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PubMed1992

Evidence for paternal imprinting in familial Beckwith-Wiedemann syndrome.

A previously unreported family in which seven members in two generations have Beckwith-Wiedemann syndrome (BWS) is documented. Paternal imprinting of the gene responsible for BWS is involved as the mechanism responsible for the aberrant inheritance pattern in this kindred. A review of published reports showed 27 previously published pedigrees with two or more affected subjects with BWS. Paternal imprinting would explain the non-mendelian inheritance of BWS in all but four kindreds. The latter families are examined in more detail and in only one example is the evidence against imprinting totally unexplained.

Beckwith-Wiedemann Syndrome↗
PubMed1986

Intellectual and cognitive function in adults with myotonic muscular dystrophy.

Intellectual and cognitive function was studied in 43 patients (21 men and 22 women) with myotonic muscular dystrophy (MMD). The inheritance distribution was 18 paternal, 10 maternal, and 15 unknown. All patients received the Wechsler Adult Intelligence Scale-Revised, the Wechsler Memory Scale, the Halstead-Reitan Neuropsychological Test Battery, and the Aphasia Screening Test. Significantly lower scores (p less than 0.05) were found on all intellectual and cognitive impairment tests in both men and women of the maternal inheritance MMD subgroup, compared with the paternal inheritance MMD subgroup and with the normative data. Scores for patients with paternally inherited disease did not differ significantly from normative data for verbal, performance, or full scale intelligence quotients and memory quotients. There were no significant differences in intellectual and cognitive test scores between men and women for the group as a whole, for the maternal inheritance subgroup, or for the paternal inheritance subgroup. It is suggested that inheritance pattern is a necessary variable in studies investigating intellectual and cognitive function in MMD. Although the reason for the association of lower intellectual and cognitive function in MMD of maternal inheritance is not known, the data presented here may be useful for genetic counseling.

Adolescent↗
PubMed1995

Developmental regulation of genomic imprinting during gametogenesis.

Successful mammalian development requires both the male and female genomes. This is due in part to genomic imprinting, which results in offspring inheriting only one functional copy of a gene from either the mother or the father. Evidence suggests that this specialization of the parental genomes is established during gametogenesis when the imprint pattern inherited from the parent is switched to reflect the sex of the progeny. We used reverse transcription-PCR to analyze the allele-specific expression of Igf-2, Igf-2r, and H19 in the testes and ovaries of mice derived from an interspecies cross between Mus musculus and Mus spretus. Because of genomic imprinting, Igf-2 is expressed only from the paternal allele and Igf-2r and H19 only from the maternal allele, in most tissues. Although allele-specific expression was maintained in the neonatal testis and ovary, relaxation of imprinting was detected by 7 days after birth in the male and continued during testis development. In the female, relaxation of the Igf-2 and Igf-2r parental imprints was observed in the adult ovary and oocyte. These results (1) indicate that imprinted expression is relaxed during gametogenesis, presumably as a consequence or prerequisite of the imprinting mechanism, and (2) predict a subsequent imprinting event after which the allele-specific expression of Igf-2, Igf-2r, and H19 reflects the parent of origin.

Alleles↗
PubMed1976

Craniosynostosis, midfacial hypoplasia and foot abnormalities: an autosomal dominant phenotype in a large Amish kindred.

An unusual spectrum of craniofacial and foot abnormalities has been detected within a large midwestern Amish kindred. Enlarged great toes and craniofacial abnormalities suggested Pfeiffer acrocephalosynadactyly type V; however, thumb abnormalities were not present. Eighty-eight affected individuals were observed and another 50 were reliably reported to be affected. An autosomal dominant inheritance pattern was observed associated with variable expressivity. All affected individuals had some clinical or radiologic abnormality of the feet. The phenotypic expression was so variable that the entire spectrum of dominantly inherited craniofacial dysotoses-acrocephalosyndactylys (except the typical Apert syndrome) was seen within this kindred.

Child, Preschool↗
PubMed1997

Identification of a complex congenital heart defect susceptibility locus by using DNA pooling and shared segment analysis.

The identification of genetic loci involved in most forms of congenital heart disease has been hampered by the complex inheritance patterns of these disorders. Atrioventricular canal defects (AVCDs) are most commonly associated with Down syndrome, although non-syndromic cases also occur. Non-syndromic AVCDs have been attributed to multifactorial inheritance. However, the occurrence of a few kindreds with multiple affected individuals has suggested that a major genetic locus can account for the disorder in some families. We have used a combination of DNA pooling and shared segment analysis to perform a high density screen of the entire autosomal human genome in an extended kindred. In so doing, we have identified a genetic locus on chromosome 1 shared by all affected individuals. Our data demonstrate the existence of a congenital heart defect susceptibility gene, inherited as an autosomal dominant with incomplete penetrance, involved in AVCD. Furthermore, our data demonstrate the power of using key isolated kindreds in combination with high density genomic screens to identify loci involved in complex disorders such as congenital heart defects.

