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PubMed2006

Identification of chromosomal regions linked to premature myocardial infarction: a meta-analysis of whole-genome searches.

Myocardial infarction (MI) is a complication of coronary artery disease and the leading cause of death in the Western world. MI is considered a distinct phenotype with an increased genetic component for its premature type. MI's exact inheritance pattern is still unknown. Genome searches for identifying susceptibility loci for premature MI produced inconclusive or inconsistent results. Thus, a genome search meta-analysis (GSMA) was applied to available genome search data on premature MI. GSMA is a non-parametric method to identify genetic regions that rank high, on average in terms of linkage statistics across genome searches unweighted or weighted by study size. The significance of each region's average and heterogeneity, unadjusted or adjusted by neighbouring average simulated ranks, was calculated using a Monte Carlo test. The meta-analysis involved five genome searches in Caucasians. Eight regions (6p22.3-6p21.1, 14p13-14q13.1, 13q33.1-13q34, 5p15.33-5p15.1, 8q13.2-8q22.2, 1p36.21-1p35.2, 12q24.31-12q24.33, 8q24.21-8q24.3) were found to have significant average rank by either unweighted or weighted analyses. In addition, region 8q24.21-8q24.3 produced significant low heterogeneity (P (unadjusted)=0.03 and P (adjusted)=0.05). Four regions (6p22.3-6p21.1, 14p13-14q13.1, 8q13.2-8q22.2, 8q24.21-8q24.3) were not identified by the individual studies. The meta-analysis suggests that these four regions should be further investigated for genes that confer susceptibility to MI.

Adult↗
PubMed2007

Three novel mutations in the activin receptor-like kinase 1 (ALK-1) gene in hereditary hemorrhagic telangiectasia type 2 in Brazilian patients.

Hereditary hemorrhagic telangiectasia (HHT) or Osler-Rendu-Weber disease is a systemic fibrovascular dysplasia with an autosomal dominant inheritance pattern. Mutations in two genes, endoglin and ALK-1, are known to cause HHT, both of which mediate signaling by transforming growth factor beta ligands in vascular endothelial cells. Ten patients were analyzed. Diagnosis of HHT was carried out by means of family history, recurrent bleeding, and the presence of multiple telangiectases lesions. Conformation-sensitive gel electrophoresis analyses with consistent abnormal migration patterns were cloned and sequenced using the MegaBace 1000 DNA automated analyzer. Three novel mutations were identified in the coding sequence of the ALK-1 gene in five patients and their families, which demonstrated clinical manifestations of HHT type 2. These mutations included a G insertion and a T deletion of single base pairs in exons 3 and 7, as well as missense mutations in exons 7 and 8 of the ALK-1 gene. These data indicate that loss-of-function mutations in a single allele of the ALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity. We suggest the high rate of mutation detection and the small size of the ALK-1 gene make genomic sequencing a viable diagnostic test for HHT2.

Activin Receptors, Type II↗
PubMed1999

Familial isolated noncompaction of ventricular myocardium.

We report a family in which two male sibs were affected with isolated noncompaction of ventricular myocardium (INVM). The familial occurrence of INVM suggests a genetic basis. We review the literature of familial and nonfamilial cases and discuss the inheritance pattern of INVM.

Child↗
PubMed2003

Nonsyndromic sensorineural deafness associated with the A1555G mutation in the mitochondrial small subunit ribosomal RNA in a Balinese family.

Sensorineural deafness associated with increased sensitivity to aminoglycoside antibiotics as the consequence of an A1555G mutation in the mitochondrial DNA (mtDNA) in a highly conserved region of the small (12S) rRNA gene has been reported in Caucasian, Chinese, and Japanese individuals. We report here a large family of Balinese Indonesian origin with progressive/congenital sensorineural deafness who carry the A1555G mutation. The pedigree shows a generally maternal inheritance pattern with some exceptions, which is the result of an unusual multiple entry of the mutation into the pedigree. A complete mtDNA genome sequence from three Balinese individuals revealed a relatively large number of single- nucleotide polymorphisms (20) not previously reported, and confirmed the genetic distance of Southeast Asian populations from those of Caucasians and Japanese. The biochemical expression of the A1555G mutation under the influence of this mtDNA background was investigated. Examination of respiratory enzyme activities showed a significant decrease in respiratory complex I activity, particularly in symptomatic family members.

DNA, Mitochondrial↗
PubMed1997

Mutations in the delta-sarcoglycan gene are a rare cause of autosomal recessive limb-girdle muscular dystrophy (LGMD2).

