Genetic analysis of juvenile periodontitis in families ascertained through an affected proband.

Data from 28 families ascertained through a proband with juvenile periodontitis were used to test a series of Mendelian models of inheritance that included both autosomal and X-linked transmission. There was strong evidence of familial aggregation of this progressive dental disease, and the best-fitting model was an autosomal recessive model. Because of the rather limited age range for expression of the disease in this situation, simulations were done, in a model-choice analysis using samples of this size, to assess the chance of mistaking an autosomal dominant disease (with masking of the affected phenotype outside a specified age range) for an autosomal recessive disease. While the rate of Type II error was fairly high (40%) when competing models in these simulations were compared, these data suggest that it is reasonable to infer that juvenile periodontitis is an autosomal recessive disorder.     

Definitive evidence for an autosomal recessive form of hypohidrotic ectodermal dysplasia clinically indistinguishable from the more common X-linked disorder.

A crucial issue in genetic counseling is the recognition of nonallelic genetic heterogeneity. Hypohidrotic (anhidrotic) ectodermal dysplasia (HED), a genetic disorder characterized by defective development of hair, teeth, and eccrine sweat glands, is usually inherited as an X-linked recessive trait mapped to the X-linked ectodermal dysplasia locus, EDA, at Xq12-q13.1. The existence of an autosomal recessive form of the disorder had been proposed but subsequently had been challenged by the hypothesis that the phenotype of severely affected daughters born to unaffected mothers in these rare families may be due to marked skewing of X inactivation. Five families with possible autosomal recessive HED have been identified, on the basis of the presence of severely affected females and unaffected parents in single sibships and in highly consanguineous families with multiple affected family members. The disorder was excluded from the EDA locus by the lack of its cosegregation with polymorphic markers flanking the EDA locus in three of five families. No mutations of the EDA gene were detected by SSCP analysis in the two families not excluded by haplotype analysis. The appearance of affected males and females in autosomal recessive HED was clinically indistinguishable from that seen in males with X-linked HED. The findings of equally affected males and females in single sibships, as well as the presence of consanguinity, support an autosomal recessive mode of inheritance. The fact that phenotypically identical types of HED can be caused by mutations at both X-linked and autosomal loci is analogous to the situation in the mouse, where indistinguishable phenotypes are produced by mutations at both X-linked (Tabby) and autosomal loci (crinkled and downless).     

常染色体非特异性精神发育迟滞相关基因研究进展

常染色体上一些基因与神经系统的发育和功能密切相关, 突变后可导致非特异性精神发育迟滞。文章从基因定位、表达、生物学功能与突变后致病机理等方面, 对常染色体非特异性精神发育迟滞相关基因的研究现状进行了综述, 并展望了今后这一领域的研究前景。     

Autosomal recessive and dominant forms of polycystic kidney disease are not allelic

Linkage analysis has been carried out in 11 kindreds with autosomal recessive polycystic kidney disease (ARPKD) using the genetic marker 3'HVR, closely linked (theta = 0.05) to the gene of the autosomal dominant type. Close linkage (theta less than or equal to 0.20) between the locus of the marker and that of ARPKD can be excluded. These data strongly suggest that the loci for the autosomal recessive and dominant forms of polycystic kidney disease are not allelic.     

Spectrum and territorial distribution of hereditary diseases in the population of the Krasnodar Krai]

The analysis of the spectrum of hereditary diseases in the population of the Krasnodar province is performed and the influence of the population dynamics factors on the spectrum is discussed. More than 130 nosological forms were discovered in the population of approx. 200,000. Among these, there are 63 autosomal dominant, 49 autosomal recessive and 17 X-linked recessive forms. Of the most frequent autosomal dominant diseases (more than 1 per 50,000) autosomal recessive and X-linked recessive disorders 13, 7 and 7 forms, respectively, were picked up. The coefficient of diversity of hereditary diseases (the number of nosological forms per 10 inhabitants) with different types of inheritance is higher in the Krasnodar population, as compared with the Kostroma population. The problem of similarity of the "nucleus" of autosomal-recessive disorders in Russian populations is discussed.     

Autosomal recessive familial exudative vitreoretinopathy is associated with mutations in LRP5

Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disorder that affects both the retina and vitreous body. Autosomal recessive FEVR was diagnosed in multiple individuals from three consanguineous families of European descent. A candidate-locus-directed genome scan shows linkage to the region on chromosome 11q flanked by markers D11S905 and D11S1314. The maximum LOD score of 3.6 at theta =0 is obtained with marker D11S987. Haplotype analysis confirms that the critical region is the 22-cM (311-Mb) interval flanked by markers D11S905 and D11S1314. This region contains LRP5 but not FZD4; mutations in both of these genes cause autosomal dominant FEVR. Sequencing of LRP5 shows, in all three families, homozygous mutations R570Q, R752G, and E1367K. This suggests that mutations in this gene can cause autosomal recessive as well as autosomal dominant FEVR.     

