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Results for “Genotype-phenotype”

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PubMed1992

Short stature in a girl with a terminal Xp deletion distal to DXYS15: localisation of a growth gene(s) in the pseudoautosomal region.

This report describes a Japanese girl with short stature and a rearranged X chromosome. Her height remained below the 3rd centile growth curve for Japanese girls, and her predicted adult height (148.5 cm) was below her target height (163 cm) and target range (155 to 171 cm). Cytogenetic studies showed that the rearranged X chromosome was formed by a breakage at q26 and a transfer of the Xq fragment onto the tip of Xp. The abnormal X was always late replicating. No mosaicism was detected. Molecular analysis showed an Xp terminal deletion distal to DXYS15. Biochemical and radiological studies for short stature disclosed no abnormality. On the basis of height analysis of previous reports and a genotype-phenotype correlation of this patient, we propose that a growth gene(s) is present in the distal part of the pseudoautosomal region.

Blotting, Southern↗

PubMed1991

Human beta-galactosidase gene mutations in GM1-gangliosidosis: a common mutation among Japanese adult/chronic cases.

Molecular analysis of the human beta-galactosidase gene revealed six different mutations in 10 of 11 Japanese GM1-gangliosidosis patients. They were the only abnormalities in each allele examined in this study. A 165-nucleotide duplication (positions 1103-1267) was found in two infantile patients, producing an abnormally large mRNA; one patient was probably a homozygote, and the other was a heterozygote of this mutation. The other two infantile patients had different mutations; a 123 Gly(GGG)----Arg(AGG) mutation in one patient and a 316 Tyr(TAT)----Cys(TGT) mutation in the other. A 201 Arg(CGC)----Cys(TGC) mutation, eliminating a BspMI site, was detected in a late-infantile/juvenile patient; the restriction-site analysis of amplified genomic DNA confirmed his heterozygosity for this mutation. A 51 Ile(ATC)----Thr(ACC) mutation was found in all five adult/chronic patients examined in this study. It created a SauI site, and restriction-site analysis confirmed that four patients were homozygous mutants. The other was a compound heterozygote for this mutation and another 457 Arg(CGA)----Gln(CAA) mutation. These mutant genes expressed markedly decreased or completely deficient enzyme activities in beta-galactosidase-deficient human fibroblasts transformed by adenovirus-SV40 recombinants. We conclude that gene mutations are heterogeneous in GM1-gangliosidosis but that the 51 Ile(ATC)----Thr(ACC) mutation is common among the Japanese adult/chronic cases. Genotype-phenotype correlations in GM1-gangliosidosis are briefly discussed.

Adolescent↗

PubMed1991

Single-strand conformation polymorphism for detection of mutations and base substitutions in phenylketonuria.

In the past few years, more than 20 different mutations have been reported in hyperphenylalaninemias. In southwestern Europe and Mediterranean countries, however, the mutant genotypes reported account for only a fraction (27%) of all mutant alleles at the phenylalanine hydroxylase (PAH) locus, and most of the mutations causing the disease remain unknown. In order to develop a strategy for rapid detection of mutation-containing exons, we applied the single-strand conformation-polymorphism (SSCP) technique to exons 3, 5, 7, and 12 of the PAH gene. We observed five abnormal patterns of migration in mutant PAH genes, and we consistently found base substitutions in the corresponding exons, with no false-positive results. By this procedure, two novel putative mutations were detected in the seventh exon of the PAH gene, (A259V and Y277D) and we were able to demonstrate that the delta I94, R158Q, R408W, and E280K mutations were easily detectable by the SSCP technique. This procedure is therefore of particular interest for rapid detection of mutation-containing exons and for determination of further genotype-phenotype correlations in hyperphenylalaninemias.

Base Sequence↗

PubMed1983

A family with segregating triplicated alpha globin loci and beta thalassemia.

In this article we report a Sardinian family, in which a beta-thalassemia gene and a triple alpha-globin loci, counterpart of the rightward deletion type alpha-thalassemia-2, were segregating. The analysis of the genotype-phenotype correlations in the different family members allowed us to give an outline of the manifestations associated with different genotype combinations. The heterozygote for the triple alpha-loci showed no consistent abnormal clinical or hematologic characteristics and presented balanced alpha/beta-globin chain synthesis. In the homozygous state for this lesion, the only phenotypic expression was a slightly imbalanced globin chain synthesis. The combination of heterozygous beta-thalassemia with the heterozygous state for the triple alpha-globin loci produced no clinical manifestations and showed a hematologic phenotype indistinguishable from that of heterozygous beta-thalassemia. On the other hand, the combination of the homozygous state for the triple alpha-globin gene loci and the heterozygous state for beta-thalassemia produced a clinical picture of thalassemia intermedia with a very mild clinical course, minor increase of fetal hemoglobin (HbF) levels, and a pronounced imbalance of globin chain synthesis.