The dystrophin-based membrane cytoskeleton of muscle fibers has emerged as a critical multi-protein complex which seems to impart structural integrity on the muscle fiber plasma membrane. Deficiency of dystrophin causes the most common types of muscular dystrophy, Duchenne and Becker muscular dystrophies. Muscular dystrophy patients showing normal dystrophin protein and gene analysis are generally isolated cases with a presumed autosomal recessive inheritance pattern (limb-girdle muscular dystrophy). Recently, linkage and candidate gene analyses have shown that some cases of limb-girdle muscular dystrophy can be caused by deficiency of other components of the dystrophin membrane cytoskeleton. The most recently identified component, delta-sarcoglycan, has been found to show mutations in a series of Brazilian muscular dystrophy patients. All patients were homozygous for a protein-truncating carboxy-terminal mutation, and showed a deficiency of the four sarcoglycan proteins. To determine if delta-sarcoglycan deficiency occurred in other world populations, to identify the range of mutations and clinical phenotypes, and to test for the biochemical consequences of delta-sarcoglycan gene mutations, we studied Duchenne-like and limb-girdle muscular dystrophy patients who we had previously shown not to exhibit gene mutations of dystrophin, alpha-, beta-, or gamma-sarcoglycan for delta-sarcoglycan mutations (n = 54). We identified two American patients with novel nonsense mutations of delta-sarcoglycan (W30X, R165X). One was apparently homozygous, and we show likely consanguinity through homozygosity for 13 microsatellite loci covering a 38 cM region of chromosome 5. The second was heterozygous. Both were girls who showed clinical symptoms consistent with Duchenne muscular dystrophy in males. Our data shows that delta-sarcoglycan deficiency occurs in other world populations, and that most or all patients show a deficiency of the entire sarcoglycan complex, adding support to the hypothesis that these proteins function as a tetrameric unit.

Chromosomes, Human, Pair 5↗
PubMed2005

Polyendocrine autoimmunity.

Autoimmune polyendocrine disorders are characterized by the presence of more than one autoimmune endocrine disease. Study of such disorders has provided unique insight into the pathogenesis of autoimmunity and the development of tolerance in the normal individual. Autoimmune polyendocrine syndromes I and II have distinctive inheritance patterns, genetic causes, component diseases, and implications for follow-up. Care for individuals with these diseases requires monitoring for additional autoimmune disorders and aggressive treatment of identified diseases to prevent morbidity and mortality in affected individuals.

Autoimmune Diseases↗
PubMed2001

The genetics of obsessive-compulsive disorder.

A significant amount of evidence has been gathered to suggest that obsessive-compulsive disorder (OCD) is a heritable disease. Despite this information, few details are understood about the genetics of the disorder. Molecular genetic techniques, especially candidate-gene association studies, have been used to try to appreciate the genetic components of this complex disorder. In addition to the complex inheritance pattern, the heterogeneous nature of the disorder complicates the analyses. This review outlines the evidence that has been gathered to date, implicating OCD as a genetic disorder. In addition, the most interesting and recent findings in the molecular genetic analyses are highlighted.

Dopamine↗
PubMed2004

Genetics of osteoarthritis.

Osteoarthritis (OA) is a major cause of morbidity, physical limitation, and health care use, including total joint arthroplasty. That OA has a genetic component has been known for some time, but only recently has formal study of this occurred. Twin studies, segregation analyses, linkage analyses, and candidate gene association studies have generated important information about inheritance patterns and the location in the genome of potentially causative mutations. Results across studies are not always concordant, however; this is likely the result of variations in study populations, disease definitions, evaluation of control subjects, and statistical analysis. Although the genetics of OA is complex and not completely understood, there is cause for optimism as rapidly improving technologies make the quest for the genes responsible for OA increasingly within reach. Family history of OA and joint replacement for OA should be assessed in the context of other potentially modifiable risk factors to attempt to alter patient outcome.

Biomedical Research↗
PubMed1976

Selective immunoglobulin M (IgM) deficiency in two immunodeficient adults with recurrent staphylococcal pyoderma.