Genetic load of hereditary diseases in populations of the Krasnodar Krai]

Medico-genetical study of populations living in Krasnodar district was carried out. The mean value of genetic load contributed by autosomal dominant diseases composed 0.92 +/- 0.06, this value being 0.56 +/- 0.04 for autosomal recessive and 0.36 +/- 0.05 for X-linked recessive disorders per one thousand. Comparative analysis of genetical load in urban and rural populations demonstrated that they had no differences in relation to genetical load contributed by autosomal recessive and X-linked recessive disorders. At the same time, significant differences were noted between the populations concerning genetic load contributed by autosomal-dominant disorders.     

Population genetic studies of retinitis pigmentosa.

A questionnaire survey characterized a sample of 670 probands with retinitis pigmentosa (RP) and allied disorders. Segregation analysis provided some evidence for a small proportion of sporadic cases and for decreased segregation ratios of the dominant and recessive genotypes, which could be attributed to delayed age of onset in some cases. The overall incidence of RP was indirectly calculated to be approximately 1 in 3,700, while the incidence of autosomal recessive RP, including at least two genocopies, was estimated to be about 1 in 4,450. Family data analysis included the calculation of the likelihood that each family represented autosomal recessive, autosomal dominant, and X-linked inheritance patterns. These likelihoods were then converted to relative probabilities and summed over the sample population to yield estimates of the proportions of the three Mendelian types. This large, heterogeneous sample indicated that approximately 84% of the cases in the United States may be autosomal recessive, while about 10% are dominant and 6% X-linked recessive.     

Medico-genetic studies of the Kostroma oblast population. X. Load of hereditary diseases in the population of Kostroma

Medical-genetic study of the population of Kostroma (the total size of the population analysed approx. 250,000) was carried on. The load of hereditary diseases in the population (per 1000) was 0.75 for autosomal dominant, 0.49 for autosomal recessive and 0.17 for X-linked recessive disorders. Significant differences in the prevalence of autosomal recessive hereditary disorders between rural populations and the population of Kostroma were observed. The dependence of the load of autosomal recessive pathology on random inbreeding was shown for the whole Kostroma province.     

Biotin-related abnormalities in human metabolism

Recent work has led to the discovery that two severe hereditary human pathologies are caused by biotin deficiency. Significantly, administration of pharmacologic doses of biotin can provide clinically effective treatment. Both diseases are autosomal recessive in inheritance but differ in their associated enzymatic deficiencies. The clinical, enzymatic, and genetic characteristics of these pathologies are reviewed here.     

Medico-genetical study of the population of the Kostroma Region. IV. Genetic load and diversity of hereditary pathology in 5 districts

Data on the prevalence of hereditary diseases in five regions of the Kostroma province were obtained and analysed. 28 autosomal recessive, 25 autosomal dominant and 4 X-linked recessive disorders were found. Segregation analysis proved the rightness of the material subdivision, according to the type of inheritance. The load of hereditary diseases in five regions was: 0.86 +/- 0.09 X 10(3) for autosomal recessive, 0.97 +/- 0.1 X 10(3) for autosomal dominant and 0.36 +/- 0.09 X 10(3) for X-linked recessive disorders. The problems of prevalence of hereditary diseases connected with population structure is discussed.     

The ABCR gene in recessive and dominant Stargardt diseases: a genetic pathway in macular degeneration.

Stargardt disease (STGD) is a juvenile-onset macular dystrophy and can be inherited in an autosomal recessive or in an autosomal dominant manner. Genes involved in dominant STDG have been mapped to human chromosomes 13q (STGD2) and 6q (STGD3). Here, we identify a new kindred with dominant STGD and demonstrate genetic linkage to the STGD3 locus. Because of a more severe macular degeneration phenotype of one of the patients in this family, the gene responsible for the recessive STGD1, ABCR, was analyzed for sequence variants in all family members. One allele of the ABCR gene was shown to carry a stop codon-generating mutation (R152X) in three family members, including the one patient who had inherited also the dominant gene. A grandparent of that patient with the same ABCR mutation developed age-related macular degeneration (AMD), consistent with our earlier observation that some variants in the ABCR gene may increase susceptibility to AMD in the heterozygous state. Based on these results, we propose that there is a common genetic pathway in macular degeneration that includes genes for both recessive and dominant STGD.     

Medico-genetic study of the population of Uzbekistan. VIII. Territorial distribution of hereditary diseases in the population of four regions of the Khorezm province and its genetic load

The load of hereditary diseases was estimated on the basis of data obtained during medical-genetic study of the population of four districts of Khorezm province. The load of autosomal recessive disorders comprised 2-3 X 10(-3) affected, that of autosomal dominant disorders - 0.4-0.5 X 10(-3) and that of X-linked disorders - 0.2-0.4 X 10(-3) males. The main part of patients with autosomal recessive disorders belonged to separate families randomly spread over the populations. A trend for local accumulation of families with the same disorder was observed in small populations. It was shown that overall frequency of autosomal recessive genes per individual increased with the increase in the population size.     

