A survey of hereditary aspects of pigmentary retinal dystrophies

A study of 707 cases of retinitis pigmentosa and choroideraemia presenting over 12 years were classified according to their modes of inheritance-439 autosomal recessive (62%), 193 autosomal dominant (27%), 75 X-linked (10.7%). The patients with autosomal recessive transmission included 58 Usher syndrome, 12 Laurence-Moon-Bardet-Biedl syndrome and 33 Leber's congenital amaurosis. Another 37 had an early onset with macular degeneration and 31 were of late onset with pericentral dystrophy. Forty two were offspring of consanguineous parents. Of 193 individuals (78 families) with autosomal dominant inheritance, 20% had night blindness from early childhood. With X-linked transmission, 33 males and 31 female carriers comprised the retinitis pigmentosa group and eight males and three carrier females, choroideraemia. Almost all this X-linked group were of British ancestry. Of patients originating from the Mediterranean area, 94% had autosomal recessive disease.     

A survey of hereditary aspects of pigmentary retinal dystrophies

A study of 707 cases of retinitis pigmentosa and choroideraemia presenting over 12 years were classified according to their modes of inheritance--439 autosomal recessive (62%), 193 autosomal dominant (27%), 75 X-linked (10.7%). The patients with autosomal recessive transmission included 58 Usher syndrome, 12 Laurence-Moon-Bardet-Biedl syndrome and 33 Leber's congenital amaurosis. Another 37 had an early onset with macular degeneration and 31 were of late onset with pericentral dystrophy. Forty two were offspring of consanguineous parents. Of 193 individuals (78 families) with autosomal dominant inheritance, 20% had night blindness from early childhood. With X-linked transmission, 33 males and 31 female carriers comprised the retinitis pigmentosa group and eight males and three carrier females, choroideraemia. Almost all this X-linked group were of British ancestry. Of patients originating from the Mediterranean area, 94% had autosomal recessive disease.     

An epidemiogenetic study of typical retinitis pigmentosa in Japan--a preliminary report of nationwide, multicenter study]

We performed a nationwide, multicenter study of typical retinitis pigmentosa with reference to the inheritance patterns of the disease. A total of 253 probands were registered during two months of 1989, and an analysis of the parental consanguinity of 182 probands with the method of inbreeding coefficient enabled us to estimate the relative prevalence of genetic types; autosomal recessive trait: 47.6%; autosomal dominant trait: 17.3%; sporadic cases: 34.6%. A comparison of the results with previous studies has indicated a decrease in the prevalence of the autosomal recessive trait and an increase in the sporadic cases, as would be expected from the decrease in consanguineous marriages and offsprings in the past few decades in Japan. X-linked retinitis pigmentosa was rarely identified, but precise evaluation of its frequency needs further investigation.     

On the heredity of retinitis pigmentosa.

The aims of this study are: (1) to determine the frequencies of the various genetic forms of retinitis pigmentosa; and (2) to perform segregation analysis on autosomal dominant, autosomal recessive, and X-linked families. The families studied consisted of 2 series of patients at Moorfields Eye Hospital: (1) 426 families seen in the Genetic Clinic; and (2) 289 families seen in the Electrodiagnostic Department. Comparison between the 2 series identified biases of ascertainment, and it was estimated that the combined series included 53% of simplex cases and a minimum of 15% of X-linked families. Segregation analysis of the Genetic Clinic series showed good agreement with expectation in autosomal dominant and X-linked families, but indicated that no more than 70% of all simplex cases were autosomal recessive. The rest of the simplex cases were mildly affected and may represent fresh autosomal dominant mutations, autosomal dominant transmission with reduced penetrance, the heterozygous state of X-linked disease in some of the females, and phenocopies.     

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.     

Prevalence of retinitis pigmentosa and allied disorders in Denmark. III. Hereditary pattern.

A national epidemiological study revealed 1301 prevalent cases of retinitis pigmentosa (RP) in the Danish population on January 1, 1988. The corresponding number of 974 families were analyzed with respect to Mendelian inheritance groups. Thirty families, comprising 6.9% of the prevalent RP-cases, were categorized with an autosomal dominant inheritance pattern. In 187 families, 22.6% of RP-cases, autosomal recessive heredity was encountered. X-linked heredity was found in 45 families, 10.8% of the RP-cases. Simplex RP-cases comprised 562 persons (43.2% of RP-cases). About a fourth of the non-systemic X-linked cases were females. Half of these had an age at onset after 30 years, but a third had their first RP-symptoms before age 18 years. A representative fraction of parents to non-systemic autosomal dominant, autosomal recessive, X-linked, and simplex cases were evaluated concerning their age at the time they had their first affected child. Mothers of the male simplex cases were of statistically significant higher age than mothers of the other inheritance groups. This may imply a high rate of new mutations among simplex cases, especially on the X-chromosome.     