Adult↗

PubMed1982

Small accessory chromosomes (SAC) and their genotype--phenotype correlation.

A total of 39 carriers of small accessory chromosomes (SAC) was found among 32,930 patients karyotyped in Division of Human Genetics, Catholic University, Leuven, Belgium, in the years 1966-1981. In majority of SAC carriers the origin of extra-chromosome material remained unknown (21 out of 29 index patients), even when applying different banding techniques. The only common feature of all described SAC seems to be the presence of C-banded heterochromatin. The genotype-phenotype correlation in SAC carriers has been discussed.

Adolescent↗

PubMed1994

Neurofibromatosis type 1.

The authors review the present data on the clinical and molecular aspects of neurofibromatosis type 1 (NF1). In the clinical part attention is given to the frequent observation of learning disabilities in NF1 children. In these children visual-spatial integration deficits and an increased incidence of school performance problems are observed. The NF1 gene is located on chromosome 17 (17q11.2), and is highly conserved across species. Up to now only a limited number of mutations in this gene have been characterized, and this shows a general lack of genotype-phenotype correlation. Evidence is given that the NF1 gene acts as a true tumor suppressor gene and that oncogenesis in NF1 is a complex multistep phenomenon with the second hit in the NF1 gene as the initiating event. The importance of specialized multidisciplinary outpatient clinics for neurofibromatosis is emphasized because of the complexity of follow-up and treatment of these patients.

Child↗

PubMed1993

Molecular cytogenetics: solid tumors and leukemia.

Acute leukemia represents one of the best-studied malignancies. Consequently, numerous dogmas have evolved over the years. One dogma to which we subscribe is that leukemia is a genetic disease and that the behavior of leukemic cells and their response to therapy is determined largely by their genetic characteristics. The relative ease of metaphase generation and culture of single leukemic cells, well-defined morphologic criteria, and availability of phenotyping reagents has contributed to a wealth of information about the karyotypic, genetic, and functional properties of these cells. Nevertheless, establishment of genotype-phenotype relationships has been particularly elusive. The genetic evolution of leukemias and the consequences of specific aberrations remains to be determined. We describe the power of new molecular cytogenetic tools, fluorescence in situ hybridization, and comparative genomic hybridization to measure the genetic evolution of leukemic cells. Lessons learned from application of these techniques to solid tumors and speculations about similar approaches to analysis of leukemia are addressed.

Cytogenetics↗

PubMed1993

[Familial form of partial androgen insensitivity (Reifenstein syndrome): arginine-histidine mutation in position 840 in the androgen receptor].

In a large kindred with Reifenstein syndrome, we performed the molecular analysis of the androgen receptor gene. Since the biochemical characteristics of the androgen receptor, determined on the cultured genital skin fibroblasts, showed a drastic decrease of the androgen binding capacity, we assumed that a point mutation was located in exons 4-8 encoding the carboxy-terminal domain of the receptor. Enzymatic amplifications of these exons did not point out any deletions. Direct sequencing showed a G-A point mutation at position 2818 of exon 7 responsible for an arginine-histidine substitution at position 840 of the androgen receptor. The presence of the same mutation has been reported by other groups in four unrelated patients. Its association with different phenotypes of androgen insensitivity and different biochemical characteristics of the androgen receptor pointed out the complexity of the genotype-phenotype relationship in androgen insensitivity. Moreover the identification of the point mutation gave us the opportunity to perform a prenatal exclusion diagnosis of Reifenstein syndrome in this high-risk family.

Arginine↗

PubMed1994

[Genetic heterogeneity of retinitis pigmentosa].

The authors present a classification of retinitis pigmentosa (rp) based on the modes of inheritance. Known genetic conditions of autosomal recessive, X-linked recessive and autosomal dominant forms of rp are shown, presenting molecular principles of the illness. They also describe clinical subtypes of rp with suggested genotype-phenotype correlations and principles of modern genetic diagnostics and genetic counselling.

Female↗

PubMed1994

DNA polymorphisms and conditions for SSCP analysis of the 20 exons of the ret proto-oncogene.

