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Targeted next?generation sequencing identifies two novel COL2A1 gene mutations in Stickler syndrome with bilateral retinal detachment.

ABSTRACT: Stickler syndrome is a group of inherited connective tissue disorders characterized by distinctive facial and ocular abnormalities, hearing loss and early?onset arthritis. The aim of the present study was to investigate the genetic changes in two Chinese patients with Stickler syndrome, manifested as bilateral retinal detachment and peripheral retinal degeneration. Complete ophthalmic examinations, including best?corrected visual acuity, slit?lamp examination and fundus examination, were performed. Genomic DNA was extracted from leukocytes of the peripheral blood collected from the patients, their unaffected family members and 200 unrelated control subjects from the same population. Next?generation sequencing of established genes associated with ocular disease was performed. A heterozygous collagen type II ?1 chain (COL2A1) mutation c.1310G>C (p.R437P) in exon 21 was identified in Family 1 and a heterozygous COL2A1 mutation c.2302?1G>A in intron 34 was identified in Family 2. The functional effects of the mutations were assessed by polymorphism phenotyping (PolyPhen) and sorting intolerant from tolerant (SIFT) analysis. The c.1310G>C mutation was predicted to damage protein structure and function, and the c.2302?1G>A mutation was predicted to result in a splicing defect. The findings of the current study expand the established mutation spectrum of COL2A1, and may facilitate genetic counseling and development of therapeutic strategies for patients with Stickler syndrome.

SUBMITTER: Huang X

PROVIDER: S-EPMC6108863 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Targeted next‑generation sequencing identifies two novel COL2A1 gene mutations in Stickler syndrome with bilateral retinal detachment.

Huang Xinhua X Lin Ying Y Chen Chuan C Zhu Yi Y Gao Hongbin H Li Tao T Liu Bingqian B Lyu Cancan C Huang Ying Y Wu Qingxiu Q Li Haichun H Jin Chenjin C Liang Xiaoling X Lu Lin L

International journal of molecular medicine 20180704 4

Stickler syndrome is a group of inherited connective tissue disorders characterized by distinctive facial and ocular abnormalities, hearing loss and early‑onset arthritis. The aim of the present study was to investigate the genetic changes in two Chinese patients with Stickler syndrome, manifested as bilateral retinal detachment and peripheral retinal degeneration. Complete ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination and fundus examination, were perform ...[more]

PMID: 30015854

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Project description:AimsTo compare the clinical and molecular genetic features of two phenotypically distinct subgroups of families with type 1 Stickler syndrome.BackgroundStickler syndrome (hereditary arthro-ophthalmopathy, McKusick Nos 108300 and 184840) is a dominantly inherited disorder of collagen connective tissue, resulting in an abnormal vitreous, myopia, and a variable degree of orofacial abnormality, deafness, and arthropathy. Stickler syndrome is the commonest inherited cause of rhegmatogenous retinal detachment in childhood with a risk of giant retinal tear (GRT) which is commonly bilateral and a frequent cause of blindness.MethodPedigrees were identified from the vitreoretinal service database and subclassified according to vitreoretinal phenotype. Ophthalmic, skeletal, auditory, and orofacial features were assessed. Linkage analysis was carried out with markers for the candidate genes COL2A1, COL11A1, and COL11A2. The COL2A1 gene was amplified as five overlapping PCR products. Direct sequencing of individual exons identified mutations.ResultsEight families exhibiting the type 1 vitreous phenotype were studied. Seven were consistent for linkage to COL2A1, with lod scores ranging from 2.1 to 0.3. In most instances linkage to COL11A1 and COL11A2 could be excluded. One family was analysed without prior linkage analysis. Three of the families exhibited a predominantly ocular phenotype with minimal or absent systemic involvement and were found to have mutations in exon 2 of COL2A1. Five other pedigrees with an identical ocular phenotype plus orofacial, auditory, and articular involvement had mutations in others regions of the COL2A1 gene. None of the pedigrees exhibited the characteristic lenticular, retinal pigment epithelial, or choroidal changes seen in Wagner syndrome.ConclusionsThese data confirm that type 1 Stickler syndrome is caused by mutations in the gene encoding type II collagen (COL2A1). In addition, data are submitted showing that mutations involving exon 2 of COL2A1 are characterised by a predominantly ocular variant of this disorder, consistent with the major form of type II procollagen in non-ocular tissues having exon 2 spliced out. Such patients are all at high risk of retinal detachment. This has important implications for counselling patients with regard to the development of systemic complications. It also emphasises the importance and reliability of the ophthalmic examination in the differential diagnosis of this predominantly ocular form of Stickler syndrome from Wagner's vitreoretinopathy.

Project description:Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer. Using a custom-made breast cancer gene sequencing panel, we investigated somatic mutations in IBC to better understand the genomic differences compared with non-IBC and to consider new targeted therapy in IBC patients.Targeted next-generation sequencing (NGS) of 91 candidate breast cancer-associated genes was performed on 156 fresh-frozen breast tumor tissues from IBC patients. Mutational profiles from 197 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as non-IBC controls for comparison analysis. The mutational landscape of IBC was correlated with clinicopathological data and outcomes.After genotype calling and algorithmic annotations, we identified 392 deleterious variants in IBC and 320 variants in non-IBC cohorts, respectively. IBC tumors harbored more mutations than non-IBC (2.5 per sample vs. 1.6 per sample, p?<?0.0001). Eighteen mutated genes were significantly different between the two cohorts, namely TP53, CDH1, NOTCH2, MYH9, BRCA2, ERBB4, POLE, FGFR3, ROS1, NOTCH4, LAMA2, EGFR, BRCA1, TP53BP1, ESR1, THBS1, CASP8, and NOTCH1. In IBC, the most frequently mutated genes were TP53 (43.0%), PIK3CA (29.5%), MYH9 (8.3%), NOTCH2 (8.3%), BRCA2 (7.7%), ERBB4 (7.1%), FGFR3 (6.4%), POLE (6.4%), LAMA2 (5.8%), ARID1A (5.1%), NOTCH4 (5.1%), and ROS1 (5.1%). After grouping 91 genes on 10 signaling pathways, we found that the DNA repair pathway for the triple-negative breast cancer (TNBC) subgroup, the RTK/RAS/MAPK and cell cycle pathways for the HR-/HER2+ subgroup, the DNA repair, RTK/RAS/MAPK, and NOTCH pathways for the HR+/HER2- subgroup, and the DNA repair, epigenome, and diverse pathways for the HR+/HER2+ subgroup were all significantly differently altered between IBC and non-IBC. PIK3CA mutation was independently associated with worse metastasis-free survival (MFS) in IBC since the median MFS for the PIK3CA mutant type was 26.0 months and for the PIK3CA wild type was 101.1 months (p?=?0.002). This association was observed in TNBC (p?=?0.04) and the HR-/HER2+ subgroups (p?=?0.0003), but not in the HR+/HER2- subgroup of IBC.Breast cancer-specific targeted NGS uncovered a high frequency of deleterious somatic mutations in IBC, some of which may be relevant for clinical management.

Dataset Information

Targeted next?generation sequencing identifies two novel COL2A1 gene mutations in Stickler syndrome with bilateral retinal detachment.

Publications

Targeted next‑generation sequencing identifies two novel COL2A1 gene mutations in Stickler syndrome with bilateral retinal detachment.

Similar Datasets

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