Chromosome Mapping↗
PubMed1995

Periodic catatonia: a schizophrenic subtype with major gene effect and anticipation.

In a family study involving 139 probands with DSM-III-R catatonic schizophrenia and 543 first-degree relatives, we investigated age-specific morbidity risk according to Leonhard's clinical distinction between systematic and periodic catatonia. This dichotomy is based on different types of symptomatology, course, and outcome. In systematic catatonia the age-corrected morbidity risk was 4.6%. In periodic catatonia, however, there was an age-corrected morbidity risk with homogenous psychoses of 26.9%, and more parents than siblings were affected. This points strongly to a major gene effect in periodic catatonia. Furthermore, a pairwise comparison of patients and their parents revealed patterns of anticipation, i.e., the probands' age at the onset of disease was significantly earlier than that of their parents (P < 0.001). Similarly, anticipation was apparent in pedigrees with three successive generations affected. This inheritance pattern with homogenous psychoses and anticipation indicates that genes with trinucleotid repeat expansion or other repetitive elements affecting gene expression may be involved in the etiology of periodic catatonia. Thus, periodic catatonia as a specific clinical subtype of schizophrenia is a promising candidate for molecular genetic evaluation.

Adult↗
PubMed1998

[Positional cloning of susceptibility genes for non-insulin-dependent diabetes mellitus].

Although studies of families and twin studies have demonstrated that non-insulin-dependent diabetes mellitus (NIDDM) has a strong genetic component, the genes responsible for the common forms of NIDDM are largely unknown, due to the complex and heterogeneous nature of the disease. To study the genetics of NIDDM, we used an inbred animal model of NIDDM, the NSY mouse, in which NIDDM spontaneously develops in an age-dependent manner. The inheritance pattern of glucose tolerance, fasting insulin levels, insulin response to glucose, body mass index, and epididymal fat pad weight in F 1 hybrids of NSY with control C3H/He mice suggested the different modes of inheritance in these phenotypes. Multipoint linkage analysis of glucose tolerance in F2 mice with microsatellite markers throughout the genome mapped at least three loci on different chromosomes. Positional cloning of susceptibility genes for NIDDM in NSY mice may increase our understanding of the genetics and etiology of human NIDDM and may lead to more effective methods for prevention and intervention.

Animals↗
PubMed1976

Deafness and vitiligo.

Seven cases of congenital deafness and an autosomal recessive pedigree pattern were observed in an inbred kindred. Three of the cases also had vitiligo, and there were 2 other cases of vitiligo in this kindred. The vitiligo also appeared to have an autosomal recessive inheritance pattern.

Deafness↗
PubMed1997

Further epidemiological evidence for anticipation in schizophrenia.

Anticipation describes an inheritance pattern within a pedigree in which disease severity increases, and/or age at onset decreases, in successive generations. This phenomenon has been described in different samples of schizophrenic subjects, and could explain many inconsistencies in the inheritability of schizophrenia. Anticipation is, however, subject to numerous and significant biases, partially controlled by different methodologies used in different studies. We analyzed the anticipation effect on an original sample of schizophrenic patients (n = 57) who had at least one other schizophrenic in their family belonging to another generation (father/mother, uncle/aunt, son/daughter). We tested the anticipation effect according to previously published methodologies, such as percentages of parent-child pairs showing negative versus positive anticipation, comparison of anticipation limited to parent-child or uncle-nephew pairs, anticipation analysis on the basis of families with unilineal origins only, and comparison of the age at onset-survival distribution of the two generations. The 31 schizophrenic subjects who belonged to the younger generation had a significantly earlier age at onset (24.58 years) than the 26 schizophrenic subjects who belonged to the older generation (36.46 years). Whatever the method used to control biases, we significantly found earlier age at onset for schizophrenic patients from the younger generation. There is strong evidence for the existence of the anticipation effect in schizophrenia in our sample, as well as in various others, which may elucidate numerous inconsistencies in clinical and epidemiological data which characterize schizophrenia. Looking for expanded trinucleotide repeats is thus the next step to detect the gene(s) that are potentially involved.

Adult↗
PubMed1999

Lymphoproliferative syndrome with autoimmunity: A possible genetic basis for dominant expression of the clinical manifestations.

