Specific Clinical Phenotype Research Articles

Genetic analysis of cardiac-specific transcription factors reveals insights into congenital heart disease

Heart development is complex and requires the sequential and timely interplay of regulatory master proteins, notably several transcription factors. Germline mutations in the human transcription factor genes such as NKX2-5, TBX5 and GATA4 are associated with cardiac anomalies. Familial cases so far studied have different mutations and no mutation can be associated with a specific clinical phenotype. Many cases of CHD come from unaffected family members. We searched for sequence alterations in cardiac specific transcription factor genes that would lead to loss-of-function of the protein in 68 malformed hearts from the Leipzig heart collection. By direct DNA sequencing, we obtained mutations in several transcription factors e.g. NKX2-5, TBX5 and GATA4 in the diseased heart tissues, which were mainly absent in normal heart tissues of the same CHD patients. We also observed multiple mutations in patients, multiple haplotypes, and detection of mutations in Down syndrome patients, all suggesting somatic origin of mutations and genomic instability in the diseased cardiac tissues of patients with CHD. Somatic mutations may provide an alternate mechanism of disease.

Bereit für neue medizinische Herausforderungen –die «Genetics HIV Cohort» der Schweizerischen HIV Kohortenstudie

Host genetic factors determine the individual natural course of HIV infection and influence the response to therapy and the occurrence of adverse events to treatment. Variants of multiple genes are associated with faster but also slower development of severe immunodeficiency. However, only very rarely the variant of one single gene explains a specific clinical phenotype. But multiple genetic marker form a complex trait, which is difficult to analyse biostatistically. Research in this rapidly evolving field asks for structures in which hypotheses can be generated and evaluated and which combine basic and diagnostic and therapeutic research. The large amount of prospective information on HIV disease natural history and treatment response of the Swiss HIV Cohort Study will make of the Genetics project an excellent test-setting for some of the immediate difficulties in this research field: validation of new markers and modelling of complex traits.

Diagnostic criteria, clinical characteristics, and natural history of Cohen syndrome

Cohen syndrome is a rare, recessively inherited condition associated with facial dysmorphism, developmental delay, and visual disability. A delay in making the diagnosis commonly occurs, contributed to by the lack...

LTC4-synthase A-444C polymorphism: lack of association with NSAID-induced isolated periorbital angioedema in a Spanish population

The mechanism of nonsteroidal anti-inflammatory drug (NSAID)-induced reactions is unknown. However, strong evidence supports the hypothesis of an enhanced production of cysteinyl-leukotrienes. The existence of a polymorphism (A-444C) in the promoter region of the leukotriene (LT)C4-synthase gene (the terminal enzyme in the LTC4 production pathway) has been reported. This polymorphism has yielded contradictory results on its association with aspirin-induced asthma. The present study was designed to investigate the possible genetic association of C(-444) allele and a specific clinical phenotype of NSAID sensitivity, the NSAID-induced isolated periorbital angioedema, via a case/control study. The polymorphism A-444C was analyzed in 58 patients with NSAID-induced periorbital angioedema and 61 control subjects, who had undergone single-blind, placebo-controlled oral challenge. Genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. We have not found an association of C(-444), allele with NSAID-induced isolated periorbital angioedema. Further studies are needed to determine whether polymorphisms in the LTC4-synthase gene or other leukotriene-forming enzymes are involved in the pathogenesis of the different subsets of NSAID sensitivity.

A founder mutation in French-Canadian families with X-linked hereditary neuropathy.

The aim of the present study was to identify the mutations in the connexin 32 gene in French-Canadian families with X-linked Charcot-Marie-Tooth disease (CMTX). Molecular analysis was performed by nonisotopic single strand conformation polymorphism (SSCP) analysis and sequencing. Clinical evaluation was carried out according to the scale defined by the European Hereditary Motor and Sensory Neuropathy Consortium. In one family, the mutation Arg142Trp was located in the transmembrane domain III whereas, in four other families we identified a novel mutation (Ser26Trp) located in the transmembrane domain I of the connexin 32 gene. Haplotype analysis revealed that these four families are related and suggests a founder mutation. Sixteen patients from these four families were studied. As expected, all the affected males were more clinically affected than the females and all affected patients exhibited some electrophysiological characteristics of demyelination. Our study suggests that the Ser26Trp mutation may cause a primary demyelinating neuropathy that is not associated with a specific clinical phenotype. We also find evidence that the majority of kindreds share a common ancestor.

