Format

Send to

Choose Destination
Cold Spring Harb Mol Case Stud. 2019 Dec 13;5(6). pii: a004176. doi: 10.1101/mcs.a004176. Print 2019 Dec.

Novel in-frame FLNB deletion causes Larsen syndrome in a three-generation pedigree.

Author information

1
Department of Pediatrics, The Ohio State University, Columbus, Ohio 43205, USA.
2
Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
3
Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
4
Center for Cardiovascular Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, USA.

Abstract

A 4-yr-old female with congenital knee dislocations and joint laxity was noted to have a strong maternal family history comprising multiple individuals with knee problems and clubfeet. As the knee issues were the predominant clinical features, clinical testing included sequencing of LMX1B, TBX2, and TBX4, which identified no significant variants. Research genome sequencing was performed in the proband, parents, and maternal grandfather. A heterozygous in-frame deletion in FLNB c. 5468_5470delAGG, which predicts p.(Glu1823del), segregated with the disease. The variant is rare in the gnomAD database, removes a residue that is evolutionarily conserved, and is predicted to alter protein length. Larsen syndrome may present with pathology that primarily involves one joint and thus may be difficult to differentiate clinically from other skeletal dysplasias or arthrogryposis syndromes. The p.(Glu1823del) variant maps to a filamin repeat domain where other disease-causing variants are clustered, consistent with a probable gain-of-function mechanism. It has reportedly been observed in two individuals in the gnomAD database, suggesting that mild presentations of Larsen syndrome, like the individual reported here, may be underdiagnosed in the general population.

KEYWORDS:

aplasia/hypoplasia of the patella; bilateral talipes equinovarus; congenital knee dislocation; joint laxity

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center