Knobloch syndrome caused by homozygous frameshift mutation of the COL18A1 gene in a Chinese pedigree

AIM: To explore the clinical feature and genetic etiology of a Chinese Knobloch syndrome family. METHODS: Ocular examinations and magnetic resonance imagings (MRIs) were performed on the family. Whole exome sequencing was conducted on the two patients. Sanger sequencing was utilized to validate the presence of variation in the family as well as in 100 normal controls. Real-time quantitative polymerase chain reaction (PCR) was used to detect the expression level of COL18A1 in peripheral blood lymphocytes of the patients and normal carriers. RESULTS: The affected subjects presented with vision loss, exotropia, cataracts, retinal detachment, and other complications. A homozygous c.4759_4760delCT (p.Leu1587ValfsX72) mutation (rs398122391) in COL18A1 was identified in the two patients, cosegregating with the phenotypes, and did not be detected in 100 normal controls. This mutation caused significant decreased expression of COL18A1 mRNA in the patients. CONCLUSION: The findings strongly indicate that this mutation is the disease-causing mutation. Moreover, this is the first Knobloch syndrome pedigree reported in the Chinese population.     

A new familial case of Jalili syndrome caused by a novel mutation in CNNM4

Jalili syndrome (JS) is a rare autosomal recessive disorder characterized by the combination of cone-rod dystrophy (CRD) and amelogenesis imperfecta. To date, 18 families with JS have been reported, 16 of which were found to have a mutation in CNNM4. We describe three siblings with clinical features of JS with a homozygous missense mutation in exon 4 of CNNM4, c.1781A>G (p.N594S). They demonstrated phenotypic variability in terms of ocular and dental findings. Although fundus examination and optical coherence tomography results were normal, the electroretinogram was compatible with CRD, supporting the diagnosis of JS. The dental phenotype severity also varied among the siblings.     

HSF4基因突变导致常染色体显性遗传核性白内障

目的 鉴定一个延续5代常染色体显性遗传核性白内障家系的致病基因。方法 根据已知先天性白内障致病基因在染色体上的定位，选择了D16S539分子标记，对该家系进行连锁分析，通过基因测序鉴定致病基因。结果 该69名家系成员中有16例患有先天性核性白内障，致病基因定位于16q21-q22，并在候选基因HSF4外显子3检测到一新的突变杂合子134456G-A，该突变导致112E的同义突变，而在家系正常成员中则未检测到该突变。结论 该家系核性白内障表型很可能系由HSF4基因134456G-A突变所致，且此突变尚未见报道。     

Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene.

PURPOSE: A 5-bp deletion in ELOVL4, a photoreceptor-specific gene, has been associated with autosomal dominant (ad) macular dystrophy phenotypes in five related families, in which phenotypes range from Stargardt-like macular dystrophy (STGD3; Mendelian Inheritance in Man 600110) to pattern dystrophy. This has been the only mutation identified in ELOVL4 to date, which is associated with macular dystrophy phenotypes. In the current study, the potential involvement was investigated of an ELOVL4 gene variation in adSTGD-like and other macular dystrophy phenotypes segregating in a large unrelated pedigree from Utah (K4175). METHODS: The entire open reading frame of the ELOVL4 gene was analyzed by direct sequencing in a proband from the K4175 family. The combination of denaturing high-performance liquid chromatography (DHPLC) analysis and direct sequencing of all available family members was used to further assess segregation of identified ELOVL4 variants in the pedigree. RESULTS: A complex mutation, two 1-bp deletions separated by four nucleotides, was detected in all affected members of the family. The mutation results in a frameshift and the truncation of the ELOVL4 protein, similar to the effect of the previously described 5-bp deletion. CONCLUSIONS: The discovery of a second mutation in the ELOVL4 gene segregating with macular dystrophy phenotypes confirms the role of this gene in a subset of dominant macular dystrophies with a wide range of clinical expressions and suggests a role for modifying genes and/or environmental factors in the disease process.     

