Simplex Cases Research Articles

Clinical Genetic Analysis of Retinitis Pigmentosa in Indian Population

Four hundred families affected with Retini- tis Pigmentosa (RP), from 16 different states of India were analysed to ascertain segregation pattern of RP and to study the association of clinical variables like "age of onset" and "rate of progression" with the different clinical subtypes of RP. Families were categorized on the basis of clinical types and inheritance pattern. Segregation analysis, based on the maximum likelihood estimate, was carried out on 426 sibships from 400 families. 75% of the cases were autoso- mal recessive (AR), 10% autosomal dominant (AD) and 1% X-linked. In the remaining 14%, the inheritance pat- tern was not clear. Segregation analysis of the sibship data showed good agreement with respect to the AR cases, with a segregation value of 0.23. Penetrance was relatively low (42%) in AD cases. Segregation analysis of AR cases, with the inclusion of simplex cases, indicated that these cases might be having an underlying recessive mode of inherit- ance. High frequency of recessive cases could be attributed to inbreeding and consanguinity in families. Statistically significant differences with respect to "age of onset" and "rate of progression" were observed among different clini- cal types of RP, which could be of importance in counsel- ing.

Fitting a Slack-Variable Model to Mixture Data: Some Questions Raised

Designating one of the mixture components as the slack variable and leaving it out of the fitted model is known as the slack-variable (SV) approach. Some who use this approach rationalize they understand what information is provided by the resulting slack-variable model better than what the fitted Scheffé-type model in all the components gives them. The question addressed in this paper is, “Does it matter which one of the q mixture components is designated the slack variable when arriving at the final form of the slack-variable model?” Both the simplex region and a constrained subregion of the simplex cases are discussed with examples of each leading to some conclusions and recommendations.

Asociación entre el fenotipo fisura labiopalatina no sindrómica y marcadores de microsatélite ubicados en 4q

Background: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common craniofacial defect. Association studies have suggested that a clefting locus is located on chromosome 4q at or near two microsatellite markers D4S175 and D4S192. Aim: To test the hypothesis on the possible presence of a clefting locus on chromosome 4q. Material and methods: We carried out an association study on a sample of unrelated NSCLP patients, of their unaffected relatives and in controls. Both probands and relatives were further analyzed depending if they originated from simplex or multiplex families. DNA was analyzed with two PCR markers close to the putative NSCLP locus, dinucleotide repeats D4S175 and D4S192. PCR products were resolved by PAGE and visualized by silver staining. Statistical analysis was performed by means of c2 log ratio. Results: Significant differences between NSCLP and controls were observed when comparing the allele frequency distribution of D4S192 both in the total sample as well as in NSCLP-multiplex and simplex cases. No significant differences for D4S175 were observed in any of the comparisons. Unaffected relatives showed significant differences with controls both for D4S175 and D4S192. Conclusions: Our results support the hypothesis that a NSCLP locus maps on chromosome 4q close to the microsatellite marker D4S192. No differences were observed between NSCLP multiplex and simplex cases versus controls, implying that they do not represent different etiologic entities. The results of the present and previous studies in the same group of patients support the hypothesis that several major interacting genes participate in the etiology of NSCLP.

Genetic and segregation analysis of congenital cataract in the Indian population.

Congenital cataract is a major cause of blindness in children, and there is wide variation in the few reports available on the frequencies of its different inheritance patterns. Two hundred and fifty-two families with congenital cataract belonging to 13 different states of India, were clinically and genetically investigated to study their inheritance and segregation patterns. Twenty-one percent of the cases were autosomal recessive, 15% autosomal dominant, 63% were simplex cases, and in the remaining cases the inheritance pattern was not clear. A high incidence of consanguinity (50.9%) was observed in autosomal recessive cases. Out of 340 affected individuals, 222 (65.3%) were males and 118 (34.7%) were females. Segregation analysis showed good agreement in autosomal dominant and recessive families and the data are indicative of the prevalence rate for different inheritance patterns of congenital cataract within the Indian population.

