Problems in detecting etiological heterogeneity in genetic disease illustrated with retinitis pigmentosa

Simulated data were generated under four etiologic mechanisms for each of 20 different pedigree structures drawn from a study of families ascertained through a proband with retinitis pigmentosa. These simulated data were then used to identify subgroups of pedigrees which best supported each of three genetic mechanisms (autosomal dominant, autosomal recessive, X-linked recessive with 10% penetrance of disease in heterozygous females) and a non-genetic, sporadic mechanism. Results of these studies show that pedigrees identified as supporting one genetic model in a 'model choice' approach tend to be etiologically homogeneous, but are not truly representative of all the phenotypic combinations possible under that mechanism. The problem of etiologic heterogeneity is most acute when dealing with pedigrees less than size 10. Pedigrees lumped under a non-genetic, sporadic mechanism are extremely heterogeneous and studies of the natural history of diseases where both genetic and non-genetic mechanisms may be operating (such as with retinitis pigmentosa) should avoid using this group of largely simplex pedigrees.     

Challenging colonic polyposis pedigrees: differential diagnosis, surveillance, and management concerns

Hereditary polyposis syndromes show extensive phenotypic and genotypic heterogeneity within and among families, a situation that may hinder diagnosis. In these settings, germline mutation testing may be the sine qua non for diagnosis if such a mutation is identified in a patient or family. We provide examples of phenotypically differing polyposis pedigrees depicting various challenges in hereditary polyposis syndrome diagnosis. Our purpose is to augment physician understanding of phenotypic variation and thus help identify high-risk presymptomatic family members who could benefit from highly targeted surveillance and management strategies. We describe nine familial polyposis pedigrees displaying anecdotal clinical problems that can confound the differential diagnosis. Emphasis was given to a multidisciplinary approach focusing on pathological confirmation with respect to number, histology, and location of polyps in the gastrointestinal tract; a detailed family history of cancer at all anatomic sites; noncancer phenotypic features of hereditary polyposis syndromes; and appropriate molecular genetic testing in concert with genetic counseling. Improved physician understanding of the clinical natural history features, genetic transmission patterns, and appropriate gene testing will help in diagnosis and, ultimately, surveillance and management for the various hereditary polyposis syndromes.     

Dyschromatosis universalis hereditaria: familial case and ultrastructural skin investigation

We present three families with infantile myofibromatosis (IM; OMIM no. 228550) inherited in an autosomal dominant (AD) manner. These three pedigrees prompted re-assessment of pedigrees available within the genetic, oncologic, surgical, and pathologic literature, which suggest autosomal recessive (AR) inheritance. All familial IM may be interpreted as AD or, alternatively, there may be genetic heterogeneity for IM. As most nodules tend to regress spontaneously, familial history may be difficult to obtain and/or confirm. Clinical diagnosis and establishment of inheritance pattern can be important for prognosis and the recognition that other family members may be affected.     

代谢性皮肤单基因病临床与分子遗传学研究进展

代谢性皮肤单基因病是由某些代谢性原因引起皮肤异常表现的单基因病,这类疾病具有遗传性、代谢异常以及皮肤异常表现等共同特点,主要涉及淀粉样蛋白、卟啉、铁、半乳糖苷酶、类脂蛋白以及苯丙氨酸等物质的代谢异常.常见的代谢性皮肤单基因病有家族性原发性皮肤淀粉样变、红细胞生成性原卟啉病、遗传性血色病、弥漫性躯体血管角皮病、类脂蛋白沉积症和苯丙酮尿症等.其中家族性原发性皮肤淀粉样变具有一定的遗传异质性,国内外很多家系尚未发现易感基因,未来需要继续探索.FECH基因的突变类型众多,这给明确红细胞生成性原卟啉病的突变位点和产前诊断带来一定困难.蛋白酶体抑制剂MG132和rhɑ-GLA联合应用可以显著恢复GLA酶的活性,未来可能有助于研发治疗弥漫性躯体血管角皮瘤的药物.     