Autosomal dominant pericentral retinal dystrophy caused by a novel missense mutation in the TOPORS gene

Purpose: This study aimed to identify the genetic cause of autosomal dominant pericentral retinal dystrophy (adPRD) in a large Norwegian family with 35 affected members. Methods: The family was characterized by clinical ophthalmological examination along with fundus photography, dark adaptometry and electroretinography. We performed a genome‐wide linkage analysis followed by sequencing of a candidate gene to identify the mutation causing the disease. Results: The ophthalmological examinations revealed an atypical form of retinitis pigmentosa (RP), which we prefer to call adPRD. Compared with classical RP, this phenotype has a favourable prognosis. Linkage analysis showed a linkage peak covering the most recently reported adRP gene TOPORS. This gene was sequenced in 19 family members and a novel missense mutation, c.1205a>c, resulting in an amino acid substitution p.Q402P, was detected in all affected members. The mutation showed complete co‐segregation with the disease in this family, with a LOD score of 7.3. It is located in a highly conserved region and alignment with the appropriate DNA sequence from other species shows complete conservation of this amino acid. The mutation was not detected in 207 healthy, unrelated controls of Norwegian origin. Conclusions: We present a novel mutation in the TOPORS gene co‐segregating with a distinct phenotype of adPRD in a large Norwegian family.     

Posterior chorioretinal atrophy and vitreous phenotype in a family with Stickler syndrome from a mutation in the COL2A1 gene

PURPOSE: To report posterior chorioretinal atrophy (PCRA) and correlate the vitreous phenotype with inheritance of the disease mutation in a family with vitreoretinal dystrophy. DESIGN: Prospective observational case series. METHODS: Twenty-four members of a family with 14 affected individuals were examined, and genetic linkage analysis was performed at the COL2A1, COL11A1, and Wagner disease loci. The vitreous phenotype was prospectively graded as optically empty with retrolenticular membrane, fibrillar, or normal. Ocular ultrasonography and optical coherence tomography (OCT) were performed on selected individuals to study the vitreous structure and vitreoretinal interface. RESULTS: The 6-year-old proband had PCRA and optically empty vitreous without systemic features, suggestive of Wagner disease. The family history was negative for systemic disease, except for one cousin with cleft palate. However, when examined, clinical features of the 14 affected subjects included 5 with small chin, 4 with at least submucosal cleft palate, and 9 with a myopic refractive error greater than 5 diopters. Lens opacity or previous cataract extraction was found in 13 family members. All affected individuals in whom the vitreous could be examined had an optically empty vitreous with retrolental membrane. Posterior chorioretinal atrophy was found in eight of the affected subjects. The finding was not limited to highly myopic subjects, nor did all the high myopes have PCRA. Ultrasonography and OCT revealed vitreous adherent to the retina, but without apparent retinal distortion or edema of the macula. Significant linkage was established to the COL2A1 locus; the other loci were excluded. A single nucleotide insertion mutation (c.2012 2013insC) was identified in exon 34, leading to a downstream premature stop codon in the COL2A1 gene. CONCLUSIONS: Although posterior chorioretinal atrophy and vitreoretinal degeneration have been classically associated with Wagner disease, we demonstrate its presence in a family with typical Stickler syndrome. On the basis of clinical, ultrasonographic, and OCT studies, the etiology of PCRA in this family does not seem to be attributable to vitreomacular traction or myopia. The vitreous findings in this large family confirm reports that mutations in the COL2A1 gene lead to the optically empty vitreous with retrolenticular membrane phenotype.     

A novel deletion mutation in RS1 gene caused X-linked juvenile retinoschisis in a Chinese family

Purpose

X-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spoke-wheel pattern in the macular region of the retina and splitting of the neurosensory retina. This study aimed to identify the underlying genetic defect in a Chinese family with XLRS.

Methods

The proband underwent complete ophthalmic examinations, including fundus examination, fundus autofluorescence, and optical coherence tomography. DNA extracted from proband and his younger brother was screened for mutations in RS1 gene. The detected RS1 mutation was tested in all available family members and 200 healthy controls.

Results

Reduced visual acuity, spoke-wheel pattern at the fovea, and split retina were observed in the proband. A novel frameshift mutation c.206-207delTG in the RS1 gene, leading to a truncated protein (p.L69fs16X), was identified in the proband and his younger brother. This mutation was not found in any unaffected member or in the healthy controls. The mother of the proband was hemizygous for this mutant allele.

Conclusions

We identified a novel causative mutation of RS1 in a Chinese family with XLRS. This finding expands the mutation spectrum of RS1 and provides evidence for a phenotype–genotype study in XLRS.     

LRP5基因一个新的突变位点相关的家族性渗出性玻璃体视网膜病变

目的:分析家族性渗出性玻璃体视网膜病变(FEVR)一家系的临床表型和基因突变特点。方法:采用家系调查研究方法,收集2019年10月于西安交通大学第一附属医院诊断为FEVR的1个汉族家系2代3名成员。对患者及其父母进行视力、眼压、裂隙灯显微镜和广角荧光素眼底血管造影(FFA)检查,采集3名成员外周血送检,应用高通量测序法...     

