A genetic analysis of retinitis pigmentosa.

Genetic analysis of 457 patients with retinitis pigmentosa (RP) included categorisation of families by recognised mendelian pattern of inheritance and formal segregation analysis of all informative sibships. Of the 368 probands a surprisingly high 18% (68) had significant congenital loss of hearing and were diagnosed as having Usher syndrome. The RP probands were categorised as: 21.7% autosomal dominant, 9.0% X-linked, 16.0% autosomal recessive, 3.3% genetic type uncertain, and 50.0% simplex. Segregation analysis reflected this high proportion of simplex cases, accounting for reduced penetrance in dominant families; only 20% remain classified as sporadic (possibly nongenetic). In the matings between normal persons estimates of the segregation ratio also indicate lower values than expected. Unlike in RP sibship, segregation in the Usher syndrome is consistent with the hypothesis of recessive inheritance. Therefore RP with significant hearing loss segregates as expected, while even if a proband is classified as a dominant or recessive the recurrence risk for the RP phenotype may be below mendelian expectation.     

Genetische Untersuchungen bei kongenitaler Katarakt

Bilateral congenital cataract is genetic in at least 25% of cases. In contrast, unilateral congenital cataract is usually sporadic. Genetic heterogeneity is significant with the involvement of more than 30 genes having been identified to date. Phenotypes are defined by the location and morphology of the lens opacities. Mutations in the same gene may result in different phenotypes (clinical heterogeneity), and mutations in different genes may be associated with similar phenotypes (genetic heterogeneity). The mode of inheritance is mostly autosomal dominant but autosomal recessive and X-linked modes also occur. Expressivity may be variable and penetrance reduced. In X-linked cataract, carriers may show carrier signs. A precise pedigree analysis and a clinical examination of further family members are mandatory for correct genetic counselling. Metabolic cataract may be diagnosed biochemically. Molecular genetic analysis is not offered routinely to date with the exemption of a few genes.     

Genetic features of retinitis pigmentosa in Turkey

Sixty-two cases with retinitis pigmentosa from 42 index families were investigated to reveal the genetic features of the disease in Turkey. There were 42 propositi of whom 5 had a systemic syndrome associated with retinitis pigmentosa. Of the remaining 37 cases the condition was autosomal recessive in 21 (56.8%), sporadic in 12 (32.4%), autosomal dominant in 3 (8.1%) and X-linked recessive in one (2.7%). Sporadic cases may be more frequent as many hereditary cases are not brought to medical attention in rural families. Male preponderance among sporadic cases may indicate that there may be more X-linked cases. Nine out of 21 cases initially classified as sporadic displayed parental consanguinity and they were included as having autosomal recessive trait. Large families with autosomal recessive inheritance may prove valuable in linkage analysis and in defining future gene abnormalities.     

Exclusion of AR-CHED from the chromosome 20 region containing the PPMD and AD-CHED loci

Congenital hereditary endothelial dystrophy (CHED) is a disorder of the corneal endothelium and has been recognized to segregate in families with both autosomal dominant (AD) and autosomal recessive (AR) modes of transmission. AD-CHED has been previously linked to the pericentric region of chromosome 20. Posterior polymorphous dystrophy (PPMD), a corneal endothelial disorder showing phenotypic overlap with CHED, has also been previously genetically mapped to this region. The genetic interval containing AD-CHED is within the larger genetic interval containing the PPMD locus. This study sought to determine whether AR-CHED segregating in a consanguineous Saudi Arabian pedigree is linked to the previously mapped and overlapping loci for AD-CHED and PPMD on the pericentric region of chromosome 20. Forty members of a consanguineous Saudi Arabian pedigree segregating AR-CHED were ascertained. Short tandem-repeat polymorphic markers from the 20 cM interval on chromosome 20 containing both the PPMD and AD-CHED loci were used to genotype these individuals. LOD score analysis of the genotype data with the MENDEL software package utilizing a model of autosomal recessive inheritance with complete penetrance showed exclusion of CHED from the entire PPMD/AD-CHED interval by utilizing overlapping intervals of LOD scores of at least -2. The results obtained demonstrate that AR-CHED is not allelic to either AD-CHED or PPMD, although it has been proposed that AD-CHED may be allelic to PPMD. Thus, there are at least two genes responsible for CHED and PPMD.     