Prevalence of retinitis pigmentosa in Maine

Between 1976 and 1980, medical and social service sources were used to ascertain cases of retinitis pigmentosa in Maine (1980 population, I, 124,660). As of July 1, 1980, 241 clinically prevalent cases of retinitis pigmentosa were ascertained. Extensive pedigrees were collected for 185 of the subjects and medical records were obtained. One hundred fourteen cases were further evaluated by clinical examination including electroretinography. Adjusting for incorrect diagnosis (eight of 114, 7%) and underascertainment (23 of 185, 12.5%), we estimated that prevalence of retinitis pigmentosa in Maine is 236 cases, 21 per 100,000 population or 1:4,756. Excluding Usher and Bardet-Biedl syndromes, the prevalence is 1:5,193. Estimated birth incidence of persons who will become affected with non-syndrome retinitis pigmentosa is 1:3,544. Incidence of newly diagnosed cases per year is about six per 1,000,000 population. Among kindreds, 16 of 85 (19%) were autosomal dominant, 55 of 85 (65%) autosomal recessive or isolated cases, seven of 85 (8%) X-linked recessive, and seven of 85 (8%) not classified by mode of transmission.     

The empirical risk of retinitis pigmentosa in Japan]

The empirical risk of hereditary retinitis pigmentosa (RP), was studied based on a survey of the data from 378 families with RP who were seen in Juntendo University hospital from 1980 to 1988. If the cases have had affected sibling, the empirical risk is 19% for the other siblings, and 29% if they have parental consanguinity. Moreover the risk for male siblings is about 1.7 times higher than for female siblings. The prevalence in the general population of carriers with autosomal recessive hereditary RP was calculated to be about 0.8 to 1.7 in 100 persons. If a hereditary RP case marries a normal and unrelated partner, the risk is 0.4-0.9% for their child. If a case has many affected relatives (parents, grandparents, uncles or aunt etc), the risk is 24% for a son, and 30% for a daughter. Some normal persons among autosomal dominant families with incomplete penetrance are suspected to be carriers. The rate of penetration of the autosomal dominant gene was estimated to be 0.54. Therefore, the risk is 8.6% for the children of such persons. If the carriers are among X-linked families, the risk is 36% for their son. The risk is 1% or more for children of sporadic cases.     

Multicenter genetic study of retinitis pigmentosa in Japan: I. Genetic heterogeneity in typical retinitis pigmentosa

A nationwide, multicenter study of typical retinitis pigmentosa (RP) was carried out in collaboration with 18 hospitals throughout Japan to obtain current information for genetic counseling. We analyzed the genetic heterogeneity of RP based on the parental consanguinity of 434 probands registered during a 6-month period in 1990. A gradual decline in the frequency of consanguineous marriage was recognized among the normal parents of RP patients. The relative frequencies of inheritance patterns were estimated as: autosomal recessive, 25.2%; autosomal dominant, 16.9%; X-linked, 1.6%; and simplex, 56.3%. A comparison of these results with previous reports in Japan revealed a decline in the relative frequency of autosomal recessive cases and an increase in simplex cases. This suggests a decrease in the incidence of autosomal recessive retinitis pigmentosa in Japan, as well as the necessity for exhaustive investigations aimed at identifying inheritance patterns for RP patients seeking genetic counseling.     

Prevalence of posterior subcapsular lens opacities in patients with retinitis pigmentosa.

We clinically evaluated 338 patients with various genetic types of retinitis pigmentosa (RP) for the presence of posterior subscapsular (PSC) lens opacities. Of these, 180 (53%) had PSC lens changes or were bilaterally aphakic. Patients with X-linked recessive RP showed a greater prevalence and patients with autosomal dominant RP a lesser prevalence of PSC lens changes compared with autosomal recessive or isolated cases.     