Estudio de asociación entre la fisura labiopalatina no sindrómica y marcadores de microsatélite ubicados en 6p

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common craniofacial defect. Association studies have suggested that a clefting locus is located on chromosome 4q at or near two microsatellite markers D4S175 and D4S192. To test the hypothesis on the possible presence of a clefting locus on chromosome 4q. We carried out an association study on a sample of unrelated NSCLP patients, of their unaffected relatives and in controls. Both probands and relatives were further analyzed depending if they originated from simplex or multiplex families. DNA was analyzed with two PCR markers close to the putative NSCLP locus, dinucleotide repeats D4S175 and D4S192. PCR products were resolved by PAGE and visualized by silver staining. Statistical analysis was performed by means of chi 2 log ratio. Significant differences between NSCLP and controls were observed when comparing the allele frequency distribution of D4S192 both in the total sample as well as in NSCLP-multiplex and simplex cases. No significant differences for D4S175 were observed in any of the comparisons. Unaffected relatives showed significant differences with controls both for D4S175 and D4S192. Our results support the hypothesis that a NSCLP locus maps on chromosome 4q close to the microsatellite marker D4S192. No differences were observed between NSCLP multiplex and simplex cases versus controls, implying that they do not represent different etiologic entities. The results of the present and previous studies in the same group of patients support the hypothesis that several major interacting genes participate in the etiology of NSCLP.

Rheumatoid arthritis in the Pima Indians: the intersection of epidemiologic, demographic, and genealogic data.

To describe the clinical features and familial distribution of rheumatoid arthritis (RA) in the Pima Indians. From 1965 through 1990, all cases of RA as defined by the American College of Rheumatology (formerly, the American Rheumatism Association) 1987 criteria or all cases of seropositive, erosive disease as defined by the Rome criteria were identified in individuals who were age 20 years and older and were of 50% or more Pima/Tohono-O'odham heritage. Radiographs were reviewed by 2 musculoskeletal radiologists who were blinded to case status. Kinship coefficients were used to evaluate familial aggregation. Eighty-eight RA cases were identified from this population-based sample. Over 66% of the cases had seropositive disease, over 60% had erosive disease, and over 40% had subcutaneous nodules. Of the 88 RA cases, 40 were members of families with more than 1 RA case. The remainder were simplex cases. In this population, clinical markers of severe RA were present in a majority of cases. The presence of familial aggregation for RA in the Pima Indians suggests underlying genetic factors in disease pathogenesis.

La variación genética de MSX1 presenta un dimorfismo sexual en la fisura labiopalatina no sindrómica en la población chilena

Recent studies in mice have demonstrated that the Msx-1 homebox gene is implicated in cleft palate. Thus, it has been suggested that its human homologue, MSX1 (HOX-7), located in chromosome 4 could be involved in the etiology of non syndromic cleft lip palate. To study the linkage between non syndromic cleft palate and variations of MSX1 gene. Seventy three patients with non syndromic cleft lip palate (34 simplex and 37 multiplex), 127 unaffected relatives of the cases (61 relatives of simplex cases and 66 relatives of multiplex cases) and 77 controls were studied. DNA was extracted from leukocytes and the intragenic microsatellite sequence was amplified by PCR. A polymorphism of four alleles was observed, 1 (175 bp), 2 (173 bp), 3 (171 bp) and 4 (169 bp). Alleles 2 and 4 showed a joint variation in males with multiplex cleft lip palate and in their respective unaffected male relatives, that was significant when compared with male controls. Instead, the joint variation of alleles 1 and 4 of unaffected female relatives had significant differences with female controls. Females with multiplex cleft lip palate differed from female controls only in allele 1. These results support the hypothesis of a genetic heterogeneity in the etiology of non syndromic cleft lip palate.

Identification of a Recurrent Missense Mutation in the Norrie Disease Gene Associated with a Simplex Case of Exudative Vitreoretinopathy

Disorders such as Norrie disease, X-linked familial exudative vitreoretinopathy, retinopathy of prematurity and X-linked primary vitreoretinal dysplasia have very similar clinical manifestations. They exhibit retinal fold, retinal detachment, retinal traction and the formation of retrolental fibrovascular membrane. In order to identify carriers for these disorders and provide precise genetic counseling of the relatives, a molecular genetic analysis will be helpful. This report describes the results of Norrie disease gene analysis in simplex cases of exudative vitreoretinopathy. The identification of a recurrent mutation in the Norrie disease gene in a simplex case of exudative vitreoretinopathy further strengthens the notion that Norrie disease and exudative vitreoretinopathy are allelic disorders.

Recessive mutations in the gene encoding the tubby-like protein TULP1 in patients with retinitis pigmentosa.

A recessive mutation in the tub gene causes obesity, deafness and retinal degeneration in tubby mice. The tub gene is a member of a family of tubby-like genes (TULPs) that encode proteins of unknown function. Members of this family have been identified in plants, vertebrates and invertebrates. The TULP proteins share a conserved carboxy-terminal region of approximately 200 amino-acid residues. Here we report the analysis of the human gene TULP1, which is expressed specifically in the retina. Upon analysing 162 patients with nonsyndromic recessive retinitis pigmentosa (RP) and 374 simplex cases of RP, we found two who were compound heterozygotes for mutations that cosegregated with disease in the respective families. Three of the mutations are missense changes affecting the conserved C-terminal region; the fourth mutation affects a splice donor site upstream of this region. Our data suggest that mutations in TULP1 are a rare cause of recessive RP and indicate that TULP1 has an essential role in the physiology of photoreceptors.

