Phenotype and genotype in patients with Larsen syndrome: clinical homogeneity and allelic heterogeneity in seven patients

Abstract

BackgroundLarsen 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.MethodsThe 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.ResultsAll 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).ConclusionsAll 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.

Fatal Myelotoxicity Following Palliative Chemotherapy With Cisplatin and Gemcitabine in a Patient With Stage IV Cholangiocarcinoma Linked to Post Mortem Diagnosis of Fanconi Anemia

“…Segregation analysis with DNA samples of both healthy parents and his brother revealed the missense variant to be paternally inherited, whereas both the mother and his brother only bear the c.710-3A>G variant (Figure 2A), confirming the compound heterozygosity and an autosomal recessive inheritance. Further, RT-PCR analysis performed with RNA isolated from lymphocytes of the healthy brother as previously described (22) revealed that the c.710-3A>G variant causes skipping of exon 8 (Figure 2B), thus confirming its pathogenicity and allowing the post mortem diagnosis of FA in the index patient. Notably, primary dermal fibroblasts from a FA patient harboring the c.710-5T>C variant of FANCA (in compound heterozygosity with c.3558insG; FA-52 cells), that also causes skipping of exon 8 (21), demonstrated chromosomal instability after exposure to diepoxybutane (23).…”

Quantification of transmission risk in a male patient with a FLNB mosaic mutation causing Larsen syndrome: Implications for genetic counseling in postzygotic mosaicism cases

“…Quantification of the mosaic c.698A>G mutation in exon 4 of FLNB , encoding the p.(Tyr233Cys) substitution in multiple tissues. A : Schematic diagram of the filamin B (FLNB) (NP_001448.2) protein indicating the main protein domains, the location of the p.(Tyr233Cys) mutation (marked by an asterisk), and other previously reported mutations associated with Larsen syndrome (Bicknell et al., ; Daniel et al., ; Dobbs, Boehm, Grange, & Gurnett, ; Girisha et al., ; Krakow et al., ; Winer et al., ; Zhang et al., ). Numbers in brackets indicate the numbers of independently reported families with a given mutation; in bold are hotspot mutations.…”

A review of skeletal dysplasia research in India

“…[ 45 46 ] The reports on IDS mutations in 17 affected families with Hunter syndrome, ARSB mutations in 15 families of Maroteaux–Lamy syndrome, MMP2 mutations in 15 affected families with multicentric osteolysis nodulosis and arthropathy, TCIRG1 and CLCN7 mutations in 8 patients with autosomal recessive osteopetrosis, CHST3 mutations in 7 patients of recessive Larsen syndrome, CTSK mutations in 5 patients with pycnodysostosis, and EIF2AK3 nonsense mutation in five Wolcott-Rallison type of diabetes mellitus were some of the notable publications describing the respective mutation profiles in Indian patients. [ 47 48 49 50 51 52 53 54 ]…”