Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients.
BMC Med Genet
; 17: 27, 2016 Apr 06.
Article
en En
| MEDLINE
| ID: mdl-27048506
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fenotipo
/
Heterogeneidad Genética
/
Genotipo
Tipo de estudio:
Prognostic_studies
Límite:
Adult
/
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
BMC Med Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2016
Tipo del documento:
Article
País de afiliación:
India