Multicenter genetic study of retinitis pigmentosa in Japan: II. Prevalence of autosomal recessive retinitis pigmentosa

Retinitis pigmentosa (RP) is a group of genetically heterogeneous diseases with autosomal recessive (AR), autosomal dominant, and X-linked modes of inheritance. Autosomal recessive retinitis pigmentosa (ARRP) is the most common form in Japan. A genetic analysis was done to determine the prevalence of ARRP indirectly, to provide an estimation of changing trends in the overall prevalence of RP. Data on the frequency of consanguinity and marriage year of normal parents of 59 ARRP patients were obtained from a nationwide multicenter survey of typical retinitis pigmentosa conducted in 1990. The gene frequency of ARRP was 0.01145 (Dahlberg's formula). In 1990, the number of young symptomatic ARRP patients decreased, while the number of patients aged 40 years and older increased. The total number of symptomatic ARRP patients in 1990 was nearly 21% higher than in 1970. Despite a dramatic decline in consanguinity in recent decades in Japan, the number of ARRP patients has increased. This increase is attributed to greater longevity and overall population growth. Our results suggest that the total number of RP patients has not decreased, and may even have increased.     

Analysis of genes coding for S-antigen, interstitial retinol binding protein, and the alpha-subunit of cone transducin in patients with retinitis pigmentosa

We screened 526 unrelated patients with autosomal dominant, autosomal recessive, or simplex retinitis pigmentosa for evidence of mutations of the genes encoding S-antigen (S-Ag), interstitial retinol binding protein (IRBP), and the alpha-subunit of cone-specific transducin. Restriction fragment length polymorphisms (RFLPs) were identified at each of these loci. Within each set of patients with a particular genetic type of retinitis pigmentosa, RFLP alleles at each of these loci showed no departure from Hardy-Weinberg equilibrium. No gene deletions or rearrangements could be detected in any patient. Furthermore, in each of six pedigrees (one autosomal dominant, one autosomal recessive, three Usher's syndrome type I, and one Laurence-Moon-Bardet-Biedl syndrome) there was no co-segregation of the disease with alleles determined by RFLPs at the locus for S-antigen. At the IRBP locus, lack of co-segregation was seen in one autosomal dominant, two autosomal recessive, and three Usher's syndrome type I pedigrees. Finally, one pedigree with autosomal recessive retinitis pigmentosa showed no co-segregation of the disease with alleles at the locus for the alpha-subunit of the cone-specific transducin. These data support the idea that the genes coding for S-Ag, IRBP, and the alpha-subunit of the cone-specific transducin do not play an etiologic role in the families with retinitis pigmentosa so far studied.     

视网膜色素变性遗传致病基因peripherin/RDS的突变筛选

目的 了解中国视网膜色素变性患者（RP）中peripherin/RDS基因的突变谱及突变率。方法 应用聚合酶链-异源双链-单链构象多态性（PCR-SSCP）及DNA序列分析技术对收集的15个常染色体显性遗传视网膜色谱变性家系和55例散发视网膜色素变性患者peripherin/RDS基因的第一，第二外显子进行检测。结果 15个家系及55例散发患者未检测到peripherin/RDS基因突变。结论 本研究所检测的视网膜色素变性患者与RDS基因无关，显示视网膜色素变性的遗传异质性。     

Genetic study of retinitis pigmentosa in China

A total of 190 patients (379 eyes), from 169 families, with retinitis pigmentosa were studied in four genetic aspects in China. A large percentage (58.9%) of affected patients appear to be sporadic cases with no family history of disease. In dermatoglyphic analysis, comparing with the controls, the increment of eight or more whorls, the increase of the number of simian and the value of atd angle in 110 patients with retinitis pigmentosa were statistically significant. In addition, the incidence of G6PD deficiency in retinitis pigmentosa (7.89%) is higher than that (3.5%) of a nonaffected population in the same area. However, there is no significant difference of ABO blood typing between 176 patients with retinitis pigmentosa and the normal population of China.     

Molecular genetics of pigmentary retinopathies: identification of mutations in CHM, RDS, RHO, RPE65, USH2A and XLRS1 genes

