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Chromosome disorders associated with mental retardation.
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Routine G-banding in prenatal diagnosis of chromosomal disorders.
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[Role of nucleases in the origination of chromosomal disorders in virus-infected cells].
It is shown that herpes simplex virus can induce the chromosome aberrations both in cells supporting the productive infection and in non-permissive cells. In virus-infected human embryo fibroblast culture the activity of cell (lysosomal) and virus-coded DNAses is elevated. Suppression of the activity of any of the enzymes leads to decreasing the number of aberrant cells. Suppression of the activity of both DNases at the same time decreases the number of aberrant cells to a control level. In M15 cells which do not support the productive infection, the activity of only lysosomal DNase is elevated. Suppression of its activity leads to the decrease of the frequency of cells with chromosome breaks to a control level. Thus, both cells and virus-coded lytic enzymes can participate in the production of chromosome breaks in virus-infected cells. Possibly, the relative role of these enzymes may be rather different in different virus-cell systems.
[Diseases related to sex chromosome disorder].
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Chromosomal breakage in systemic sclerosis and related disorders.
Chromosome aberrations such as gaps and breaks of one or both chromatids, acentric fragments, dicentrics, ring chromosomes and other abnormal chromosomes are observed in lymphocyte and fibroblast cultures as well as in direct bone marrow preparations from patients with systemic sclerosis. A serum factor producing chromosome breaks in mitoses from healthy donors was observed in 37 of 42 scleroderma patients. The biochemical nature of this breakage factor is still undefined. Increased breakage is also noted in a high percentage of healthy family members of scleroderma patients. It is also a common feature of related disorders such as lupus erythematosus, dermatomyositis, periarteritis nodosa and rheumatoid arthritis. An increase in chromosome breaks and rearrangements is also present in NZB mice developing spontaneously an autoimmune disorder that has been extensively studied by workers interested in lupus erythematosus. The similarity of the cytogenetic findings provides the opportunity to use these mice as an experimental model to investigate relationships between immunological perturbations and chromosomal aberrations.
The malformations of the urinary system in autosomal disorders.
Data from the world literature about the pathology of the urinary system in autosomal chromosomal disorders are analyzed and compared with our own morphological investigations of this system in 63 cases of chromosomal disorders (Patau's, Edwards', Down's, Orbeli's, Wolf-Hirschhorn's syndromes, partial trisomy B and inversion of chromosome 2). The urinary system is most frequently involved in "cat-eye", triploidy, Orbeli's, Patau's and Edwards' syndromes. All known malformations of the urinary system are observed in children with chromosomal diseases, except infantile polycystic kidney and medullary "sponge" kidney. The authors recognize specific and nonspecific abnormalities of the urinary system. Nonspecific abnormalities, as simple renal dysgenesis, may be observed in all chromosomal disorders. Specific abnormalities are found only in certain chromosomal diseases. These malformations are an excess of embryonal lobulation of the kidney with the increase of its weight and cystic changes (Patau's syndrome), crossed renal ectopy with fusion and horseshoe kidney (Edwards' syndrome), unilateral renal agenesis (Orbeli's syndrome), hypospadia (Wolf-Hirschhorn's syndrome). A possible pathogenesis of malformations of the urinary system in chromosomal disorders is discussed.
Co-morbid monogenic disorders at chromosome region 1q2: LMNA- and FLG-related disorders in a patient referred for assessment of joint hypermobility.
The phenotypic similarities and genetic heterogeneity occurring in diverse forms of Ehlers Danlos Syndrome (EDS) subtypes and many heritable connective tissue disorders can pose a diagnostic challenge. In the wake of the growing applications of next-generation sequencing technologies including exome and genome sequencing, opportunities for achieving definitive genetic diagnosis are increasingly arising. We present a 46-year-old man with joint laxity, recurrent joint subluxations, pelvic floor dysfunction, and postural orthostatic tachycardia syndrome (POTS), who was referred for EDS assessment. His medical history included morbid obesity requiring gastric bypass surgery, hearing loss, asthma, retinopathy, myopia, atrial septal defect, narcolepsy with cataplexy, polyneuropathy, folliculitis, lichen simplex chronicus, atopic dermatitis, and hypogonadism. His family history was significant for multiple first- and second-degree relatives who died from cardiac diseases including cases of childhood deaths. Physical examination showed joint laxity with Beighton score of 3/9, bilateral pes planus, hearing loss and macrocephaly. Exome sequencing revealed heterozygous variants LMNA c.1262 T > C p.L421P [classified as likely pathogenic], FLG c.2282_2285del p. S761Cfs*36 [classified as pathogenic], and FLG c.1501 C > T p. R501* [classified as pathogenic]. Mitochondria sequencing revealed a variant of uncertain significance (VUS), MT-ND2 m.5047 T > C p.V193A that is present at 9% heteroplasmy in blood. These findings show co-occurrence of pathogenic sequence variants in neighboring genes located in chromosome 1q2 region [LMNA and FLG] in a patient with features of hereditary connective tissue disorders. Our study highlights the capability of exome sequencing in achieving some actionable diagnosis in cases of co-morbid genetic disorders with overlapping and non-specific symptoms.
