of nonrandom X chromosome inactivation, the mutant allele was not expressed in patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The variant activates a cryptic splice site, removing the last 48 nucleotides from exon 31. At the protein level, this results in a loss of 16 amino acids (p.Val1724-Thr1739del), predicted to remove a sequence at the surface of filamin repeat 15. Our data show that TOD is caused by this single recurrent mutation in the FLNA gene.

Original languageEnglish
Pages (from-to)146-153
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number1
StatePublished - 9 Jul 2010


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