CHM基因变异女性携带者表型和基因型特点

目的 总结分析中国CHM基因变异女性携带者表型、基因型特点。设计 回顾性病例系列。研究对象 北京同仁医院眼科就诊并已确定携带CHM基因变异的5个无脉络膜症（choroideremia, CHM）家系中的6例女性携带者。方法 先证者及家系成员均进行详细的眼科检查。用sanger测序、目标区域捕获测序（target exonm sequencing，TES）、实时定量PCR实验确定5个CHM家系的CHM基因致病变异。记录并分析6例女性携带者的临床表现及变异基因分级。主要指标 视力、眼底像、光学相干断层扫描图像（OCT）、眼底自发荧光（FAF）及各携带者携带CHM基因变异及其ACMG分级。结果 6例携带者来自于5个没有血缘关系的家庭。本组携带者共检测到5种CHM基因变异，包括一个无义变异（p.Y565*），一个剪接位点变异（c.820-1G>T），一个启动子区变异（c.-98C>G）和两个拷贝数异常（Exon1_2 del；Exon5_12 dup）。其中三种变异（p.Y565*，c.-98C>G，Exon5_12 dup）为未曾报道过的新变异，根据ACMG分级标准，该三种变异的致病性评级为致病或可能致病。所有女性携带者平均年龄为（34.00±14.83）岁（范围8~53岁），视力正常，无夜盲、视野缩小等症状。眼底像上显示出点状或片状的视网膜色素减退，可伴有界限清晰的黄色点状沉着。FAF上可见斑驳样片状或马赛克样中低荧光，可伴有点状高荧光。2名携带者进行了3年的随访，视力均稳定，眼底无变化。结论 本研究拓展了CHM基因变异的变异谱，与欧美CHM基因变异携带者相比，中国女性携带者视功能损伤及眼底改变更轻微。（眼科，2021, 30： 211-216）     

里昂化作用与眼部疾病

里昂化作用（Lyonization）又称X染色体失活,是指雌性哺乳类动物细胞中两条X染色体的其中之一失去活性的现象.一些眼部X连锁隐性遗传病如先天性无脉络膜症、视网膜色素变性、X-连锁眼部白化病等都有里昂化作用的参与.通过了解里昂化作用将有助于眼部X连锁隐性遗传病的诊断及治疗.     

En face OCT in choroideremia

ABSTRACT

Purpose: To describe the outer retinal tubulation (ORT) morphology using En face OCT elaboration in a large group of patients affected by choroideremia (CHM).

Material and Methods: We retrospectively reviewed CHM patients examined at the Regional Reference Center for Hereditary Retinal Degenerations at the Eye Clinic in Florence. We took into consideration genetically confirmed CHM patients with ophthalmological, fundus autofluorescence (FAF) and optical coherence tomography (OCT) examinations.

Results: We studied en face OCT features of ORTs in 18 CHM patients, for a total of 36 eyes; (average age 33 years; SD 19,2; range 13–77 years). ORTs were found in 30 eyes of 15 patients (15/18; 83,3% of the patients). We identified 3 en face OCT patterns: round lesions with scalloped boundaries which involved the peripapillary area with more or less evident pseudodendritic ORTs (PD-ORT) (pattern p; 26,7%); central islands with PD-ORTs (pattern i; 53,3%); residual outer retinal areas with no ORTs (pattern r; 20,0%).

Conclusions: In CHM, en face OCT imaging allows us to observe various morphological features of the ORTs in different stages of disease, not detectable with other imaging techniques. ORTs were not identified in the mildest phenotypes. En face OCT is a non-invasive useful tool in the characterization and monitoring of the disease.     

Attitudes towards prenatal diagnosis and selective abortion among patients with retinitis pigmentosa or choroideremia as well as among their relatives

Genetic counselling endeavours to be nondirective. However, the availability of prenatal diagnosis may direct clients towards accepting and using these methods. It is time to investigate the attitudes of clients in order to monitor the psychological and social effects of new genetic techniques. As prenatal diagnosis was possible for choroideremia (C), but not for retinitis pigmentosa (RP) in 1988–89, we used a questionnaire to compare the attitudes of C and RP patients, their relatives and C carriers to prenatal diagnosis. The response rate was low (35%) and no significant differences between RP and C groups came to light. However, C carriers accepted prenatal diagnosis and also selective abortion more easily, but, on the other hand, they showed more uncertainty than did the other groups. This indicates that the availability of prenatal diagnosis may confuse those concerned. In general, about 60% of all the respondents had a positive attitude to the prenatal diagnosis of RP or choroideremia, though only about 30% would use it for abortion. Over 80% of all the respondents wanted to know the opinion of the genetic counsellor.     