Recently identified mutations affecting different domains of the RET proto-oncogene are associated with Multiple Endocrine Neoplasia type 2A (MEN 2A) and type 2B (MEN 2B), familial and sporadic Medullary Thyroid Carcinomas (MTC) and Hirschsprung disease (HSCR). In order to facilitate the screening for RET mutations, and to study possible genotype-phenotype correlations, we established exon-intron junctions and extended the intronic sequences flanking the 20 exons of this gene. This made it possible to design primers and to develop PCR conditions useful for SSCP analysis of the whole RET coding sequence. Nine conformational variants were observed which after sequencing turned out to be 8 silent mutations and a conservative amino acid substitution. Restriction analysis performed on DNA samples from unrelated controls confirmed the polymorphic nature of six of these nucleotide changes and made it possible to estimate the frequency of the corresponding alleles.

Base Sequence↗

PubMed1993

[Molecular genetic study of cystic fibrosis in the Chilean population. Relationship to its clinical expression].

Aiming to establish a genotype-phenotype relationship and to search a clinical expression in heterozygotes, 25 Chilean subjects with Cystic Fibrosis and 165 relatives were subjected to a clinical-molecular study. The most common mutations found worldwide were studied: delta F-508, G-542X, N-1303K, R-553X and G551D. Clinical and laboratory assessment comprised chest X-rays, spirometry, clinical evaluation, nutritional assessment, sweat test and carotenemia. Age at diagnosis was lower among homozygotes for the mutation delta F-508. In this group, Brasfield and Schawchman scores were better, probably due to an earlier initiation of treatment. No other differences were found among genotypic groups or relatives. Genetic markers indicated a higher european component of the sample, compared to the general Chilean population.

Adolescent↗

PubMed1994

Impact of molecular genetics in cardiac diseases.

Genetic linkage mapping has become an important technology applied to the study of human biology and in particular, for the delineation of the molecular basis of diseases through gene isolation and characterization of mutations in DNA. This approach was applied to cardiac hereditary disorders only a few years ago through the analysis of familial hypertrophic cardiomyopathy and congenital long QT syndrome. For both diseases, there is a striking genetic heterogeneity and analyses of genotype-phenotype correlations are underway. Familial occurrence is likely to play also an important role in idiopathic dilated cardiomyopathy. Genetic testing and risk stratification will be more complicated than it was initially expected, but hope is now there to discover new ways for preventing, diagnosing and treating deadly cardiac disorders.

Cardiomyopathy, Dilated↗

PubMed1995

[Familial polyposis coli].

Familial polyposis coli (FAP) presents multiple adenomas in the large bowel. Also, polyps in the upper gastrointestinal tract are observed in some cases of FAP. Since the risk of developing colorectal cancer is almost 100% in FAP, patients need surgical treatment (colectomy) after a diagnosis of FAP is made. After a gene for FAP (APC gene) was identified, an accurate diagnosis of FAP is becoming possible by examining APC gene, even though patients show no clinical manifestations. Many studies revealed various mutations of APC gene and examined the relation between the site of the germline APC mutation and the phenotypic expression of FAP. These studies suggested that there was a Genotype-Phenotype Correlation in FAP. Some differences of clinical features in FAP, such as profuse type and attenuated type of FAP (AAPC), are now considered to be caused by the difference of the site of the germline APC mutation.

Adenomatous Polyposis Coli↗

PubMed1996

Molecular definition of red cell Rh haplotypes by tightly linked SphI RFLPs.

The Rh blood group system of human red cells contains five major antigens D, C/c, and E/e (the latter four designated "non-D") that are specified by eight gene complexes known as Rh haplotypes. In this paper, we report on the mapping of RH locus and identification of a set of SphI RFLPs that are tightly linked with the Rh structural genes. Using exon-specific probes, we have localized the SphI cleavage sites resulting in these DNA markers and derived a comprehensive map for the RH locus. It was found that the SphI fragments encompassing exons 4-7 of the Rh genes occur in four banding patterns or frameworks that correspond to the distribution and segregation of the common Rh haplotypes. This linkage disequilibrium allowed a genotype-phenotype correlation and direct determination of Rh zygosity related to the Rh-positive or Rh-negative status (D/D, D/d, and d/d). Studies on the occurrence of SphI RFLPs in a number of rare Rh variants indicated that Rh phenotypic diversity has taken place on different haplotype backgrounds and has arisen by diverse genetic mechanisms. The molecular definition of Rh haplotypes by SphI RFLP frameworks should provide a useful procedure for genetic counseling and prenatal assessment of Rh alloimmunization.

Base Sequence↗

PubMed1996

Germ line mutation at BRCA1 affects the histoprognostic grade in hereditary breast cancer.