Genetic studies of insulin-dependent diabetes mellitus: segregation and linkage analyses

The inclusion of HLA data in genetic studies of insulin-dependent diabetes mellitus (IDDM) has not led to conclusive segregation models for IDDM so far. As a new approach, we first applied complex segregation analysis, independently of HLA data, to two combined Danish family materials. Then the best fitting segregation model was entered into linkage analysis of a third material, including family as well as HLA data. The best solution obtained in the segregation analysis was a mixed model, including an intermediate gene, which on the penetrance scale acts as a recessive, together with a polygcnic component. The linkage analysis showed an overall recombination fraction of 0.0417 with high coupling frequencies for the HLA-DR3 and HLA-DR4 alleles and the putative disease susceptibility gene. However, when the pedigrees were divided according to whether or not the proband had the heterozygous HLA-phenotype DR3/DR4, a maximum likelihood ratio test for heterogeneity was significant, with estimated recombination fractions of 0.0 and 0.0963 in HLA-DR3/DR4 pedigrees and the remaining pedigrees, respectively. In total, we found convincing evidence that two familial factors contribute to IDDM: a locus within HLA, which very well may be DR; and an unlinked mechanism which is unimportant for HLA-DR3/DR4 but simulates recombination. If confirmed, this conclusion has important implications for further genetic studies of IDDM and complex segregation analyses of family materials sampled according to criteria which include HLA data of the probands are highly needed.     

Irish study of high-density schizophrenia families: Field methods and power to detect linkage

Large samples of multiplex pedigrees will probably be needed to detect susceptibility loci for schizophrenia by linkage analysis. Standardized ascertainment of such pedigrees from culturally and ethnically homogeneous populations may improve the probability of detection and replication of linkage. The Irish Study of High-Density Schizophrenia Families (ISHDSF) was formed from standardized ascertainment of multiplex schizophrenia families in 39 psychiatric facilities covering over 90% of the population in Ireland and Northern Ireland. We here describe a phenotypic sample and a subset thereof, the linkage sample. Individuals were included in the phenotypic sample if adequate diagnostic information, based on personal interview and/or hospital record, was available. Only individuals with available DNA were included in the linkage sample. Inclusion of a pedigree into the phenotypic sample required at least two first, second, or third degree relatives with non-affective psychosis (NAP), one of whom had schizophrenia (S) or poor-outcome schizoaffective disorder (PO-SAD). Entry into the linkage sample required DNA samples on at least two individuals with NAP, of whom at least one had S or PO-SAD. Affection was defined by narrow, intermediate, and broad criteria. The phenotypic sample contained 277 pedigrees and 1,770 individuals and the linkage sample 265 pedigrees and 1,408 individuals. Using the intermediate definition of affection, the phenotypic sample contained 837 affected individuals and 526 affected sibling pairs. Parallel figures for the linkage sample were 700 and 420. Individuals with schizophrenia from these multiplex pedigrees resembled epidemiologically sampled cases with respect to age at onset, gender distribution, and most clinical symptoms, although they were more thought-disordered and had a poorer outcome. Power analyses based on the model of linkage heterogeneity indicated that the ISHDSF should be able to detect a major locus that influences susceptibility to schizophrenia in as few as 20% of families. Compared to first-degree relatives of epidemiologically sampled schizophrenic probands, first-degree relatives of schizophrenic members from the ISHDSF had a similar risk for schizotypal personality disorder, affective illness, alcoholism, and anxiety disorders. With sufficient resources, large-scale ascertainment of multiplex schizophrenia pedigrees is feasible, especially in countries with catchmented psychiatric care and stable populations. Although somewhat more severely ill, schizophrenic members of such pedigrees appear to clinically resemble typical schizophrenic patients. Our ascertainment process for multiplex schizophrenia families did not select for excess familial risk for affective illness or alcoholism. With its large sample ascertained in a standardized manner from a relatively homogeneous population, the ISHDSF provides considerable power to detect susceptibility loci for schizophrenia. © 1996 Wiley-Liss, Inc.     

Two pedigrees of autosomal dominant atrioventricular canal defect (AVCD): Exclusion from the critical region on 8p

Atrioventricular canal defects (AVCD) constitute the predominant congenital heart defect in Down syndrome. For this reason, a candidate gene involved in atrioventricular canal development was previously searched and excluded in dominant pedigrees of AVCD, using linkage analysis of polymorphisms from chromosome 21. Because of the striking association between 8p deletion and AVCD, a search for an AVCD gene was carried out in two pedigrees of individuals with autosomal dominant AVCD using a set of DNA markers of the 8pter→ql2 region. These two families include affected individuals and subjects who have transmitted the defect but are not clinically affected. Two-point lod scores were significantly negative for all markers at penetrance levels of 90% and 50%. Multipoint analysis excluded the region covered by the markers LPL-D8S262 and 30 cM to either side of this area. This result corroborates heterogeneity of this heart defect and indicates that the genetic basis of familial AVCD is different from AVCD associated to either trisomy 21 or 8p deletion. © 1995 Wiley-Liss, Inc.     