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.

Retinitis pigmentosa in Spain

Retinitis pigmentosa is a term commonly given to a group of inherited and progressive disorders which affect the photoreceptors of the retina. As part of an ongoing research programme throughout Spain, clinical, epidemiological, and genetic studies have been carried out on these diseases. Here, we report the relative frequencies of the different genetic types in 503 non-syndromic and 89 syndromic RP families of Spanish origin. The most frequent syndromic RP forms were Usher syndrome type 1 (20/89 families = 30%) and Usher syndrome type 2 (44 families = 49%). Among non-syndromic RP forms, 12% were autosomal dominant, 39% autosomal recessive and 4% X-linked. Forty-one percent were isolated or simplex cases and in 4% the genetic type could not be established.

Long-term results of fourth ventriculo-cisternostomy in complex versus simplex atresias of the fourth ventricle outlets.

Twelve cases of atresia of the fourth ventricle outlets are presented and they are classified into 2 types: simplex versus complex. Fourth ventriculo-cisternostomy is the treatment of choice. Based on the surgical experiences in simplex cases, new technical modifications were developed to make it applicable to the complex cases as well. The advantages and limitations of such operative approaches over other conventional shunt procedures are compared and the long-term postoperative results are listed. Hopefully, the surgical intervention described here may have opened a reasonable method for treating certain cases of the trapped fourth ventricle as a special variant of the complex atresia type. It is important to realize that knitted tubes are categorically unqualified for the surgical use like this.

Epidemiology of retinitis pigmentosa in the valencian community (Spain)

The purposes of this study are to determine the frequencies of the different genetic forms of retinitis pigmentosa and to perform segregation analysis in the different genetic subtypes. Retinitis pigmentosa was diagnosed in 263 persons from 132 families. The frequency of the autosomal recessive type was the highest (31.8%) while the X-linked type was very rare (1.5%). The frequency of autosomal dominant type was 14.4% and the simplex cases constituted half of the total cases of RP registered in our community. In conclusion, in our population the high proportion of simplex cases and the low number of X-linked families are noticeable. The result of segregation analysis showed good agreement with expectation in autosomal dominant and autosomal recessive families but no more than 60% of all simplex cases were autosomal recessive. The proportion of sporadic cases was estimated statistically to be 39.9% of the total simplex cases.

Identification of a novel rhodopsin mutation (Met-44-Thr) in a simplex case of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a group of genetically heterogeneous retinal degenerations that can be autosomal dominant (ADRP), autosomal recessive (ARRP), or X-linked. Approximately 30% of ADRP patients show point mutations or small deletions in the rhodopsin gene. However, over 50% of the RP patients are simplex cases (sporadic). Screening for mutations in the rhodopsin gene of 33 patients with simplex RP by denaturing gradient gel electrophoresis (DGGE) was carried out. One patient, with D-type (diffuse) RP and consanguineous parents, showed an altered electrophoretic pattern for the 5' half of exon 1. Direct sequencing revealed a new mutation ATG to ACG in codon 44; this predicts a change of Met-44-Thr in rhodopsin. The position and amino acid substitution suggest that this mutation causes the RP phenotype. Implications for genetic counselling are discussed.

Nevoid basal cell carcinoma syndrome: review of 118 affected individuals.

One hundred eighteen cases of nevoid basal cell carcinoma syndrome (NBCCS, Gorlin's syndrome or basal cell nevus syndrome) are presented in this study. In aiming to ascertain all the affected families in Australia, we have examined the largest series to date. Relative frequencies of associated complications are presented and compared with those of the recent English survey by Evans et al. [J Med Genet 30:460-464, 1993]. The frequencies of most manifestations are similar. However, one major difference is that the multiple basal cell carcinomas are manifest from an earlier age in the Australian population, which probably reflects greater exposure to ultraviolet radiation. Of the 64 families ascertained, 37 represented simplex cases, and, accordingly, the apparent new mutation rate is surprisingly high (14-81%) given the lack of impact of NBCCS on reproductive capabilities. There is some evidence to suggest that this may be attributable to anticipation.

A comparison of multiplex and simplex families with Alzheimer's disease/senile dementia of Alzheimer type within a well defined population.