Two adult men with recurrent pyoderma due to Staphylococcus aureus and a selective deficiency of immunoglobulin M (IgM) antibody synthesis are described. An analysis of each patient's polymorphonuclear leukocyte chemotaxis, phagocytosis and killing of Staph. aureus, serum opsonizaiton of Staph. aureus, and serum and lymphocyte-mediated responses to antigenic stimulation was performed. Family studies revealed a possible autosomal dominant inheritance pattern with heterogenetic expression of various dysgammaglobulinemic states in each patient's first degree relatives. In vivo studies of delayed hypersensitivity and in vitro studies of polymorphonuclear leukocyte and lymphocyte function were normal. A defect in IgM, but not in IgG (immunoglobulin G), antibody synthesis to a number of antigens, and a mild decrease in serum opsonic activity to Staph. aureus correctable by heat inactivated normal human serum were found in each patient. In these patients, the recurrent staphulococcal pyoderma prompted an investigation of host defense mechanisms and revealed low to absent IgM levels and a defect in IgM antibody synthesis.

Adult↗
PubMed1985

Familial granulomatous synovitis, uveitis, and cranial neuropathies.

A family is presented that had what is believed to be a previously undescribed syndrome of granulomatous synovitis, bilateral recurrent uveitis, and cranial neuropathies. Affected members included the proband, his brother, father, and probably the decreased paternal grandmother. Disease onset was in childhood. Each had symmetric, boggy polysynovitis of the hands and wrists, resulting in nearly identical boutonniere deformities. Hand radiography in the proband and his brother revealed no erosions or joint destruction despite more than 20 years of disease. Synovectomy specimens in the proband and his brother showed granulomatous inflammation with giant cells. Recurrent, nongranulomatous, acute iridocyclitis with visual impairment afflicted the proband, brother, and father. Apparently corticosteroid-responsive bilateral neurosensory hearing loss occurred in the proband, and a transient sixth cranial nerve palsy in his brother. All members of the family were antinuclear antibody-, rheumatoid factor-, and HLA-B27-negative. Serum angiotensin-converting enzyme levels were within normal limits in all family members. The inheritance pattern of this syndrome is most consistent with an autosomal dominant mode.

Acute Disease↗
PubMed1989

Molecular genetics of inherited antithrombin III deficiencies.

The cloning of antithrombin III (ATIII) complementary deoxyribonucleic acids and the determination of the ATIII gene structure have permitted a systematic evaluation of the molecular basis for inherited ATIII deficiencies. Sixteen kindreds with the most common form of the deficiency, in which plasma ATIII antigen levels and activity are proportionately reduced, were studied. Two polymorphic deoxyribonucleic acid markers were used to resolve parental ATIII alleles and to trace their inheritance patterns. In 15 of 16 cases, the structure of the affected ATIII allele was indistinguishable from normal, suggesting that relatively small mutations, resulting in gene inactivation, are responsible for the lower ATIII levels in these affected families. In the remaining kindred, complete deletion of one ATIII allele was seen. Also investigated was the molecular basis for a qualitative form of ATIII deficiency in a French-Canadian family with normal levels of immunoreactive protein but only half the expected levels of serine protease inhibitor activity. Using polymorphic markers, the abnormal allele was identified, cloned, and partially sequenced from the propositus. A single G----A transition was seen in the first base of codon 382, resulting in an alanine----threonine substitution in the defective protein. This mutation, together with others in this vicinity, defines a minimal length for a fully functional thrombin-binding domain.

Antithrombin III↗
PubMed1989

Thyroid hormone resistance in a large kindred: physiologic, biochemical, pharmacologic, and neuropsychologic studies.

PURPOSE: Thyroid hormone resistance affects the pituitary gland and a variety of other tissues. We studied a large kindred with this disorder and measured a number of clinical markers of tissue metabolism to determine if these markers were useful in elucidating the sites and degree of resistance. PATIENTS: A kindred of 89 persons in four generations was identified; 44 had thyroid function tests, and 14 (five to 67 years old) were found to have thyroid hormone resistance. RESULTS: The inheritance pattern was autosomal dominant, with no common HLA haplotype. Physiologic measurements in five affected members showed marked heterogeneity. Four patients had normal baseline cardiac contractility, but only two experienced a shortening of their QKd interval into the hyperthyroid range with triiodothyronine (T3) therapy. Intrathyroidal 127I content was increased in two patients and was normal in two. Bone mineral content was normal in two men, but two women had marked osteopenia. The propositus, hypothyroid after inappropriate 131I therapy, had a hypothyroid ventilatory response to hypercapnea. This response became low normal during T3 (100 micrograms/day) administration but not during long-term thyroxine (T4) (300 micrograms/day) administration. Three other patients had values within normal limits and one had a hyperthyroid ventilatory response. Peripheral biochemical markers of thyroid hormone action were measured in 13 affected and 19 unaffected family members. Sex hormone-binding globulin was increased in zero of 13 affected patients (versus 19 of 20 hyperthyroid, chi 2:p less than 0.001); ferritin was elevated in two of 13 patients (versus 11 of 20 hyperthyroid, p less than 0.02); angiotensin converting enzyme activity was increased in one of 13 patients (versus 12 of 20 hyperthyroid, p less than 0.025). The eldest patient had marked cardiac sensitivity despite normal biochemical markers. We attempted to suppress the integrated thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) using T3 (72 and 100 percent suppression in two patients), dopamine (40 percent suppression in one), 3,5,3'-triiodothyroacetic acid (TRIAC) (94 percent suppression in one), and verapamil (10 percent and 40 percent suppression in two). Neuropsychologic function was studied in 14 individuals (11 affected, three unaffected). Although mild impairments were detected, they were not specific for thyroid hormone resistance.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1975