Segregation Analysis of Prostate Cancer in France: Evidence for Autosomal Dominant Inheritance and Residual Brother-brother Dependence

Four segregation analyses concerning prostate cancer (CaP), three conducted in the United States and one in Northern Europe, have shown evidence for a dominant major gene but with different parameter estimates. A recent segregation analysis of Australian pedigrees has found a better fit of a two‐locus model than single‐locus models. This model included a dominantly inherited increased risk that was greater at younger ages and a recessively inherited or X‐linked increased risk that was greater at older ages. Recent linkage analyses have led to the detection of at least 8 CaP predisposing genes, suggesting a complex inheritance and genetic heterogeneity. To assess the nature of familial aggregation of prostate cancer in France, segregation analysis was conducted in 691 families ascertained through 691 CaP patients, recruited from three French hospitals and unselected with respect to age at diagnosis, clinical stage or family history. This mode of family inclusion, without any particular selection of the probands, is unique, as probands from all previous analyses were selected according to various criteria. Segregation analysis was carried out using the logistic hazard regressive model, as incorporated in the REGRESS program, which can accommodate a major gene effect, residual familial dependences of any origin (genetic and/or environmental), and covariates, while including survival analysis concepts. Segregation analysis showed evidence for the segregation of an autosomal dominant gene (allele frequency of 0.03%) with an additional brother‐brother dependence. The estimated cumulative risks of prostate cancer by age 85 years, among subjects with the at‐risk genotype, were 86% in the fathers' generation and 99% in the probands' generation. This study supports the model of Mendelian transmission of a rare autosomal dominant gene with high penetrance, and demonstrates that additional genetic and/or common sibling environmental factors are involved to account for the familial clustering of CaP.     

Major gene and multifactorial inheritance of mandibular prognathism

Mandibular prognathism typically shows familial aggregation. Various genetic models have been described and it is assumed to be a multifactorial and polygenic trait, with a threshold for expression. Our goal was to examine specific genetic models of the familial transmission of this trait. The study sample comprised of 2,562 individuals from 55 families. Complete family histories for each proband were ascertained and the affection status of relatives were confirmed by lateral cephalograms, photographs, and dental models. Pedigrees were drawn using PELICAN and complex segregation analysis was performed using POINTER. Parts of some pedigrees were excluded to create one founder pedigrees, so the total N was 2,050. Analysis showed more affected females than males (P = 0.030). The majority of the pedigrees suggest autosomal dominant inheritance. Incomplete penetrance was demonstrated by the ratio of affected/unaffected parents and siblings. The heritability of mandibular prognathism was estimated to be 0.316. We conclude that there is a major gene that influences the expression of mandibular prognathism with clear signs of Mendelian inheritance and a multifactorial component.     

Assessing the statistical power to detect linkage in a sample of 51 bipolar affective disorder pedigrees

We used computer simulation method to address the question of power in an initial collaborative sample of 51 bipolar affective disorder pedigrees. Simulations were performed for all possible combinations using (1) two levels of diagnostic stringency, (2) three transmission models, (3) locus heterogeneity, and (4) different assumed phenocopy rates. Some of the factors that affect the power to detect linkage are (1) the specification of the correct genetic model, (2) the degree of locus heterogeneity, and (3) the frequency of phenocopies. The first two assertions were supported by our simulation results, but varying the rates of phenocopy did not substantially alter the power of the sample until a critical point. However, it is important to point out that these results are dependent on the genetic models under study and on the use of the “correct” model (i.e., the one used to simulate the data). If we assume a dominant mode of inheritance and locus homogeneity, the power to detect linkage is 97.5% at a θ of .01. However, the power declines dramatically, to 60.5 and 14.7%, if only 75 and 50% of the families are linked, respectively. Locus heterogeneity has a similar effect on the power of the sample to exclude linkage. The relative lack of power in our data, in the presence of significant locus heterogeneity, and for an intermediate mode of inheritance, underscores the need for multicenter collaboration.     

Initial report of a genome search for the affective disorder predisposition gene in the old order Amish pedigrees: Chromosomes 1 and 11

Family data have suggested that some forms of major affective disorder are genetic. Certain of the Old Order Amish pedigrees have a familial form of the disease. In this report we present the results of genetic analyses under autosomal dominant mode of transmission with reduced pentrance and three different disease hierarchies. The pedigrees were genotyped with 28 markers from chromosome 1 and 23 markers from chromosomes 11. None of the markers result in a significantly positive lod score. © 1994 Wiley-Liss, Inc.     