A rare homozygous rhodopsin splice-site mutation: the issue of when and whether to offer presymptomatic testing

Having identified a disease-associated rhodopsin mutation in a patient with retinitis pigmentosa (RP), the issue is to address the question of whether to offer genetic testing to at-risk family members. Two members of a South African (SA) family, one of whom suffers from RP, as well as 54 unrelated SA RP patients from the same population group were investigated using single-stranded conformational polymorphism analysis followed by DNA sequencing. A rare homozygous mutation at the intron-exon boundary of exon 4 in the rhodopsin gene was identified in the proband. One of his siblings was found to be heterozygous for the same mutation. The mutation was not detected in the 54 unrelated SA RP patients examined, 11 of whom were sporadic cases. A low incidence of RP amongst heterozygous carriers of this mutation has been reported; however, in the past it has been unclear whether the mutation has an effect in single copy or dual copy. To the best of our knowledge, this is the first time that this mutation has been reported as homozygous in an affected individual, thereby resolving the issue and confirming that it is a recessive disease-associated mutation. This is also the first autosomal recessive RP disease-causing rhodopsin mutation that has been identified in Southern Africa. Analysis of the extended pedigree indicated obligate heterozygous carriers of the mutation, without obvious signs of visual impairment in early adulthood. The extent to which potential heterozygous carriers should be pursued and clinically examined is discussed and the question is addressed as to whether to inform the family of these molecular findings.     

Homozygosity mapping and linkage analysis demonstrate that autosomal recessive congenital hereditary endothelial dystrophy (CHED) and autosomal dominant CHED are genetically distinct

BACKGROUND: Congenital hereditary endothelial dystrophy (CHED) is a corneal dystrophy characterised by diffuse bilateral corneal clouding resulting in impaired vision. It is inherited in either an autosomal dominant (AD) or autosomal recessive (AR) manner. The AD form of CHED has been mapped to the pericentromeric region of chromosome 20. Another endothelial dystrophy, posterior polymorphous dystrophy (PPM), has been linked to a larger but overlapping region on chromosome 20. A large, Irish, consanguineous family with AR CHED was investigated to determine if there was linkage to this region. METHODS: The technique of linkage analysis with polymorphic microsatellite markers amplified by polymerase chain reaction (PCR) was used. In addition, a DNA pooling approach to homozygosity mapping was employed to demonstrate the efficiency of this method. RESULTS: Conventional genetic analysis in addition to a pooled DNA strategy excludes linkage of AR CHED to the AD CHED and larger PPMD loci. CONCLUSION: This demonstrates that AR CHED is genetically distinct from AD CHED and PPMD.     

Autosomal dominant congenital nystagmus is not linked to 6p12, 7p11, and 15q11 in a German family

PURPOSE: Congenital nystagmus (CN) is an eye-movement disorder that usually starts within the first months of life. Autosomal dominant, autosomal recessive, and X-chromosomal pedigree patterns are observed. Causative genes are yet unknown. Several loci were implicated to contain disease-relevant genes for autosomal dominant CN (AD CN). AD CN cosegregated with a balanced translocation of 7;15 in a family. In a large black pedigree linkage was demonstrated to 6p12. DESIGN: In this study, we describe a large German family with AD congenital nystagmus. Linkage of AD in this family was tested with previously implicated loci. METHODS: Affected family members and unaffected members underwent genetic analysis. Key family members underwent ophthalmologic testing and oculography. RESULTS: No linkage of AD CN to the implicated loci on 6p12, and 7p11, and 15q11 was found in this study. CONCLUSION: In the presented pedigree genes on 15q11, and on the assumption of full penetrance, 6p12 and 7p11 are not involved in the development of AD congenital nystagmus.     

视网膜色素变性发病机制及治疗进展

视网膜色素变性（retintis pigmentosa,RP）是指以进行性感光细胞及色素上皮功能丧失为共同表现的遗传性、退行性的疾病,RP是主要的致盲性眼病。其遗传方式包括X连锁遗传、常染色体隐性或者显性遗传,也有散发。临床表现为典型的三联征:骨细胞样色素沉着、视网膜血管缩窄和视盘蜡样苍白。RP具有高度的基因异质性(多个突变位点引起同一疾病）及表型异质性。本文对RP的发病机制和治疗方法进行简要综述。     

Oculo-orbital changes in osteopetrosis

Osteopetrosis means a low function of osteoclasts, that induces bone resorption with a decrease in bone density. It has two genetic forms: a benign form with autosomal dominant inheritance (AD) and a malignant form with autosomal recessive inheritance (AR). The most successful therapy is bone marrow transplantation (rate of success 80%). We will present a case of malignant osteopetrosis of a five years old child. The late diagnosis (at 18 month) and the malignant evolution has made possible only palliative treatment, without surgical or ophthalmologic-neurosurgical implication. The prognosis is unfavorable with 70% survival to six years and 30% to ten years.