Mutation screening of the SLC26A4 gene in a cohort of 192 Chinese patients with congenital hypothyroidism

ABSTRACT Objective Pendred syndrome (PS) is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by biallelic mutations in the SLC26A4 gene encoding for pendrin. Hypothyroidism in PS can be present from birth and therefore diagnosed by neonatal screening. The aim of this study was to examine the SLC26A4 mutation spectrum and prevalence among congenital hypothyroidism (CH) patients in the Guangxi Zhuang Autonomous Region of China and to establish how frequently PS causes hearing impairment in our patients with CH. Subjects and methods Blood samples were collected from 192 CH patients in Guangxi Zhuang Autonomous Region, China, and genomic DNA was extracted from peripheral blood leukocytes. All exons of the SLC26A4 gene together with their exon-intron boundaries were screened by next-generation sequencing. Patients with SLC26A4 mutations underwent a complete audiological evaluation including otoscopic examination, audiometry and morphological evaluation of the inner ear. Results Next generation sequencing analysis of SLC26A4 in 192 CH patients revealed five different heterozygous variations in eight individuals (8/192, 4%). The prevalence of SLC26A4 mutations was 4% among studied Chinese CH. Three of the eight were diagnosed as enlargement of the vestibular aqueduct (EVA), no PS were found in our 192 CH patients. The mutations included one novel missense variant p.P469S, as well as four known missense variants, namely p.V233L, p.M147I, p.V609G and p.D661E. Of the eight patients identified with SLC26A4 variations in our study, seven patients showed normal size/location of thyroid gland, and one patients showed a decreased size one. Conclusions The prevalence of SLC26A4 pathogenic variants was 4% among studied Chinese patients with CH. Our study expanded the SLC26A4 mutation spectrum, provided the best estimation of SLC26A4 mutation rate for Chinese CH patients and indicated the rarity of PS as a cause of CH.

摘要
研究背景与目的 彭德莱综合征（Pendred syndrome, PS）是一种常染色体隐性遗传病，以感音神经性耳聋与甲状腺激素合成障碍为特征，由编码pendrin的SLC26A4基因双等位基因突变所致。该综合征相关的甲状腺功能减退可于出生时即出现，因此可通过新生儿筛查得以确诊。本研究旨在检测中国广西壮族自治区先天性甲状腺功能减退症（congenital hypothyroidism, CH）患者的SLC26A4基因突变谱与患病率，并明确本队列中CH患者因PS导致听力损害的发生频率。

研究对象与方法 本研究纳入中国广西壮族自治区的192例CH患者，采集其外周血样本并提取外周血白细胞基因组DNA。采用下一代测序技术对SLC26A4基因的全部外显子及其外显子-内含子交界区域进行筛查。对携带SLC26A4基因突变的患者开展全面听力学评估，包括耳镜检查、听力测听及内耳形态学评估。

研究结果 对192例CH患者的SLC26A4基因进行下一代测序分析后，共在8例患者中检出5种不同的杂合变异（8/192，4%），本研究纳入的中国CH患者中SLC26A4基因突变的患病率为4%。8例患者中有3例被诊断为前庭导水管扩大症（enlargement of the vestibular aqueduct, EVA），本研究的192例CH患者中未发现PS病例。本次检出的变异包括1种新型错义变异p.P469S，以及4种已知错义变异：p.V233L、p.M147I、p.V609G及p.D661E。在检出SLC26A4变异的8例患者中，7例甲状腺大小与位置正常，仅1例存在甲状腺体积缩小的表现。

研究结论 本研究纳入的中国CH患者中，SLC26A4致病性变异的患病率为4%。本研究拓展了SLC26A4基因突变谱，为中国CH患者的SLC26A4基因突变率提供了更精准的评估数据，并表明彭德莱综合征作为CH病因的罕见性。