Mapping X-linked ophthalmic diseases. Provisional assignment of the locus for choroideremia to Xq13-q24

Choroideremia (McK 30310), an X-linked hereditary retinal dystrophy, causes nyctalopia, progressive visual field loss, and ultimately central blindness in affected males in early adulthood. We have used restriction fragment length polymorphisms from the X-chromosome to localize the region of the mutation for choroideremia in three families with this disorder. One polymorphic marker, DXYS1, located within Xq13-q21, shows no recombination with choroideremia at a LOD score of 5.78. Thus choroideremia maps within 9 centiMorgans of DXYS1 at 90% probability. Another marker, DXS11, located at Xq24-q26, shows no recombination with choroideremia but at a smaller LOD score of 1.54. These results suggest that the locus for choroideremia is distal to DXYS1 and between the two markers in the region Xq13-q24. This information may be useful for antenatal diagnosis, isolation of the mutant gene, and development of a rational therapy for the disorder.     

Choroideremia in a woman with ectodermal dysplasia and complex translocations involving chromosomes X, 1, and 3

Background: Choroideremia is an X-linked recessive disorder characterized by vision loss with progressive atrophy of the retinal photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris. Ectodermal dysplasia is a heterogeneous group of disorders characterized by a deficiency of two or more ectodermal derivatives. We report on the phenotypic and genetic characteristics of a 29-year-old woman with both choroideremia and ectodermal dysplasia.

Materials and Methods: Observational case report with physical and ophthalmic examination, fluorescein angiography (FA), visual field testing, electroretinography, and cytogenetic analysis. This study adhered to the tenets of the Declaration of Helsinki and The New York Eye and Ear Infirmary Institutional Review Board guidelines.

Results: Physical and ocular examination revealed hypotrichosis, hypohidrosis, full dentures, meibomian gland hypoplasia, and a decrease in corneal tear film. Visual acuity was hand motions in the right eye and 20/50 in the left eye. Fundus examination and fluorescein angiography were consistent with advanced choroideremia and revealed diffuse bilateral RPE and chorioretinal atrophy with sparing of the fovea. Visual field testing had less than 10-degree central islands in both eyes. Scotopic electroretinogram (ERG) was flat with a small flicker response. Cytogenetic analysis showed a complex translocation involving chromosomes X, 1, and 3: 46,X,t(X;1;3)(q13;q24;q21),inv(9)(p11q13). Selective inactivation of the normal X chromosome was present in blood and skin. Chromosomal analyses of the proband’s family (mother and two brothers) were normal.

Conclusion: An X-autosome chromosomal translocation combined with non-random inactivation of the normal X-chromosome in a woman resulted in the phenotypic findings of choroideremia and ectodermal dysplasia.     

Choroideremia: New Findings from Ocular Pathology and Review of Recent Literature

Histopathology of young individuals affected by choroideremia is rarely available to allow correlation with the clinical presentation. A 30-year-old man with choroideremia died in a motor vehicle accident and one eye was subjected to histopathological examination. Immunoblot analysis of protein derived from white blood cells of a living brother, also affected with choroideremia, confirmed the absence of Rab escort protein-1, the normal CHM gene product. Direct sequencing of the coding region and adjacent splice sites of the CHM gene was undertaken on genomic DNA from the living brother and revealed a transition mutation, C to T, in exon 6 (R253X) which resulted in a stop codon and was predicted to truncate the protein product. Histopathological examination of the eye of the deceased brother showed relative independent degeneration of choriocapillaris, retinal pigment epithelium, and retina, similar to observations in the mouse model of choroideremia. In addition, mild T-lymphocytic infiltration was found within the choroid. The ophthalmic features and the pathology of choroideremia are discussed in light of new findings in the current case.