目的:本研究的目的是确定一组台湾Stickler综合征患者的基因突变和表型相关性。
方法:纳入临床诊断为Stickler综合征或疑似Stickler综合征的患者。从静脉血样品中提取DNA。对于靶向下一代测序(NGS)方法,针对所有COL2A1,COL11A1,COL11A2,COL9A1和COL9A2外显子和侧翼内含子序列设计了特异性引物。
结果:本研究纳入了来自12个家庭的23名患者。23例(35眼)的近视度数范围为-4.625至-25.625D,中位数为-10.00D。4例患者出现视网膜脱离。14例患者有腭裂。这23名患者和13名健康对照被纳入NGS研究。三个家族在COL2A1中具有显著的单核苷酸变异(SNV)。本次调查的突变率分别为25%(3/12家族)和35%(8/23例)。1号家族的SNV,位于外显子27,c.1753G>T,p.Gly585Val,是新颖的,尚未在ClinVar数据库中报告。家庭#10和#11有相同的SNV,位于外显子33,c.21C>T,p.Arg701X。根据美国医学遗传学和基因组学学会指南,这两种变体都被归类为可能的致病性。
结论:在25%的台湾Stickler综合征家庭中发现COL2A1基因突变。使用NGS鉴定了一个新的变体,这扩大了COL2A1的突变谱。分子遗传学分析有助于明确疑似Stickler综合征患者的临床诊断。
OBJECTIVE: The purpose of this study was to identify gene mutation and phenotype correlations in a cohort of Taiwanese patients with Stickler syndrome.
METHODS: Patients clinically diagnosed with Stickler syndrome or suspected Stickler syndrome were enrolled. DNA was extracted from venous blood samples. For the targeted next-generation sequencing (NGS) approach, specific primers were designed for all COL2A1, COL11A1, COL11A2, COL9A1, and COL9A2 exons and flanking intron sequences.
RESULTS: Twenty-three patients from 12 families were enrolled in this study. The myopia power in these 23 cases (35 eyes) ranged from -4.625 to -25.625 D, with a median of -10.00 D. Four patients had retinal detachment. Fourteen patients had a cleft palate. These 23 patients and 13 healthy controls were enrolled in the NGS study. Three families had significant single nucleotide variants (SNVs) in COL2A1. The mutation rates in this survey were 25% (3/12 families) and 35% (8/23 cases). The SNV of family #1, located at exon 27, c.1753G >T, p. Gly585Val, was novel and has not yet been reported in the ClinVar database. Families #10 and #11 had the same SNV, located in exon 33, c.2101C >T, p. Arg701X. Both variants were classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines.
CONCLUSIONS: Genetic mutations in COL2A1 were found in 25% of Taiwanese families with Stickler syndrome. One novel variant was identified using NGS, which expanded the COL2A1 mutation spectrum. Molecular genetic analysis is helpful to confirm the clinical diagnosis of patients with suspected Stickler syndrome.