Fas (CD95/Apo-1) mutations were previously reported as the genetic defect responsible for human lymphoproliferative syndrome associated with autoimmune manifestations (also known as autoimmune lymphoproliferative syndrome or Canale-Smith syndrome). We have identified 14 new heterozygous Fas mutations. Analysis of patients and families allow us to further dissect this syndrome with regards to the relationship between Fas mutations, inheritance pattern, and phenotype as observed on long-term follow-up. In vitro studies show that lymphocytes from all Fas mutant carriers exhibit a Fas-antibody-induced apoptosis defect. However, among the 8 inherited mutations, 4 of 4 Fas missense mutations were associated with high clinical penetrance, whereas 3 of 4 mutations leading to a truncated Fas product were associated with variable clinical penetrance. This suggests that a second defect, in another yet undefined factor involved in apoptosis and/or lymphoproliferation control, is necessary to induce full clinical expression of the disease. These results also indicate that the currently available antibody-mediated in vitro apoptosis assay does not necessarily reflect the in vivo ability of abnormal Fas molecules to trigger lymphocyte death. In addition, we found that lymphoproliferative manifestations resolved with age, whereas immunological disorders [ie, hypergammaglobulinemia and detection of TcR alphabeta(+) CD4(-) CD8(-) lymphocytes] persisted. This observation suggests that Fas-mediated apoptosis plays a more important role in lymphocyte homeostasis in early childhood than later on in life.

Adolescent↗
PubMed1997

Paternal transmission of the mouse Thp mutation is lethal in some genetic backgrounds.

Thp is a large deletion on chromosome 17 which includes the maternal lethal gene Tme. Documentation of inheritance patterns suggests that Tme is an imprinted gene which is required for viability; maternal deletion is lethal while paternal deletion is viable. However, paternal transmission of Thp is rarely the expected 50%. We show here that paternally inherited Thp is lethal in some strains, providing evidence of an incompletely penetrant, dosage sensitive lethal allele of a locus that probably maps to the hairpin tail region of chr. 17. Interpretation of the various phenotypes associated with loss of the putative Tme gene, Igf2r, may need to be revised in view of these observations.

Abnormalities, Multiple↗
PubMed1992

Dermatopathia pigmentosa reticularis: a report of a family demonstrating autosomal dominant inheritance.

Dermatopathia pigmentosa reticularis is a rare heritable disorder consisting of a triad of cutaneous findings including reticulate hyperpigmentation, noncicatricial alopecia, and onychodystrophy. In addition to this triad, other variable features of dermatopathia pigmentosa reticularis have been described, including adermatoglyphia, hypohidrosis or hyperhidrosis, and palmoplantar hyperkeratosis. Only 10 cases have been described in the world literature to date, and no clear inheritance pattern has been demonstrated. We present a patient with the classic features of the dermatopathia pigmentosa reticularis triad, along with adermatoglyphia, hypohidrosis, and punctate hyperkeratosis of the palms and soles. A family pedigree demonstrates the autosomal dominant inheritance of dermatopathia pigmentosa reticularis.

Adult↗
PubMed1995

Guess LOD approach: sufficient conditions for robustness.

Analysis of genetic linkage between a disease and a marker locus requires specifying a genetic model describing both the inheritance pattern and the gene frequencies of the marker and trait loci. Misspecification of the genetic model is likely for etiologically complex diseases. In previous work we have shown through analytic studies that misspecifying the genetic model for disease inheritance does not lead to excess false-positive evidence for genetic linkage provided the genetic marker alleles of all pedigree members are known, or can be inferred without bias from the data. Here, under various selection or ascertainment schemes we extend these previous results to situations in which the genetic model for the marker locus may be incorrect. We provide sufficient conditions for the asymptotic unbiased estimation of the recombination fraction under the null hypothesis of no linkage, and also conditions for the limiting distribution of the likelihood ratio test for no linkage to be chi-squared. Through simulation studies we document some situations under which asymptotic bias can result when the genetic model is misspecified. Among those situations under which an excess of false-positive evidence for genetic linkage can be generated, the most common is failure to provide accurate estimates of the marker allele frequencies. We show that in most cases false-positive evidence for genetic linkage is unlikely to result solely from the misspecification of the genetic model for disease or trait inheritance.

Genetic Linkage↗
PubMed1997

Genetic analysis of adult-onset cataract in a city-based ophthalmic hospital.

Adult-onset cataract (AOC) is a major ocular health problem and is the number one cause of blindness in the world. It is interesting to note that if the development of cataract is delayed by 10 years, the number of cataract surgeries needed would decrease by 45%. To prevent or delay cataract, the molecular pathological mechanisms underlying the lens change have to be understood, and this requires that the genes involved in such mechanisms should be identified. Hence, in this study we aim to identify AOC families which show a clear mendelian inheritance pattern, as only these families would be ideal for mapping the genes responsible. Over a period of 8 months, from September 1995-April 1996, 17 families with two or more affected members were identified. Segregation analysis showed autosomal dominant inheritance in multiple affected families. We propose to map the genes responsible for cataract in these families by linkage analysis and mutational screening of candidate genes.

Adult↗
PubMed1977

Spectrum of von Willebrand's Disease: a study of 100 cases. Italian Working Group.