A novel compound heterozygous mutation in the RDH5 gene in a patient with fundus albipunctatus

PURPOSE: To report a novel compound heterozygous mutation in the 11-cis retinol dehydrogenase (RDH5) gene in a patient with fundus albipunctatus. METHOD: We examined the RDH5 gene genotype in members of a Japanese family. Clinical examination showed that the proband had fundus albipunctatus and his aunt had retinitis pigmentosa. The RDH5 gene was analyzed by direct genomic sequencing. RESULTS: The proband had a compound heterozygotic missense mutation of Val177Gly (GTC-->GGC) and Arg280His (CGC-->CAC) in his RDH5 gene. His mother had the Arg280His mutation and his father had the Val177Gly mutation, but his father's aunt who has typical retinitis pigmentosa had the wild type RDH5 gene. The occurrence of Val177Gly has not been reported in the RDH5 gene of fundus albipunctatus. CONCLUSION: A novel compound heterozygous missense mutation in the RDH5 gene was found in a patient with fundus albipunctatus.     

NDP基因新突变G113D导致X连锁隐性遗传家族性渗出性玻璃体视网膜病变

目的对一个X连锁隐性遗传家族性渗出性玻璃体视网膜病变（FEVR）家系进行致病基因的突变筛查研究。设计基因研究。研究对象一个中国北方FEVR家系。方法应用聚合酶链式反应（PCR）和sanger测序法对FEVR的致病候选基因LRP5、FZD4、TSPAN12和NDP的全部外显子进行突变筛查,将测序结果与Genebank数据库的正常序列进行比对,将所发现的候选基因碱基改变在50个无关正常对照人群中进行PCR和测序验证。主要指标基因序列。结果在NDP基因的外显子3发现一个半合子错义突变G113D与家系男性先证者共分离,先证者母亲显示为G113D的杂合携带者,该突变在家系其他成员及正常人群中没有检测到。结论该家系的FEVR系由ⅣDP基因外显子3的一个新的错义突变G113D导致。     

A novel Nance-Horan syndrome mutation identified by next-generation sequencing in a Chinese family

AIM: To identify the disease-causing mutation in a four-generation Chinese family diagnosed with Nance-Horan syndrome (NHS). METHODS: A Chinese family, including four affected patients and four healthy siblings, was recruited. All family members received ophthalmic examinations with medical histories provided. Targeted next-generation sequencing approach was conducted on the two affected males to screen for their disease-causing mutations. RESULTS: Two male family members diagnosed with NHS manifested bilateral congenital cataracts microcornea, strabismus and subtle facial and dental abnormalities, while female carriers presented posterior Y-sutural cataracts. A novel frameshift mutation (c.3916_3919del) in the NHS gene was identified. This deletion was predicted to alter the reading frame and generate a premature termination codon after a new reading frame. CONCLUSION: The study discovers a new frameshift mutation in a Chinese family with NHS. The findings broaden the spectrum of NHS mutations that can cause NHS in Chinese patients.     

A novel mutation in the ELOVL4 gene causes autosomal dominant Stargardt-like macular dystrophy

PURPOSE: To conduct clinical and genetic studies in a European family with autosomal dominant Stargardt-like macular dystrophy (adSTGD-like MD) and to investigate the functional consequences of a novel ELOVL4 mutation. METHODS: Ophthalmic examination and mutation screening by direct sequencing of the ELOVL4 gene was performed in two affected individuals. Wild-type and mutant ELOVL4 genes were expressed as enhanced green fluorescent protein (EGFP) fusion proteins in transient transfection in NIH-3T3 and HEK293 cells. To determine the subcellular localization of ELOVL4, an endoplasmic-reticulum (ER)-specific marker for pDsRed2-ER was cotransfected with ELOVL4 constructs. Transfected cells were viewed by confocal microscopy. Western blot analysis was performed to assess protein expression using an anti-GFP antibody. RESULTS: Affected patients exhibited macular atrophy with surrounding flecks characteristic of adSTGD-like MD. A novel ELOVL4 p.Tyr270X mutation was detected in affected individuals. In cell-transfection studies, wild-type ELOVL4 localized preferentially to the ER. In contrast, the mutant protein appeared to be mislocalized within transfected cells. CONCLUSIONS: In a European family with adSTGD-like MD, a novel ELOVL4 mutation was found to underlie the disorder. Transfection studies indicated that, unlike wild-type ELOVL4, the mutant protein does not localize to the ER but rather appears to be sequestered elsewhere in an aggregated pattern in the cytoplasm. Further analysis of the function of normal and mutant ELOVL4 will provide insight into the mechanism of macular degeneration.