DNA repair defects and chromosome instability disorders.
Xeroderma pigmentosum (XP), Fanconi anaemia (FA), ataxia telangiectasia (AT) and Bloom disease (BS) are four rare autosomal recessive disorders in which there is defective DNA repair and/or chromosome instability and proneness to malignancy. Between 80 and 90% of patients with XP have a defect, demonstrable at cell level, of excision of DNA lesions induced by ultraviolet rays, while the remainder have a cellular error of post-replication repair. XP cells are also deficient in repairing DNA damage caused by a variety of chemical mutagens. There are at least five different complementation groups of the first, or classical, type of XP (A to D, etc.) Apparently group C patients, as well as those with defective post-replication repair, do not show the progressive neurological illness found in a proportion of the other patients. AT is heterogeneous clinically and genetically. Clinically it presents with a progressive neurological illness, progressive telangiectases and a developmental disorder of the thymus. AT is characterized by sensitivity to X-rays and AT cells are unable to repair gamma-ray-induced damage to bases in the DNA. It appears that in many cases of the disorder a chromosomally marked cellular clone is found. In BS the main defect, which results in growth retardation, sun-induced lesions of the face and susceptibility to infection, appears to be a slow DNA chain maturation during DNA synthesis. An increase of sister chromatid exchanges is characteristically seen in the chromosomes of cultured BS cells. In FA, in which there is progressive pancytopenia with eventual bone marrow exhaustion and a tendency to haemorrhage and infection, the cellular defect seems to consist of faulty removal of repair of cross-links in the DNA. In this condition, as in BS and AT, various structural chromosome changes are detected in cultured cells. Patients with XP develop skin cancers in early life and often maligant melanomas. In the other three disorders, in which an immune deficiency is often present, leukaemia and related proliferative disorders are a frequent cause of death while other malignancies also occur. There is some evidence that points to an increased risk of malignancy in heterozygotes who carry the FA and AT genes.
Genetic aspects of orthopedic conditions.
Genetic conditions seen by orthopedists may be divided into Mendelian disorders, chromosome abnormalities and multifactorial conditions. Mendelian disorders involve the abnormality of a single gene and obey the rules of Mendelian inheritance. Chromosome abnormalities are caused by the absence or duplication of a sufficient number of genes to allow this abnormality to be detected by chromosome studies. Chromosome studies are used to confirm the diagnosis of well described syndromes of deletion or trisomy. These studies are also necessary to determine whether mongolism has been caused by non-disjunction or translocation, so that proper genetic counseling can be carried out in these conditions. Multifactorial conditions are determined by several genes or more commonly, by a combination of genetic and environmental factors. These conditions recur in families in a greater incidence than one would expect in the general population but do not obey the rules of Mendelian inheritance. Genetic counseling cannot be performed without an absolute diagnosis, an absolute knowledge of the patterns of inheritance and a well documented family pedigree. The basic principles of genetics covered in this article should allow the orthopedist to understand when genetic counseling is indicated for his patients.
Abnormal skin fibroblast cytogenetics in four dysmorphic patients with normal lymphocyte chromosomes.
Four patients with features suggestive of chromosome disorders but with normal lymphocyte karyotypes were found to have chromosome aberrations in skin fibroblast karyotypes. Although mosaicism for chromosome abnormalities in lymphocyte cultures is common, apparent restriction of mosaicism to one tissue is unusual. We suggest that after examination of lymphocyte karyotypes, certain patients warrant cytogenetic evaluation of a second tissue, usually cultured skin fibroblasts.
