Ann Lab Med.  2014 Mar;34(2):134-138. 10.3343/alm.2014.34.2.134.

Identification of a De Novo Heterozygous Missense FLNB Mutation in Lethal Atelosteogenesis Type I by Exome Sequencing

• Jeon GW
• Lee MN
• Jung JM
• Hong SY
• Kim YN
• Sin JB
• Ki CS

• KMID: 1791906
• DOI: http://doi.org/10.3343/alm.2014.34.2.134

Abstract

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.

Keyword

Atelosteogenesis type I; FLNB; Mutation; Exome sequencing

MeSH Terms

Exome
Female
Filamins/chemistry/*genetics
Gene Frequency
Heterozygote
Humans
Infant, Newborn
Mutation, Missense
Osteochondrodysplasias/*genetics/pathology/radiography
Polymorphism, Single Nucleotide
Sequence Analysis, DNA
Filamins

Figure

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  Fig. 1 Radiograph showing incomplete ossification and hypoplasia of the vertebrae, humeri, femora, tarsals, phalanges, and pelvis. The clavicles are relatively elongated (A), the thorax is small and bell-shaped (B), and the vertebrae have scoliosis and coronal clefts (C). The humeri are severely shortened and distally hypoplastic (D), the fibulae are completely absent, and both ankle joints, knee joints, and elbow joints are dislocated (E).

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  Fig. 2 Data analysis algorithm applied to the exome sequencing data. A data analysis algorithm was used to filter all the single nucleotide polymorphisms (SNPs) detected using exome sequencing, with numerous variants excluded at every filtering step.Abbreviation: MAF, minor allele frequency.

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  Fig. 3 Integrative Genomics Viewer snapshot of the novel FLNB mutation (NM_001457.3: c.517G>A; p.Ala173Thr) identified by exome sequencing.

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