Kniest dysplasia is caused by dominant collagen II (COL2A1) mutations: Parental somatic mosaicism manifesting as Stickler phenotype and mild spondyloepiphyseal dysplasia

1994 ◽  
Vol 24 (6) ◽  
pp. 431-435 ◽  
Author(s):  
J. Spranger ◽  
H. Menger ◽  
S. Mundlos ◽  
A. Winterpacht ◽  
B. Zabel
Keyword(s):  
Somatic Mosaicism ◽  
Spondyloepiphyseal Dysplasia ◽  
Collagen Ii ◽  
Kniest Dysplasia

Spondyloepiphyseal Dysplasia Congenita and Related Type 2/Type 11 Collagen Disorders

2018 ◽  
pp. 65-108
Author(s):  
Jürgen W. Spranger ◽  
Paula W. Brill ◽  
Christine Hall ◽  
Gen Nishimura ◽  
Andrea Superti-Furga ◽  
...  
Keyword(s):  
Clinical Findings ◽  
Differential Diagnoses ◽  
Radiographic Features ◽  
Metaphyseal Dysplasia ◽  
Spondyloepiphyseal Dysplasia ◽  
Bone Dysplasias ◽  
Spondyloepiphyseal Dysplasia Congenita ◽  
Kniest Dysplasia

This chapter further discusses bone dysplasias, and explores achondrogenesis II (hypochondrogenesis), platyspondylic dysplasia (Torrance type), spondyloepiphyseal dysplasia congenita, spondylo-epi-metaphyseal dysplasia (Strudwick type), Kniest dysplasia, spondyloepiphyseal dysplasia (Stanescu type), spondyloperipheral dysplasia, spondyloepiphyseal dysplasia with short metatarsals, Stickler dysplasia, fibrochondrogenesis, and oto-spondylo-megaepiphyseal dysplasia. Each discussion includes major clinical findings, major radiographic features, genetics, major differential diagnoses, and a bibliography.

Type 2 Collagen Group

2012 ◽  
pp. 127-153 ◽  
Author(s):  
Jürgen W. Spranger ◽  
Paula W. Brill ◽  
Gen Nishimura ◽  
Andrea Superti-Furga ◽  
Sheila Unger
Keyword(s):  
Autosomal Dominant ◽  
Clinical Findings ◽  
Differential Diagnoses ◽  
Spondyloepiphyseal Dysplasia ◽  
Collagen Group ◽  
Spondyloepiphyseal Dysplasia Congenita ◽  
Epiphyseal Dysplasia ◽  
Achondrogenesis Type ◽  
Kniest Dysplasia

Chapter 24 covers disorders of the Type 2 collegen group (achondrogenesis type 2 (MIM100610), hypochondrogenesis (MIM 200610), spondyloepiphyseal dysplasia Torrance type (MIM 151210), spondyloepiphyseal dysplasia congenita (MIM 183900), Kniest dysplasia (MIM 256550), spondyloperipheral dysplasia (MIM 271700), spondyloepiphyseal dysplasia with metatarsal shortening (MIM 609162), autosomal dominant spondyloarthropathy (MIM 604864), vitreoretinopathy with phalangeal epiphyseal dysplasia (MIM 120140.0037), Stickler dysplasia (MIM 108300, 604841)), including major clinical findings, radiographic features, and differential diagnoses.

scholarly journals Prospects and limitations of improving skeletal growth in a mouse model of spondyloepiphyseal dysplasia caused by R992C (p.R1192C) substitution in collagen II

PLoS ONE ◽  
2017 ◽  
Vol 12 (2) ◽  
pp. e0172068 ◽  
Author(s):  
Machiko Arita ◽  
Jolanta Fertala ◽  
Cheryl Hou ◽  
James Kostas ◽  
Andrzej Steplewski ◽  
...  
Keyword(s):  
Mouse Model ◽  
Skeletal Growth ◽  
Spondyloepiphyseal Dysplasia ◽  
Collagen Ii

scholarly journals Phenocopy of a heterozygous carrier of X-linked retinitis pigmentosa due to mosaicism for a RHO variant

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ine Strubbe ◽  
Caroline Van Cauwenbergh ◽  
Julie De Zaeytijd ◽  
Sarah De Jaegere ◽  
Marieke De Bruyne ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Somatic Mosaicism ◽  
Retinal Disease ◽  
Hair Follicles ◽  
Disease Genes ◽  
Female Carrier ◽  
Autofluorescence Imaging ◽  
Targeted Next Generation Sequencing ◽  
Whole Exome ◽  
Next Generation Sequencing Ngs