Model-Based Multifactor Dimensionality Reduction to detect epistasis for quantitative traits in the presence of error-free and noisy data

Detecting gene-gene interactions or epistasis in studies of human complex diseases is a big challenge in the area of epidemiology. To address this problem, several methods have been developed, mainly in the context of data dimensionality reduction. One of these methods, Model-Based Multifactor Dimensionality Reduction, has so far mainly been applied to case-control studies. In this study, we evaluate the power of Model-Based Multifactor Dimensionality Reduction for quantitative traits to detect gene-gene interactions (epistasis) in the presence of error-free and noisy data. Considered sources of error are genotyping errors, missing genotypes, phenotypic mixtures and genetic heterogeneity. Our simulation study encompasses a variety of settings with varying minor allele frequencies and genetic variance for different epistasis models. On each simulated data, we have performed Model-Based Multifactor Dimensionality Reduction in two ways: with and without adjustment for main effects of (known) functional SNPs. In line with binary trait counterparts, our simulations show that the power is lowest in the presence of phenotypic mixtures or genetic heterogeneity compared to scenarios with missing genotypes or genotyping errors. In addition, empirical power estimates reduce even further with main effects corrections, but at the same time, false-positive percentages are reduced as well. In conclusion, phenotypic mixtures and genetic heterogeneity remain challenging for epistasis detection, and careful thought must be given to the way important lower-order effects are accounted for in the analysis.     

Telomere dysfunction and tumor suppression responses in dyskeratosis congenita: Balancing cancer and tissue renewal impairment

Dyskeratosis congenita (DC) encompasses a large spectrum of diseases and clinical manifestations generally related to premature aging, including bone marrow failure and cancer predisposition. The major risk factor for DC is to carry germline telomere-related mutations – in telomerase or telomere shelterin genes – which results in premature telomere dysfunction, thus increasing the risk of premature aging impairments. Despite the advances that have been accomplished in DC research, the molecular aspects underlying the phenotypic variability of the disease remain poorly understood. Here different aspects of telomere biology, concerning adult stem cells senescence, tumor suppression and cancer are considered in the context of DC, resulting in two translational models: late onset of DC symptoms in telomere-related mutations carriers is a potential indicator of increased cancer risk and differences in tumor suppression capacities among the genetic subgroups are (at least partial) causes of different clinical manifestations of the disease. The limitations of both models are presented, and further experiments for their validation, as well as clinical implications, are discussed.     

特发性癫痫遗传方式的研究

目的为了探讨特发性癫痫（ＩＥＰ）的遗传方式。方法采用家系分析、多基因分析和分离分析的方法，对山东省遗传病群体调查中发现的２１０个ＩＥＰ家系进行了研究。结果ＩＥＰ不符合多基因遗传，而主要为常染色体隐体遗传。分离分析结果显示，Ｕ×Ｕ多发家庭组和Ｕ×Ａ家庭组可以接受常染色体隐性遗传的假设；部分Ｕ×Ｕ组的家庭可以接受常染色体隐性遗传的假设，但是大多数Ｕ×Ｕ组的家庭为散发病例，散发病例比例为７８．５％。结论散发病例和Ｕ×Ｕ（ｆ）家庭组可能存在遗传异质性，其原因有待进一步的研究。     

Challenges and solutions for gene identification in the presence of familial locus heterogeneity

Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3% (95% confidence interval: 11.9%, 19.9%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification.     

Localization of a gene for Mobius syndrome to chromosome 3q by linkage analysis in a Dutch family

Mobius syndrome (MIM no. 157900) consists of a congenital paresis or paralysis of the VIIth cranial nerve, frequently accompanied by paralysis of other cranial nerves, orofacial and limb malformations, defects of the musculoskeletal system and mental retardation. Although most patients are sporadic cases, familial recurrence is not rare. Different pedigrees suggest different modes of inheritance. We performed linkage analysis in a large family with autosomal dominantly inherited Mobius syndrome, consisting essentially of asymmetric bilateral facial pareses. After exclusion of the candidate region for Mobius syndrome on 13q12.2-q13, we localized the gene to chromosome 3q21-22, indicating genetic heterogeneity of Mobius syndrome. This heterogeneity is further proven by the exclusion of both loci in a second family with Mobius syndrome.      