Evidence for common genetic elements in allergic disease

Genetic research in allergic disease has focused primarily on asthma and its associated phenotypes (eg, total IgE), with very little attention given to the presence or absence of concomitant allergic diseases, especially allergic rhinitis and atopic dermatitis. Because asthma, allergic rhinitis, and atopic dermatitis share common systemic characteristics, it is reasonable to propose that a number of susceptibility genes could contribute to the allergic process regardless of the specific clinical phenotype. Consequently, the many genetic linkages previously reported for asthma may not be specific for asthma per se but rather may reflect an overall predisposition for allergic disease. Finally, epidemiologic data suggest that asthma and allergic rhinitis represent a continuum of disease, whereby those individuals with less severe disease will express rhinitis without asthma and those individuals with more severe disease express more than 1 phenotype. Alternatively, it is plausible that, in addition to the “allergic disease genes,” there are “phenotype-specific genes” or possibly certain combinations of susceptibility genes (eg, gene-gene interactions) that contribute to the expression of asthma, allergic rhinitis, or atopic dermatitis. (J Allergy Clin Immunol 2000;106:S192-200.)

Fanconi anemia proteins FANCA, FANCC, and FANCG/XRCC9 interact in a functional nuclear complex.

Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome with at least eight complementation groups (A to H). Three FA genes, corresponding to complementation groups A, C, and G, have been cloned, but their cellular function remains unknown. We have previously demonstrated that the FANCA and FANCC proteins interact and form a nuclear complex in normal cells, suggesting that the proteins cooperate in a nuclear function. In this report, we demonstrate that the recently cloned FANCG/XRCC9 protein is required for binding of the FANCA and FANCC proteins. Moreover, the FANCG protein is a component of a nuclear protein complex containing FANCA and FANCC. The amino-terminal region of the FANCA protein is required for FANCG binding, FANCC binding, nuclear localization, and functional activity of the complex. Our results demonstrate that the three cloned FA proteins cooperate in a large multisubunit complex. Disruption of this complex results in the specific cellular and clinical phenotype common to most FA complementation groups.

Primary gastrointestinal non‐Hodgkin's lymphoma in adults: a population‐based clinical and histopathologic study

Abstract. Hansen PB, Vogt KC, Skov RL, Pedersen‐Bjergaard U, Jacobsen M, Ralfkiaer E (Herlev Hospital, University of Copenhagen and Gentofte Hospital, University of Copenhagen, Denmark). Primary gastrointestinal non‐Hodgkin's lymphoma in adults: a population‐based clinical and histopathologic study. J Intern Med 1998; 244: 71–8.ObjectivesTo analyse the clinical course and the histopathology of primary gastrointestinal non‐Hodgkin's lymphoma (GI‐NHL) in adult patients and to investigate a possible impact of Helicobacter pylori.Design/settingRetrospective study of all adult patients in Copenhagen county diagnosed during a6‐year period with NHL.SubjectsA total of 55 patients with GI‐NHL diagnosed during the period from 1985 to the end of 1990.ResultsTwenty‐eight patients had primary lymphoma in the stomach, 14 in the small intestine, 11 in the large intestine and two patients had multifocal involvement. The dominant presenting symptoms were abdominal pain, weight loss, diarrhoea, constipation and fatigue. Acute emergency problems such as severe haemorrhage or perforation at initial presentation were unusual. According to the revised European‐American lymphoma (REAL) classification, diffuse large B‐cell lymphoma was the most frequent histologic subtype comprising 53% of the cases. Helicobacter pylori infection was documented in 15 of 25 evaluable patients (60%) with gastric lymphomas and was not associated with any specific histological subtype. Endoscopic procedures and barium X‐rays were the diagnostic approaches with highest sensitivity. In total, 30 patients (58%) achieved complete remission, 10 (19%) achieved partial remission, and 12 (23%) did not respond to treatment. The overall 5 year survival rate was 0.36 without statistically significant difference between the histological subtypes. Likewise the presence of Helicobacter pylori did not affect survival.ConclusionPrimary GI‐NHL is a heterogeneous disease entity with considerable therapeutic controversies. No specific clinical or histological phenotype was associated with the presence of Helicobacter pylori.

Primary gastrointestinal non-Hodgkin's lymphoma in adults: a population-based clinical and histopathologic study.

To analyse the clinical course and the histopathology of primary gastrointestinal non-Hodgkin's lymphoma (GI-NHL) in adult patients and to investigate a possible impact of Helicobacter pylori. Retrospective study of all adult patients in Copenhagen county diagnosed during a 6-year period with NHL. A total of 55 patients with GI-NHL diagnosed during the period from 1985 to the end of 1990. Twenty-eight patients had primary lymphoma in the stomach, 14 in the small intestine, 11 in the large intestine and two patients had multifocal involvement. The dominant presenting symptoms were abdominal pain, weight loss, diarrhoea, constipation and fatigue. Acute emergency problems such as severe haemorrhage or perforation at initial presentation were unusual. According to the revised European-American lymphoma (REAL) classification, diffuse large B-cell lymphoma was the most frequent histologic subtype comprising 53% of the cases. Helicobacter pylori infection was documented in 15 of 25 evaluable patients (60%) with gastric lymphomas and was not associated with any specific histological subtype. Endoscopic procedures and barium X-rays were the diagnostic approaches with highest sensitivity. In total, 30 patients (58%) achieved complete remission, 10 (19%) achieved partial remission, and 12 (23%) did not respond to treatment. The overall 5 year survival rate was 0.36 without statistically significant difference between the histological subtypes. Likewise the presence of Helicobacter pylori did not affect survival. Primary GI-NHL is a heterogeneous disease entity with considerable therapeutic controversies. No specific clinical or histological phenotype was associated with the presence of Helicobacter pylori.