[Human chromosome polymorphism and disordered reproductive function. I. Routine chromosome variants].
Routine polymorphic variants of chromosomes of 58 married couples with reproductive failure (two or more spontaneous abortions, stillbirths and malformed children) and 48 control couples, having two or more normal children and no spontaneous abortions and stillbirths, were investigated by conventional staining technique. Extreme variants of chromosomes 1, 9, 16, 17, 13--15, 21--22 and Y were found in 17.2% of subjects with reproductive loss and in 15.6% of control individuals. No significant differences in frequencies of scored routine variants were noted between married couples with reproductive failure and couples with normal reproduction.
Prospective study of genetic counselling.
A prospective study was carried out on 200 consecutive subjects seen for counselling (consultands) for serious genetic disorders. Educational and social background of consultands and their knowledge and understanding of their particular problem were assessed before counselling, and their response was determined immediately afterwards and three months and two years later by an independent observer not concerned in the genetic counselling. The husband's educational background was particularly important in influencing a couple's comprehension of counselling. X-linked recessive and chromosomal disorders presented the most difficulties in comprehension. The counsellors' assessment of comprehension was a good guide to the consultands' comprehension as assessed at subsequent follow-up. The proportion deterred from having children increased with time and over a third had been sterilised within two years of counselling. It is suggested that follow-up after counselling should be routine, especially when the counsellor suspects that comprehension has not been good, in X-linked recessive and chromosomal disorders, and when the risks of having an affected child are considered to be high.
[Role of DNA repair disorders in chromosome instability, decreased longevity and neoplastic cell transformation in hereditary human diseases].
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Status and prospects of genetic disease.
The current status of our knowledge of genetic diseases is reviewed. The incidence of monogenic, multifactorial and chromosomal disorders, according to the literature to date, is given, and the possibilities of mass screening programmes are discussed. The prospects for antenatal diagnosis of genetic diseases are reviewed, with emphasis on the indications for amniocentesis and the safety of the procedure. Finally, speculations are made regarding the possible effects of medical and social practices on the frequency of genetic disorders in future generations.
[Human chromosome polymorphism and disordered reproductive function. II. C-variant chromosomes].
C-stained polymorphic variants of chromosomes 1, 9, 13--16, 21, 22 and Y were studied in married couples with reproductive failure (200 individuals) and in control couples having normal children and no spontaneous abortions and stillbirths. Location of heterochromatic segments, their size and heteromorphism of homologues were estimated. The individuals with reproductive failure were carriers of variants of chromosomes 9 and acrocentrics with higher content of heterochromatic material as well as with heterochromatic chromosome 9 significantly more frequently as compared with control individuals.
An evaluation of cytogenetic analysis as a primary tool in the assessment of recurrent pregnancy wastage.
Cytogenetic evaluation of couples with recurrent pregnancy wastage is frequently performed only after other possible etiologic factors have been excluded. Previous reports of studies using conventional and G-banding chromosome techniques in these couples have shown a higher frequency of translocations than that found in the general population. In the study reported here, both conventional and G-banded chromosome analyses were performed as a primary method of evaluation in 34 couples with recurrent fetal loss not ascertained by the birth of a child with a diagnosed chromosome disorder. Balanced translocations were found in 5 partners of the 34 couples studied. In only 2 of these cases was the translocation detected by conventional chromosome analysis. These results suggest that G-banded chromosome analysis should be a useful tool in the initial evaluation of couples with recurrent fetal wastage, rather than being recommended only after extensive investigation of other factors is unrewarding. The reproductive counseling of couples with a translocation detected on this basis is discussed.
Genetic counseling and the pediatrician.
The assistance of the pediatrician, following diagnosis of a child with a genetic disorder, towards his family consists today in giving genetic counseling for prevention of recurrence in future pregnancies. The process of genetic counseling, once the right diagnosis is made, should not be difficult as concerns Mendelian inheritance. It is well known that several chromosomal disorders follow the rules of Mendelian inheritance. The theory of polygenic or multifactorial inheritance may create problems in the accurate estimation of risks. An effort is made to discover the mechanisms of genetic "predisposition" or the adverse environmental factors, in order to minimize the occurrence of such disorders. An important tool in prevention of several genetic disorders, which should be mentioned in genetic counseling, is prenatal diagnosis.