The clinical picture, family history and laboratory findings of 100 patients with von Willebrand's disease (VWD) have been studied in Italy in a multicentre survey from two rural areas with a known high incidence of the disease and from two large cities (Rome and Milan). Bleeding time, procoagulant factor-VIII (VIIIAHF) assay, platelet retention and PRP-ristocetin aggregation were measured in each centre, and plasma samples were frozen and subsequently assayed for factor VIII-related antigen (VIIIAGN) and ristocetin co-factor (VIIIVWF) in one laboratory (Milan). On the basis of the inheritance pattern, clinical severity of the disease and laboratory findings, patients with VWD were separated into two groups. In 17 patients the absence of a family history of bleeding, a high incidence of parental consanguinity and involvement of both sexes suggested an autosomal recessive mode of inheritance; the unusual severity of the disease with markedly abnormal results of all six laboratory measurements (and frequent reduced levels of VIIIAGN and VIIIVWF in the unaffected parents) were consistent with the homozygous state. In 83 patients, the disease was familial (being transmitted as an autosomal dominant trait) and of moderate clinical severity. In these, VIIIVWF was usually much lower than VIIIAHF and VIIIAGN. The findings suggest that although some patients may present with simultaneous abnormalities of all six studied laboratory measurements, the majority show a variation in the spectrum of the abnormal results, without any obvious simple pattern.

Antigens↗
PubMed2025

Bistable Mutation-Selection Equilibria and Violations of Fisher's Theorem in Tetraploids: Insights from Nonlinear Dynamics.

Polyploidy and whole genome duplication (WGD) are widespread biological phenomena with substantial cellular, meiotic, and genetic effects. Despite their prevalence and significance across the tree of life, population genetics theory for polyploids is not well developed. The lack of theoretical models limits our understanding of polyploid evolution and restricts our ability to harness polyploidy for crop improvement amidst increasing environmental stress. To address this gap, we developed and analyzed deterministic models of mutation-selection balance for tetraploids under polysomic (autotetraploid) and disomic (allotetraploid) inheritance patterns and arbitrary dominance relationships. We also introduced a new mathematical framework based on ordinary differential equations and nonlinear dynamics for analyzing the models. We find that autotetraploids approach Hardy-Weinberg Equilibrium 33% faster than allotetraploids, but the different tetraploid inheritance models show little differences in mutation load and allele frequency at mutation-selection balance. Our model also reveals two bistable points of mutation-selection balance for dominant alleles with biased mutation rates over a wide range of selection coefficients in the tetraploid models compared to bistability in only a narrow range for diploids. Finally, using discrete time simulations, we explore the temporal dynamics of allele frequency and fitness change and compare these dynamics to the predictions of Fisher's Fundamental Theorem of Natural Selection. While Fisher's predictions generally hold, we show that the bistable dynamics for dominant mutations fundamentally alter the associated temporal dynamics. Overall, this work develops foundational theoretical models that will facilitate the development of population genetic models and methodologies to study evolution in empirical tetraploid populations.

Fisher&#x2019;s Fundamental Theorem↗
PubMed1992

Mitochondrial DNA and genetic disease.

Since the human mitochondrial genome was characterised and sequenced in 1981, it has been viewed as the likely site of genetic diseases showing a maternal inheritance pattern and associated with defects of the respiratory chain, such as the mitochondrial myopathies (MMs). The properties that make it a candidate for the source of such conditions are that it encodes polypeptides involved in electron transport and that it is maternally inherited. However, several of the mtDNA diseases only fulfill one or other of these criteria: the first group of mtDNA diseases showed only sporadic deletions, and the first point mutation in Leber's Hereditary Optic Neuropathy (LHON) is not associated with a clear biochemical defect. Furthermore, it is now clear that both autosomal dominant and probably recessive nuclear genes can cause abnormalities of mtDNA. Each of these major groups will be considered in turn.

Adult↗
PubMed1995

Intermediate inheritance of Tourette syndrome, assuming assortative mating.

Segregation analysis incorporating assortative mating was used to test for major locus inheritance of Tourette syndrome in a single large pedigree containing 182 members. The analysis provided evidence of a major locus with an intermediate inheritance pattern for which the penetrance was estimated from the data as 28% in heterozygotes and 98%-99% in homozygotes. A significant assortative mating correlation was estimated from the data as 70%-79%. In contrast, when assortative mating was not included in the model, intermediate inheritance was not inferred. If, in addition, constancy of the allele frequencies across generations was not assumed, Mendelian transmission was rejected. Each subject, affected or unaffected, was assigned a score reflecting the presence and severity of symptoms. Higher means scores in affected homozygotes than in affected heterozygotes suggested greater severity in homozygotes: genotype information was obtained from genotype probabilities computed assuming intermediate inheritance.

Adolescent↗