A family study of fundus flavimaculatus.

Three sisters, aged 14 to 25 years, showed ophthalmoscopic findings typical for fundus flavimaculatus with atrophic macular disturbances. Examination of all surviving family members did not disclose any additional affected persons. This four-generation pedigree indicated an autosomal recessive inheritance pattern.

Adolescent↗
PubMed1977

Posterior amorphous corneal dystrophy.

A family of ten individuals aged 18 months to 75 years had biomicroscopic findings consisting of large, amorphous, sheet-like opacifications of the posterior stroma and Descemet's membrane, and alterations of the endothelium. A uniform thinning of the cornea was present. These findings do not conform to previously described corneal dystrophies. The condition appears minimally progressive and the three-generation pedigree indicated an autosomal-dominant inheritance pattern.

Adolescent↗
PubMed1977

Keratoglobus and blue sclera.

Five patients from two families had similar features including keratoglobus, blue scleras, hyperextensibility of the hand, wrist, and ankle joints, sensorineural conduction hearing alterations, and mottling of the teeth. Keratoglobus had been observed in all patients at, or shortly after, birth. Corneal perforations developed in seven of the ten eyes after minimal trauma. Repair of these perforations was complicated by the extremely thin corneas and six eyes had to be either enucleated or eviscerated. Histopathological examination of two of the enucleated eyes showed the corneal stromas of both eyes to be estremely thin, Bowman's membrane was absent, and Descemet's membrane was unusually thick. This condition has an autosomal-recessive inheritance pattern.

Adolescent↗
PubMed1978

Crystalline retinopathy.

A 34-year-old woman had crystalline dystrophy of the retina associated with atrophy of the choriocapillaris and pigment epithelium, and pigment clumping in the fundus periphery. Consanguinity of her parents suggested an autosomal recessive inheritance pattern for this type of crystalline retinal dystrophy. The patient did not have corneal crystals. Her electroretinogram was normal, although her electro-oculogram was abnormal.

Adult↗
PubMed1988

Pseudoinflammatory macular dystrophy.

We studied a family with a dominantly inherited macular dystrophy resembling Sorsby's pseudoinflammatory dystrophy. Retinal pigment epithelial atrophy and varying degrees of pigment epithelial metaplasia were prominent fundus features in this pedigree. However, findings on electro-oculography were abnormal, unlike previous findings in patients with Sorsby's dystrophy. Histopathologic study of an eye from one patient demonstrated widespread atrophy of the retina, retinal pigment epithelium, and choroid. Although the pseudoinflammatory fundus appearance is common to several macular dystrophies and some eyes with end-stage, age-related macular degeneration, abnormal electro-oculograms and a dominant inheritance pattern distinguish the dystrophy in the present pedigree from other dystrophies and age-related macular degeneration.

Aged↗
PubMed1989

Familial cavernous angiomas manifesting with an acute chiasmal syndrome.

We studied a family in which the proband had an acute chiasmal syndrome secondary to a cavernous angioma of the optic nerve and chiasm. A brain magnetic resonance imaging scan indicated additional asymptomatic intracerebral cavernous angioma, and several of the patient's relatives were found to have various central nervous system vascular malformations. Magnetic resonance imaging may distinguish, noninvasively, symptomatic and asymptomatic carriers of cavernous angiomas and further delineate their inheritance patterns. Asymptomatic cavernous angiomas of the central nervous system are best followed without intervention, whereas symptomatic patients should be treated on an individual basis, depending on the location of lesion and the risk of surgical removal.

Adolescent↗