PURPOSE: To evaluate the occurrence and inheritance of various types of pigmentary retinopathy in patients followed at the outpatient clinic in the university hospital, Montpellier, France. To characterize genes and mutations causing these conditions. METHODS: Ophthalmic examination and various visual tests were performed. Mutations were sought from genomic DNA by PCR amplification of exons associated with single-strand conformation analysis and/or direct sequencing. RESULTS: Among 315 patients over an 8-year period, cases of retinitis pigmentosa (63.2%), Usher's syndrome (10.2%), Stargardt's disease (5.4%), choroideremia (3.2%), Leber's congenital amaurosis (3.2%), congenital stationary night blindness (2.9%), cone dystrophy (2.5%), dominant optic atrophy (1.9%), X-linked juvenile retinoschisis (1.6%), Best's disease (1.6%), and others (4.3%) were diagnosed. In retinitis pigmentosa, inheritance could be determined in 54.2% of the cases including dominant autosomic (26.6%), recessive autosomic (22.6%), and X-linked cases (5%) while it could not be confirmed in 45.7% of the cases (simplex cases in the majority). For the 6 examined genes, mutations were found in 22 out of 182 propositus (12.1%). Analysis of phenotype-genotype correlations indicates that in retinitis pigmentosa, RDS is more frequently associated with macular involvement and retinal flecks, RHO with regional disease, and RPE65 with the great severity of the disease with some cases of Leber's congenital amaurosis. CONCLUSIONS: Identification of genes may help in diagnosis and in genetic counseling, especially in simplex cases with retinitis pigmentosa. In this latter condition, molecular diagnosis will be necessary to rationalize future treatments.     

视网膜色素变性中视紫红质与Peripherin／RDS基因的突变筛查

目的:迄今尚未见在国人中经序列分析确定该基因突变的报道。了解国人遗传性视网膜色素变性人群中视紫红质和peripherin/RDS基因的突变情况。方法:对83例遗传性视网膜色素变性先证者视紫红质基因全部编码区和peripherin/RDS部分编码区进行PCR扩增,用异源双链-SSCP法对扩增产物进行分析,寻找有差异电泳带纹的突变样本,序列分析确定突变。结果:83例中3例有视紫红质基因突变(Va1104Phe、Lys311Glu、Pro347Leu),其中两个新突变分别见于散发病例(Va1104Phe,杂合性)和常染色体隐性遗传视网膜色素变性家系(Lys311Glu,纯合性)。在peripherin/RDS基因中未发现突变。结论:在国人视网膜色素变性患者中视紫红质基因突变为常见致病原因。眼科学报1998;14:210～214     

Electroretinographic testing as an aid in detection of carriers of X-chromosome-linked retinitis pigmentosa.

Twenty-two of 23 obligate female carriers in nine families with known X-chromosome-linked retinitis pigmentosa were detected on the basis of abnormal full-field electroretinograms (ERGs). Only 14 of these carriers had fundus findings characteristic of the carrier state. Electroretinograms of carriers were either reduced in amplitude to white light under dark-adapted conditions or delayed in cone b-wave implicit time, or both. Daughters of obligate carriers had either normal ERGs or abnormal ERGs similar to those recorded from obligate carriers. Abnormal ERGs of carriers of X-chromosome-linked retinitis pigmentosa contrasted with the normal ERGs recorded from female carriers of autosomal recessive disease. These data support the idea that ERG testing of female relatives of males with retinitis pigmentosa can help to establish for a given family whether the mode of inheritance is X-chromosome-linked or autosomal recessive.     

Autosomal recessive retinitis pigmentosa is associated with mutations in RP1 in three consanguineous Pakistani families

PURPOSE: To localize and identify the gene and mutations causing autosomal recessive retinitis pigmentosa in three consanguineous Pakistani families. METHODS: Blood samples were collected and DNA was extracted. A genome-wide scan was performed by using 382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and lod scores were calculated. RESULTS: A genome-wide scan of 25 families gave an hlod = 4.53 with D8S260. Retinitis pigmentosa in all three families mapped to a 14.21-cM (21.19-Mb) region on chromosome 8 at q11, flanked by D8S532 and D8S260. This region harbors RP1, which is known to cause autosomal dominant retinitis pigmentosa. Sequencing of the coding exons of RP1 showed mutations in all three families: two single-base deletions, c.4703delA and c.5400delA, resulting in a frame shift, and a 4-bp insertion, c.1606insTGAA, all causing premature termination of the protein. All affected individuals in these families are homozygous for the mutations. Parents and siblings heterozygous for the mutant allele did not show any signs or symptoms of RP. CONCLUSIONS: These results provide strong evidence that mutations in RP1 can result in recessive as well as dominant retinitis pigmentosa. The findings suggest that truncation of RP1 before the BIF motif or within the terminal portion results in a simple loss of RP1 function, producing a recessive inheritance pattern. In contrast, disruption of RP1 within or immediately after the BIF domain may result in a protein with a deleterious effect and hence a dominant inheritance pattern.