Clinical implications of anti-heart autoantibodies in myocarditis and dilated cardiomyopathy

Dilated cardiomyopathy (DCM), a leading cause of heart failure and heart transplantation in younger adults, is characterized by dilatation and impaired contraction of the left or both ventricles; it may be idiopathic, familial/genetic (20–30%), viral, and/or immune. On endomyocardial biopsy there is chronic inflammation in 30–40% of cases. Mutations in genes encoding myocyte structural proteins, cardiotoxic noxae and infectious agents are known causes; due to high aetiologic and genetic heterogeneity, the gene defects identified so far account for a tiny proportion of the familial cases. In at least two thirds of patients, DCM remains idiopathic. Myocarditis may be idiopathic, infectious or autoimmune and may heal or lead to DCM. Circulating heart-reactive autoantibodies are found in myocarditis/DCM patients and symptom-free relatives at higher frequency than in normal or noninflammatory heart disease control groups. These autoantibodies are directed against multiple antigens, some of which are expressed only in the heart (organ-specific); some autoantibodies have functional effects on cardiac myocytes in vitro as well as in animal models. Depletion of nonantigen-specific antibodies by extracorporeal immunoadsorption is associated with improved ventricular function and reduced cardiac symptoms in some DCM patients, suggesting that autoantibodies may also have a functional role in humans. Immunosuppression seems beneficial in patients who are virus-negative and cardiac autoantibody positive. Prospective family studies have shown that cardiac-specific autoantibodies are present in at least 60% of both familial and non familial pedigrees and predict DCM development among asymptomatic relatives, years before clinical and echocardiographic evidence of disease. Animal models have shown that autoimmune myocarditis/DCM can be induced by virus as well as reproduced by immunization with a well-characterized autoantigen, cardiac myosin. Thus, in a substantial proportion of patients, myocarditis and DCM represent different stages of an organ-specific autoimmune disease, that represents the final common pathogenetic pathway of infectious and noninfectious myocardial injuries in genetically predisposed individuals.     

Emerging pathways for hereditary axonopathies

Motor neurons are affected in a number of neurological diseases. Their unifying pathological signature is degeneration of extended projecting axons and loss of motor neurons in the prefrontal cortex and/or the spinal cord. Based on clinical criteria, hereditary forms have been traditionally divided into distinct entities, such as familial amyotrophic lateral sclerosis, hereditary motor neuropathy, spinal muscular atrophy, familial spinal paraplegia, and Charcot–Marie–Tooth disease type 2, also known as hereditary motor and sensory neuropathy II. Genetic research of the last decade has revealed remarkable heterogeneity within these disorders. Most of the identified genes to date cause disease in a classic Mendelian inheritance pattern with a high phenotypic penetrance. This rich source of molecular genetic data has already provided insight into the underlying major pathways of these diseases and should continue to do so in the future. This review attempts to cross the traditional clinical classifications in order to draw an emerging picture of common pathways between causative genes, providing a different perspective of this rapidly growing scientific field.     

Clinical implications of anti-heart autoantibodies in myocarditis and dilated cardiomyopathy

Dilated cardiomyopathy (DCM), a leading cause of heart failure and heart transplantation in younger adults, is characterized by dilatation and impaired contraction of the left or both ventricles; it may be idiopathic, familial/genetic (20-30%), viral, and/or immune. On endomyocardial biopsy there is chronic inflammation in 30-40% of cases. Mutations in genes encoding myocyte structural proteins, cardiotoxic noxae and infectious agents are known causes; due to high aetiologic and genetic heterogeneity, the gene defects identified so far account for a tiny proportion of the familial cases. In at least two thirds of patients, DCM remains idiopathic. Myocarditis may be idiopathic, infectious or autoimmune and may heal or lead to DCM. Circulating heart-reactive autoantibodies are found in myocarditis/DCM patients and symptom-free relatives at higher frequency than in normal or noninflammatory heart disease control groups. These autoantibodies are directed against multiple antigens, some of which are expressed only in the heart (organ-specific); some autoantibodies have functional effects on cardiac myocytes in vitro as well as in animal models. Depletion of nonantigen-specific antibodies by extracorporeal immunoadsorption is associated with improved ventricular function and reduced cardiac symptoms in some DCM patients, suggesting that autoantibodies may also have a functional role in humans. Immunosuppression seems beneficial in patients who are virus-negative and cardiac autoantibody positive. Prospective family studies have shown that cardiac-specific autoantibodies are present in at least 60% of both familial and non familial pedigrees and predict DCM development among asymptomatic relatives, years before clinical and echocardiographic evidence of disease. Animal models have shown that autoimmune myocarditis/DCM can be induced by virus as well as reproduced by immunization with a well-characterized autoantigen, cardiac myosin. Thus, in a substantial proportion of patients, myocarditis and DCM represent different stages of an organ-specific autoimmune disease, that represents the final common pathogenetic pathway of infectious and noninfectious myocardial injuries in genetically predisposed individuals.