AbstractWe describe both phenotype and pathogenesis in two male siblings with typical retinitis pigmentosa (RP) and the potentially X-linked RP (XLRP) carrier phenotype in their mother. Two affected sons, two unaffected daughters, and their mother underwent detailed ophthalmological assessments including Goldmann perimetry, color vision testing, multimodal imaging and ISCEV-standard electroretinography. Genetic testing consisted of targeted next-generation sequencing (NGS) of known XLRP genes and whole exome sequencing (WES) of known inherited retinal disease genes (RetNet-WES). Variant validation and segregation analysis were performed by Sanger sequencing. The mutational load of the RHO variant in the mother was assessed in DNA from leucocytes, buccal cells and hair follicles using targeted NGS. Both affected sons showed signs of classical RP, while the mother displayed patches of hyperautofluorescence on blue light autofluorescence imaging and regional, intraretinal, spicular pigmentation, reminiscent of a carrier phenotype of XLRP. XLRP testing was negative. RetNet-WES testing revealed RHO variant c.404G > C p.(Arg135Pro) in a mosaic state (21% of the reads) in the mother and in a heterozygous state in both sons. Targeted NGQSS of the RHO variant in different maternal tissues showed a mutation load between 25.06% and 41.72%. We report for the first time that somatic mosaicism of RHO variant c.404G > C p.(Arg135Pro) mimics the phenotype of a female carrier of XLRP, in combination with heterozygosity for the variant in the two affected sons.

scholarly journals De novo TRPV4 Leu619Pro variant causes a new channelopathy characterised by giant cell lesions of the jaws and skull, skeletal abnormalities and polyneuropathy

2021 ◽  
pp. jmedgenet-2020-107427
Author(s):  
Aviel Ragamin ◽  
Carolina C Gomes ◽  
Karen Bindels-de Heus ◽  
Renata Sandoval ◽  
Angelia V Bassenden ◽  
...  
Keyword(s):  
Giant Cell ◽  
De Novo ◽  
Neuromuscular Disorders ◽  
Somatic Mosaicism ◽  
Ion Leakage ◽  
Gain Of Function ◽  
Therapeutic Modalities ◽  
Organ Systems ◽  
Heterozygous Variant ◽  
Systemic Disorder

BackgroundPathogenic germline variants in Transient Receptor Potential Vanilloid 4 Cation Channel (TRPV4) lead to channelopathies, which are phenotypically diverse and heterogeneous disorders grossly divided in neuromuscular disorders and skeletal dysplasia. We recently reported in sporadic giant cell lesions of the jaws (GCLJs) novel, somatic, heterozygous, gain-of-function mutations in TRPV4, at Met713.MethodsHere we report two unrelated women with a de novo germline p.Leu619Pro TRPV4 variant and an overlapping systemic disorder affecting all organs individually described in TRPV4 channelopathies.ResultsFrom an early age, both patients had several lesions of the nervous system including progressive polyneuropathy, and multiple aggressive giant cell-rich lesions of the jaws and craniofacial/skull bones, and other skeletal lesions. One patient had a relatively milder disease phenotype possibly due to postzygotic somatic mosaicism. Indeed, the TRPV4 p.Leu619Pro variant was present at a lower frequency (variant allele frequency (VAF)=21.6%) than expected for a heterozygous variant as seen in the other proband, and showed variable regional frequency in the GCLJ (VAF ranging from 42% to 10%). In silico structural analysis suggests that the gain-of-function p.Leu619Pro alters the ion channel activity leading to constitutive ion leakage.ConclusionOur findings define a novel polysystemic syndrome due to germline TRPV4 p.Leu619Pro and further extend the spectrum of TRPV4 channelopathies. They further highlight the convergence of TRPV4 mutations on different organ systems leading to complex phenotypes which are further mitigated by possible post-zygotic mosaicism. Treatment of this disorder is challenging, and surgical intervention of the GCLJ worsens the lesions, suggesting the future use of MEK inhibitors and TRPV4 antagonists as therapeutic modalities for unmet clinical needs.

scholarly journals Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

2021 ◽  
Author(s):  
Pauline Arnaud ◽  
Hélène Morel ◽  
Olivier Milleron ◽  
Laurent Gouya ◽  
Christine Francannet ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Somatic Mosaicism ◽  
Variant Calling ◽  
Copy Number Variations ◽  
Pathogenic Variant ◽  
Single Nucleotide Variants ◽  
Bioinformatics Analyses ◽  
Single Nucleotide ◽  
Fbn1 Gene ◽  
Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

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