两个X连锁遗传先天性特发性眼球震颤家系FRMD7基因突变的研究

目的　研究两个Ｘ连锁遗传先天性特发性眼球震颤（ｃｏｎｇｅｎｉｔａｌｉｄｉｏｐａｔｈｉｃｎｙｓｔａｇ-ｍｕｓ,ＣＩＮ）家系的致病基因突变。方法　在获取知情同意后,对两个家系进行病史采集及临床检查以确定其遗传表型;通过系谱分析,确定遗传模式;筛选致病基因进行直接测序,分析发现致病突变。结果　两个家系均为Ｘ连锁遗传,其中ＣＩＮ-０１家系所有患者均携带错义突变ｃ．６８５Ｃ＞Ｔ,位于ＦＲＭＤ７基因外显子８上,该突变可导致ＦＲＭＤ７编码的精氨酸被半胱氨酸替换（ｐ．Ｒ２２９Ｃ）;ＣＩＮ-０２家系所有患者及携带者均携带错义突变ｃ．８８７Ｇ＞Ｃ,位于ＦＲＭＤ７基因外显子９上,该突变使ＦＲＭＤ７蛋白第２９６位的甘氨酸被替换为精氨酸（ｐ．Ｇ２９６Ｒ）。结论　ＦＲＭＤ７基因ｃ．６８５Ｃ＞Ｔ及ｃ．８８７Ｇ＞Ｃ分别是引起ＣＩＮ-０１家系及ＣＩＮ-０２家系致病的主要原因。     

两个Usher综合征家系的临床表型分析及致病基因位点的初步定位

目的:分析2个Usher综合征家系USH-001,USH-002的临床表型特征及遗传学特点,对已知致病基因位点进行筛查,确定可能的候选基因。方法:分析USH-001,USH-002家系患者的临床表型特征、系谱特征,利用连锁分析的原理和方法,对12个已知致病基因位点周围的微卫星标记进行扫描,筛选可能的致病基因位点。结果:USH-001,USH-002家系中的患者在10～13岁出现夜盲症状,随年龄增长夜盲逐渐加重,并出现视野逐渐缩窄至管状视野,中心视力下降不明显,眼底周边见骨细胞样色素沉着;患者在儿童期出现双耳听力下降,为非渐进性、中-重度感音神经性耳聋,以高频听力损失为主,前庭功能正常。表型未出现连续遗传的现象。USH-001家系中所有患者的D11S902,D17S785微卫星标记的Allele值完全一致,USH-002家系所有患者的微卫星标记D1S425,D9S1776的Allele值完全一致。结论:USH-001,USH-002家系临床表现符合USH2型,为常染色体隐性遗传家系。USH1C,USH1G可能为USH-001家系的致病基因;USH2A,USH2D可能为USH-002家系的致病基因。     

Identification of a novel mutation in the FGF10 gene in a Chinese family with obvious congenital lacrimal duct dysplasia in lacrimo-auriculo-dento-digital syndrome

AIM: To identify the pathogenic gene variant in a family with lacrimo-auriculo-dento-digital syndrome [LADD (MIM 149730)] showing congenital lacrimal duct dysplasia as the main clinical manifestation and lay the foundation for future research on the pathogenic gene.METHODS: Ophthalmological examinations, including slit-lamp biomicroscopy and lacrimal duct probing, and computed tomography dacryocystography (CT-DCG) were performed for all participants. The family pedigree was drawn, genetic features were analyzed, and the genomic DNA of the subjects was extracted. Pathogenic genes were screened via whole exome sequencing (WES) and confirmed using Sanger sequencing.RESULTS: Six patients belonged to this three-generation family, and their clinical manifestations included congenital nasolacrimal duct obstruction, congenital absence of lacrimal puncta and canaliculi, lacrimal fistulae, and limb deformities. This pattern indicates autosomal dominant inheritance. Diagnosis was based on the clinical characteristics of LADD syndrome, which presented in all the patients in this family. A novel frameshift mutation in the FGF10 gene (NM_004465.1), c.234dupC (p.Trp79Leus*15), was identified in all patients via WES. The variant was confirmed by Sanger sequencing and classified as a “pathogenic mutation” according to the American College of Medical Genetics and Genomics (ACMG) variant interpretation guidelines.CONCLUSION: A novel frameshift mutation in the FGF10 gene is found in all patients. This finding helps this family with LADD syndrome receiving a more accurate clinical diagnosis and genetic counseling by extending the mutation range of the FGF10 gene.