ESPE Abstracts

Background: FLNB encodes filamin B (FLNB), a protein expressed in human growth plate chondrocytes, building the cytoskeleton that gives structure to cells and allows them to change shape and move. Biallelic loss-of-function mutations in FLNB result in spondylocarpotarsal synostosis (SCT; OMIM: 272460), while heterozygous null mutations related isolated short stature (ISS) have not been well described previously.

Objective: Describe the clinical characteristics of four unrelated ISS families with novel FLNB heterozygous null mutations.

Design and Participants: We performed whole exome sequencing in an ISS cohort of 189 unrelated patients, and found heterozygous FLNB null mutations in four patients. Detailed genotyping and phenotyping were analyzed in the members of these four families. We confirmed these four mutations by Sanger sequencing, and further verified the pathogenicity of the two splicing variants via splicing assays.

Results: The four probands mainly presented with short stature, short arm span, brachydactyly, and relatively large head. They all had delayed bone age. By whole exon sequencing (WES), we successfully identified the genetic cause of short stature in these four patients: two with splicing mutations c.5888-2A>C (p.?) and c.5110-1G>A (p.?), one with a frameshift mutation (c.2905delA (p.R969Gfs*11)), and one with a nonsense mutation (c.6637G>T (p.E2213*)). The pathogenicity of the two splicing variants was further confirmed by splicing assays.

Conclusions: Heterozygous null mutations of FLNB lead to apparent ISS characterized by short stature with short arm span and relatively large head. FLNB related short stature may not be a rare cause of ISS in the Chinese children.