Histoprognostic grade is a determinant parameter to select the initial therapeutic strategy in breast cancer. Our aim was to analyze the grade repartition in BRCA1-associated breast cancer (BC) and to explore the possible connections between grade and the BRCA1 gene function. We first compared 27 BRCA1-associated BCs from 14 families with 4,461 cases from an administrative district registry and 242 cases from a hospital-based registry, matching for grade and constitutive elements, and then considered their repartition in families. We observed a prevalence of grade 3 (P < 0.0001) in BRCA1-associated BC. This was attributed mainly to nuclear polymorphism (P < 0.0001), mitotic activity (P < 0.0001), and tubular differentiation (P = 0.0004), implying that BRCA1-associated BCs are highly proliferating tumors. Moreover, it is suggested that grade segregates as a genetic trait within families (P = 0.0015), and this was attributed to the mitotic index segregation only (P = 0.0005). Therefore grade, through its components, could be interpreted as the morphological translation of the BRCA1 germ line mutation. Thus, a genotype-phenotype correlation may exist between the type of mutation and the aggressiveness of the disease. These findings are bound to have an important impact in the care management of hereditary breast cancer at the individual and at the familial level and in the comprehensive approach of breast cancer development.

Adult↗

PubMed1995

[A study evaluating the correlation between the phenotype and genotype among 65 cystic fibrosis patients].

Among 65 CF diagnosed patients with both CFTR gene mutations known genotype-phenotype studies were performed. Correlation between pancreatic insufficiency and so called "severe mutations" was found. Respiratory tract symptoms do not seem to depend on one specific mutation as well as meconium ileus is not only limited to the group of patients with delta F508/delta F508 genotype. Some other genotype - clinical features correlation in CF patients are discussed.

Adolescent↗

PubMedDate not supplied

[Mutation analysis in Hunter patients].

Mutations of the iduronate-2-sulfatase gene have been identified as responsible of Hunter syndrome or mucopolysaccharidosis type II. About 20% of the patients have deletions of the whole gene or other major structural alterations. The mutations found so far include: 34 missense, 8 nonsense, 11 small deletions from 1 to 3 bp, 2 deletions of 8 pb, 2 insertions of 1 bp and 2 insertions of 14 bp, with most leading to a frameshift and premature chain termination. Also 8 different splice-site mutations leading to insertions or deletions in the mRNA have been tabulated. Knowledge of the primary genetic defect allows insight into genotype-phenotype correlation and allows a better understanding of the structure and function of iduronate-2-sulfatase.

Base Sequence↗

PubMed1993

Correlation between genotype and phenotype in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis is the most common lethal autosomal recessive disorder among whites. Seventy-two percent of patients with this disease are homozygotes or compound heterozygotes for eight mutations of the cystic fibrosis transmembrane conductance regulator gene on chromosome 7: delta F508, G542X, R553X, W1282X, N1303K, 621 + 1G-->T, 1717-1G-->A, and R117H. We studied the relation between genotype and phenotype in patients from 14 countries. METHODS: Each of 399 patients who were compound heterozygotes for delta F508 and one other mutation was matched with the delta F508 homozygote of the same sex who was the closest in age from the same center. A paired analysis was performed of the following outcome variables: age at diagnosis, sweat chloride concentration, growth percentiles, pulmonary-function values, chest-film score, pseudomonas colonization, nasal polyps, pancreatic sufficiency, pancreatitis, diabetes mellitus, meconium ileus, distal intestinal obstruction syndrome, rectal prolapse, cirrhosis, and gallbladder disease. RESULTS: The compound heterozygotes having the genotype R117H/delta F508 clearly differed from the age- and sex-matched delta F508 homozygotes: they more often had pancreatic sufficiency (87 percent vs. 4 percent, P < 0.001), were older when the diagnosis was first made (mean [+/- SD] age, 10.2 +/- 10.5 vs. 2.5 +/- 4.3 years; P = 0.002), and had lower sweat chloride concentrations (80 +/- 18 vs. 108 +/- 14 mmol per liter, P < 0.001). There were no statistically significant differences between delta F508 homozygotes and other compound heterozygotes with regard to any variable tested. CONCLUSIONS: Prenatal and prognostic counseling for patients with the R117H/delta F508 genotype should include the likelihood that they will have long-term pancreatic sufficiency. Patients with the other genotypes should expect the early onset of pancreatic insufficiency. For none of the genotypes studied can predictions be made about the occurrence of common complications or the severity or course of pulmonary disease.

Adolescent↗