Clinical Features of Sporadic and Familial Alzheimer's Disease

Alzheimer's disease is increasingly seen as an heterogeneous disorder with a variety of molecular pathologies converging on a final common pathway of abnormal amyloid deposition and tau phosphorylation. These result in the appearance of the senile plaques and neurofibrillary tangles and in the subsequent development of a cortical dementia with a prominent memory deficit, reflecting the regional distribution of pathology. Age and mode of onset, additional neurological features and family history have all been used as a basis for classification. A family history has proved most robust with the identification of three genetic loci associated with autosomal dominant familial Alzheimer's disease (FAD). Genetically defined pedigrees are important for exploring the relationships between specific molecular pathology and clinical phenotype and, by following at risk individuals, identifying the earliest features.

Partial monosomy of chromosome 1p36.3: Characterization of the critical region and delineation of a syndrome

We describe 5 patients ranging in age from 3 to 47 years, with karyotypic abnormalities resulting in monosomy for portion of 1p36.3, microcephaly, mental retardation, prominent forehead, deep-set eyes, depressed nasal bridge, flat midface, relative prognathism, and abnormal ears. Four patients have small hands and feet. All exhibited self-abusive behavior. Additional findings in some of the patients include brain anomalies, optic atrophy, hearing loss and skeletal deformities. The breakpoints within chromosome 1 were designated at 1p36.33 (1 case). Thus, the smallest region of deletion overlap is 1p36.33-->1pter. Detection of the abnormal 1 relied on high resolution G-band analysis. Fluorescence in situ hybridization (FISH) utilizing a DNA probe (Oncor D1Z2) containing the repetitive sequences in distal 1p36, confirmed a deletion of one 1 homologue in all 5 cases. The abnormal 1 resulted from a de novo deletion in only one patient. The remaining patients were either confirmed (3 cases) or suspected (1 case) to have unbalanced translocations. Despite the additional genetic imbalance present in these four cases, monosomy of 1p36.33 appears to be responsible for a specific clinical phenotype. Characterization of this phenotype should assist in the clinical diagnosis of this chromosome abnormality.

AMLI fusion transcripts in t(3;21) positive leukemia: Evidence of molecular heterogeneity and usage of splicing sites frequently involved in the generation of normal AMLI transcripts

The t(3;21)(q26;q22) is associated with chronic myelogenous leukemia in blast crisis (CML-BC), leukemia evolving from (therapy-related) myelodysplasia, and with leukemia following other hematopoietic proliferative diseases. Molecular cytogenetic analysis and cloning of a few t(3;21) cases indicate that the breakpoints are quite heterogeneous even within a specific clinical phenotype. Interestingly some of the (3;21) breakpoints involve the AML1 gene previously found rearranged in the t(8;21) associated with acute myelogenous leukemia. AML1 is related to the Drosophila gene runt and is the human counterpart of the gene for the alpha subunit of the nuclear polyoma enhancer binding protein (PEBP2) also known as the core binding factor (CBF). In the t(3;21) AML1 was found rearranged with EAP, a gene on chromosome 3 encoding a small ribosomal protein, as well as with EV11, another gene on chromosome 3. Here we report our study of six cases of t(3;21). By using fluorescence in situ hybridization (FISH) analysis and AML1 probes we could conclude that at least in two CML-BC cases the breakpoint occurred in the AML1 intron that is disrupted by the t(8;21). An AML1/EAP fusion transcript, different from the one described in a therapy-related myelodysplasia, was detected in both CML-BC cases. This transcript is expected to result in a predicted protein containing the AML1 nuclear binding domain with an attached stretch of 17 amino acids unrelated to the EAP small ribosomal protein. In the other t(3;21) patients we could not detect an AML1/EAP transcript or an AML1/EV11 transcript. This result suggests heterogeneity of the t(3;21) at the molecular level. The AML1 chimeric transcripts identified so far, both in the t(3;21) and in the t(8;21), diverge from the normal transcripts either after exon 5 or exon 6. Here we show that in normal AML1 transcripts different splicing events are seen to occur after AML1 exon 5 as well as exon 6.