Identification of a de novo heterozygous missense FLNB mutation in lethal atelosteogenesis type I by exome sequencing.

BACKGROUND

Atelosteogenesis type I (AO-I) is a rare lethal skeletal dysplastic disorder characterized by severe short-limbed dwarfism and dislocated hips, knees, and elbows. AO-I is caused by mutations in the filamin B (FLNB) gene; however, several other genes can cause AO-like lethal skeletal dysplasias.

METHODS

In order to screen all possible genes associated with AO-like lethal skeletal dysplasias simultaneously, we performed whole-exome sequencing in a female newborn having clinical features of AO-I.

RESULTS

Exome sequencing identified a novel missense variant (c.517G>A; p.Ala173Thr) in exon 2 of the FLNB gene in the patient. Sanger sequencing validated this variant, and genetic analysis of the patient's parents suggested a de novo occurrence of the variant.

CONCLUSIONS

This study shows that exome sequencing can be a useful tool for the identification of causative mutations in lethal skeletal dysplasia patients.