title: Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients.
abstract: BACKGROUND
  Larsen syndrome is an autosomal dominant skeletal dysplasia characterized by large joint dislocations and craniofacial dysmorphism. It is caused by missense or small in-frame deletions in the FLNB gene. To further characterize the phenotype and the mutation spectrum of this condition, we investigated seven probands, five sporadic individuals and a mother-son-duo with Larsen syndrome.
  
  
  METHODS
  The seven patients from six unrelated families were clinically and radiologically evaluated. All patients were screened for mutations in selected exons and exon-intron boundaries of the FLNB gene by Sanger sequencing. FLNB transcript analysis was carried out in one patient to analyse the effect of the sequence variant on pre-mRNA splicing.
  
  
  RESULTS
  All patients exhibited typical facial features and joint dislocations. Contrary to the widely described advanced carpal ossification, we noted delay in two patients. We identified the five novel mutations c.4927G  A/p.(Gly1643Ser), c.4876G > T / p.(Gly1626Trp), c.4664G > A / p.(Gly1555Asp), c.2055G > C / p.Gln685delins10 and c.5021C > T / p.(Ala1674Val) as well as a frequently observed mutation in Larsen syndrome [c.5164G > A/p.(Gly1722Ser)] in the hotspot regions. FLNB transcript analysis of the c.2055G > C variant revealed insertion of 27 bp intronic sequence between exon 13 and 14 which gives rise to in-frame deletion of glutamine 685 and insertion of ten novel amino acid residues (p.Gln685delins10).
  
  
  CONCLUSIONS
  All seven individuals with Larsen syndrome had a uniform clinical phenotype except for delayed carpal ossification in two of them. Our study reveals five novel FLNB mutations and confirms immunoglobulin-like (Ig) repeats 14 and 15 as major hotspot regions. The p.Gln685delins10 mutation is the first Larsen syndrome-associated alteration located in Ig repeat 5. All mutations reported so far leave the filamin B protein intact in accordance with a gain-of-function effect. Our findings underscore the characteristic clinical picture of FLNB-associated Larsen syndrome and add Ig repeat 5 to the filamin B domains affected by the clustered mutations.
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
authors.forename: Katta Mohan
authors.initials: KM
authors.lastname: Girisha
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
authors.forename: Abdul Mueed
authors.initials: AM
authors.lastname: Bidchol
authors.affiliation: Ambulantes Gesundheitszentrum der Charité, Campus Virchow, Humangenetik, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Luitgard
authors.initials: L
authors.lastname: Graul-Neumann
authors.affiliation: Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Center for and Department of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hehr
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
authors.forename: Davor
authors.initials: D
authors.lastname: Lessel
authors.affiliation: Kinderorthopädie, Schön Klinik Vogtareuth, Prien am Chiemsee, Germany.
authors.forename: Sean
authors.initials: S
authors.lastname: Nader
authors.affiliation: Pediatric Orthopedic Services, Department of Orthopedics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Shah
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Wickert
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany. kkutsche@uke.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
mesh_terms: D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D064448:Filamins / Q000235:genetics; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D008297:Male; D010009:Osteochondrodysplasias / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: C578662:FLNB protein, human; D064448:Filamins; D012333:RNA, Messenger
keywords: Autosomal-dominant; FLNB; Gain-of-function; Larsen syndrome; Mutation; Pre-mRNA splicing