Closing the gap on autosomal dominant connexin-26 and connexin-43 mutants linked to human disease

Cells within the vast majority of human tissues communicate directly through clustered arrays of intercellular channels called gap junctions. Gene ablation studies in mouse models have revealed that these intercellular channels are necessary for a variety of organ functions and that some of these genes are essential for survival. Molecular genetics has uncovered that germ line mutations in nearly half of the genes that encode the 21-member connexin family of gap junction proteins are linked to one or more human diseases. Frequently, these mutations are autosomal recessive, whereas in other cases, autosomal dominant mutations manifest as disease. Given the broad and overlapping distribution of connexins in a wide arrangement of tissues, it is hard to predict where connexin-linked diseases will clinically manifest. For instance, the most prevalent connexin in the human body is connexin-43 (Cx43), yet autosomal dominant mutations in the GJA1 gene, which encodes Cx43, exhibit modest developmental disorders resulting in a disease termed oculodentodigital dysplasia. Autosomal recessive mutations in the gene encoding Cx26 result in moderate to severe sensorineural hearing loss, whereas autosomal dominant mutations produce hearing loss and a wide range of skin diseases, including palmoplantar keratoderma. Here, we will focus on autosomal dominant mutations of the genes encoding Cx26 and Cx43 in relation to models that link genotypes to phenotypic outcomes with particular reference to how these approaches provide insight into human disease.     

Recessive male-determining genes

The autosomal dominant gene polled (P) causes hornlessness in goats. Chromosomal females (XX) that are P/P homozygotes develop testes or ovotestes. Thus with respect to its testis-determining properties, P or a closely linked gene acts as an autosomal recessive.Polled intersex goats are H-Y⁺. This finding is consistent with the view that there may be a cluster of testis-determining H-Y genes on the Y chromosome, and that translocation of a subcritical portion of these genes may generate a recessive mode of sex determination.     

Contribution of DFNB1 and DFNB2 loci to neurosensory deafness in affected Tunisian families

Classical studies have demonstrated genetic heterogeneity for nonsyndromic autosomal recessive congenital neurosensory deafness. The first two DFNB1 and DFNB2 locations were found using two consanguineous Tunisian families respectively from north and south. We tested these loci for cosegregation with deafness in twenty four southern families with nonsyndromic presumed congenital sensorineural deafness and a pedigree structure consistent with autosomal recessive inheritance. Only in our families, did deafness cosegregate with DFNB1. Although our families are from the south, none of them showed linkage to DFNB2.     

On the genetics of prelingual deafness.

In view of the many discordant findings in previous studies regarding the genetics of prelingual deafness, family data (133 nuclear families and 25 pedigrees) were gathered from India. Analysis of these data has revealed that the defect is primarily genetic, which is in agreement with earlier findings. Segregation analysis was performed to compare various autosomal diallelic one-locus and multilocus models. Our analysis revealed that the most parsimonious model for prelingual deafness is that it is controlled by recessive genes at a pair of unlinked diallelic autosomal loci. Individuals are affected if and only if they are recessive homozygous at both loci. The likelihood of the present data under this two-locus multiple recessive homozygosis model is at least 10(8) times higher than that of the one-locus models that were examined in previous studies. This model is also the best-fitting model among other plausible two-locus models.     

PARK7, a Novel Locus for Autosomal Recessive Early-Onset Parkinsonism, on Chromosome 1p36

Although the role of genetic factors in the origin of Parkinson disease has long been disputed, several genes involved in autosomal dominant and recessive forms of the disease have been localized. Mutations associated with early-onset autosomal recessive parkinsonism have been identified in the Parkin gene, and recently a second gene, PARK6, involved in early-onset recessive parkinsonism was localized on chromosome 1p35-36. We identified a family segregating early-onset parkinsonism with multiple consanguinity loops in a genetically isolated population. Homozygosity mapping resulted in significant evidence for linkage on chromosome 1p36. Multipoint linkage analysis using MAPMAKER-HOMOZ generated a maximum LOD-score of 4.3, with nine markers spanning a disease haplotype of 16 cM. On the basis of several recombination events, the region defining the disease haplotype can be clearly separated, by > or =25 cM, from the more centromeric PARK6 locus on chromosome 1p35-36. Therefore, we conclude that we have identified on chromosome 1 a second locus, PARK7, involved in autosomal recessive, early-onset parkinsonism.     

Medico-genetic study of the population of Uzbekistan. VII. Variability of hereditary pathology in 4 regions of Khorezm province

Medical-genetic study was carried out in the population of Khorezm province (population size above 200 000 persons). Hereditary pathology was ascertained among families having two or more members affected with chronic non-infectious diseases. 155 families with 348 members affected with hereditary diseases were registered. The most frequent were autosomal recessive diseases (55 nosological forms in 104 families with 271 affected), then followed the autosomal dominant conditions (10 nosological forms in 21 families with 53 affected). The less frequent was X-linked recessive pathology (6 forms in 12 families with 20 affected). The main part of cases of autosomal recessive pathology were found in separate families and were not observed during previous medical-genetic studies in Uzbekistan. Three autosomal recessive conditions are probably new forms of hereditary pathology. The important role of assortative matings in manifestation of rare autosomal recessive genes in Uzbek population is discussed.