A study was made on 150 clinically demented patients presenting at autopsy at Umeå University Hospital in Sweden. In 90 of the cases dementia was considered to be primary in nature and of these forty six per cent (41 cases), fulfilled both the clinical and histopathological criteria for the diagnosis of Alzheimer's disease/Senile dementia of Alzheimer type (AD/SDAT). The families of these 41 AD/SDAT cases were then studied, and a family history obtained through interviews with multiple family informants and from civil and medical records. Additional diseased family members suffering from progressive dementia (multiplex families) were observed in 12 probands out of 41 (29%). Multiplex families exhibited similar clinical and histopathological characteristics as simplex families containing a single affected individual. The secondary cases in the multiplex families exhibited similar demographic and clinical characteristics as the probands. 39% of the multiplex and 14% of the simplex cases had an early age of onset of the disease, that was under 65 years. The overall prevalence of progressive dementia disorders in the 41 families was 5.9%. The prevalence of a progressive dementia disorder was 11% in the multiplex families (14% for the early onset cases) and 3.5% in the simplex families (2% for the early onset cases). The prevalence of progressive dementia disorder for family members who had passed the mean age of the onset of the disease for their family, was 45% for multiplex and 18% for simplex families. Furthermore the incidence rate for dementia was significantly higher (p < 0.005) in multiplex families (5.5 per 1,000 person years) when compared to simplex families (2.5 per 1,000 person years). No differences could be seen in parental age at birth of the diseased when comparing the two sets of families. However in multiplex families the duration of the disease was significantly (p < 0.025) shorter, in subjects with parental age at birth over 35 years compared to those with a parental age under 35 years. The multiplex families contained significantly (p < 0.025) larger sibships; and showed a significantly lower age of onset for the disease (p < 0.001), and a significantly longer duration of disease (p < 0.05) compared to the simplex families. A significant intra familial correlation of age at disease onset was observed in both sets of the families.

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.

A retrospective study of registered retinitis pigmentosa patients in The Netherlands.

A retrospective study was performed of patients with retinitis pigmentosa (RP) registered at the Department of Ophthalmogenetics of the Netherlands Ophthalmic Research Institute. The aim was to establish the relative frequencies of the genetic modes and to attempt a clinical subclassification. Of the 575 RP patients, 10.4% were X-linked, 22.4% autosomal dominant, 30.1% autosomal recessive, and 37.1% simplex cases. Clinical classification was inconclusive, and consequently correlation of phenotype to genotype impossible in most cases. One exception was the occurrence of a tapetal reflex, which seemed to differentiate between RP2 and RP3. Gene defects have not been detected so far in Dutch families with either autosomal dominant or autosomal recessive RP. In the future, simplex cases will have to be classified according to their genetic defects. It is probable that results of DNA studies may prove a better basis for classification of RP than clinical data.

Prevalence of tapeto-retinal dystrophies among Danish children.

Age specific prevalence rates are presented based on 110 cases of pigmentary retinopathy (RP) recorded in the Danish child population of a little over one million individuals on January 1, 1988. A steady and steep rise in age specific prevalences of notified RP throughout infancy and childhood was found. The material consisted in 52 non-systemic and 58 systemic cases. 35 of the systemic cases could be nosologically identified, leaving 23 cases unidentified with respect to known diseases or syndromes. Among the genetic types autosomal recessive inheritance was the most common with 60 cases (55%). Parental consanguinity was less frequent than hitherto reported. On the other hand undetected carrier state for X-linked tapeto-retinal dystrophy played a more significant role than expected. A clear excess of males among the simplex cases indicated that some X-linked cases may still be unrecognized. A significant proportion of non-systemic, early infantile RP with an autosomal recessive or simplex mode of inheritance are clinically and electrophysiologically characterised as cone-rod dystrophies.

Congenital stationary night blindness.

Congenital stationary night blindness (CSNB) seems to be a very rare condition in Scandinavia. From Denmark a 7-generation family with the dominant form was published in 1909, and one family with the X-linked recessive form was reported from Norway. On going through the files of the National Eye Clinic for Visually Impaired, 7 patients were found (1 dominant, 4 X-linked recessive, 1 simplex case and 1 autosomal recessive). Including anamnestic information on relatives, 17 patients had a diagnosis of CSNB. The clinical findings in these cases are reported with stress on alteration in ERG, dark adaptation and the optic discs. The loss of oscillatory potentials in a carrier of CSNB is described. The provisional findings seem to indicate that 3 genetic variants are present in the Danish population. The real prevalence is estimated considerably higher than 17 out of 5 million.