I MONOGENIC MENDELIAN INHERITANCE
I.4.1 MOST FREQUENT CASE / MARRIAGE HEZ WOMAN / NORMAL MAN
II MULTIFACTORIAL INHERITANCE
III MITOCHONDIAL INHERITANCE
Mendelian inheritance is based on the transmission of a single gene on a dominant, recessive or X-linked pattern. Discoveries on DNA structure, the genetic code, the genome and the observation that some characters and hereditary diseases do not follow classical mendelian inheritance have led researchers to define other patterns of transmission, referring particularly to multifactorial and mitochondrial inheritance. Multifactorial inheritance is based on the synergy of genes and environmental factors. Extra nuclear mitochondrial heredity can only be transmitted by the mother whose cells contain a number of mitochondria. Several factors can modify the expected individual phenotypes.There will undoubtedly be important advances in our knowledge of the pattern of inheritance of characters and diseases given a better understanding of gene structure and role, interaction of genes between them and with the environment.
I MONOGENIC MENDELIAN INHERITANCE
I.2 Autosomal dominant inheritance (AD):
Most frequent instance: Aa x AA ( marriage of an affected individual HEZ with a normal individual).
Examples of AD diseases :
I.3 Autosomal recessive inheritance
Most frequent case: Aa x Aa (marriage of 2 normal heterozygotes).
Parental genotype: Aa x Aa
Examples of AR diseases:
I.4 X linked recessive inheritance (RLX)
I.4.1 Most frequent case: heterozygote woman, a normal carrier who marries a normal man.
- Affected individuals are usually born of normal parents.
- In the paternal progeny all individuals are normal.
- In the maternal progeny one often finds affected brothers or male sibs.
- Usually affected individuals are male.
- In the affected sibship , one male out of two is affected, and one female out of two is carrier.
I.4.2 Mating normal female / affected male
Parental genotype : XX * xY
- All boys are normal and carry no mutation.
- All girls are normal but are HEZ carriers.
I.4.3 Marriage HEZ female / affected male
Parental genotype: Xx / xY
Fig. 6Rare situation if the mutation is severe.
- One boy out of two is affected.
- Normal girls are HEZ.
- Girls can be affected.
Situation not likely to happen for a rare gene, but more frequent if the gene frequency is high ( ex: colour blindness).
---> The fact that the disease is restricted to males is not an absolute criterion of X linked inheritance. The criterion of n on transmission from father to son is more objective
---> (it allows to differentiate between autosomal dominant diseases with sex limitation).
Remarks: to detect heterozygote carriers for genetic counseling.
Examples of RLX diseases :
- Colour blindness
- Hemophilia A and B
- Angiokeratosis (Fabry disease)
- Duchenne muscular dystrophy
- Incontinentia pigmentosum
- Agammaglobulinemia, Bruton type
- G6PD deficiency
I.5 Factors affecting the phenotype
Some individuals who carry the deleterious gene ( for instance in an autosomal dominant disease) do not present the expected phenotype: we then say that the penetrance is incomplete. The number of individuals who carry a mutation is less than the number of individuals who have an abnormal phenotype. This is a quantitative estimate. In the neurofibromatosis type I, penetrance is evaluated at approximately 80 % , but it is often difficult to detect a mild form of the disease. An improved method to evaluate mutations in those families will allow us to better understand this notion of penetrance.
C not to confound an isolate case due to a reduced penetrance with a sporadic case due to a mutation.
The phenotype can be more or less severe among affected individuals. This a variable expressivity of the deleterious gene. It is a qualitative evaluation.
In Marfan syndrome for an identical familial gene mutation, some individuals will have a severe form of the disease affecting the cardio-vascular, ocular and skeletal systems while for other individuals only the tall stature and arachnodactyly, without lens dislocation or aortic aneurysm, will be noted.
--->Reduced penetrance and incomplete expressivity are described mainly in autosomal dominant diseases.
I.5.3 Age of onset of the disease / anticipation
Although they are present at birth several diseases manifest only later in life. A normal physical examination of a 20 year old individual, from a family at risk for Huntington disease, does not rule out the possibility that this individual is affected with the disease.
---> If the genetic defect is known in a family, the molecular analysis will allow an early detection of the mutation or rule out this possibility before the expected age of onset of the disease.
---> Anticipation refers to a phenomenon characterizing the earlier onset of a disease in younger generations accompanied by more severe manifestations. The phenomenon is mainly observed in autosomal dominant diseases, when there is an increased elevation of triplet repeats from one generation to the next as for instance in myotonic dystrophy (CTG) and Huntington disease (CAG). In Friedreich ataxia, an autosomal recessive disease, the literature reports several families in which the increased triplet repeats (GAA) from one generation to the next is accompanied by an early onset and a more severe symptomatology. However one also finds in Fragile X syndrome, a X-linked disease, a more severe expressivity in the presence of increased triplet repeats without necessarily considering this an anticipation phenomenon.
In a number of genetic diseases the mutation can produce alterations in more than one system. For instance in the < Moon Biedl > syndrome, an autosomal recessive disease, malformations are seen in the nervous, endocrine, skeletal and ocular systems. The mutant gene effects are found at different stages of the development.
1.5.5 Mutation / Heterogeneity
The heterogeneity of mutations will lead to variable manifestations :
- The same mutation can induce different phenotypes.
- Some diseases are due to a mutant gene with a variable structure then susceptible to produce different phenotype effects. In cystic fibrosis there are several mutations at the locus of gene CFTR. More especially in this disease we find patients mainly affected with pulmonary disease, pancreatic insufficiency and / or intestinal disease.
In contrast with genes that code for one disease, the opposite is also noted that is that more than one gene can be responsible for the same disease: in <ectodermal dysplasia> syndrome, finger nail dysplasia, oligodonty and absence of hair can be attributed to 3 different mutant genes, inherited as dominant, X linked or a less frequent recessive patterns, all producing a similar phenotype.
Infrequently homologous chromosomes can have an uniparental origin. This is called a maternal or paternal disomy for a pair of homologous chromosomes. For example an individual affected with cystic fibrosis had one parent carrier of a known mutation for which he was homozygous having received two chromosomes 7 from the same parent carrier of this mutation and none from the other. Disomies are rare and their effect is not well known yet.
1.5.7 Imprinting / parental sex influence
During the course of development maternal and paternal genomes are not equivalent but complementary due to an epigenetic phenomenon that occurred during gametogenesis
Gene function can vary depending upon the maternal or paternal origin of the allele in question.
- A deletion on chromosome 15 ( 15q11-13) in the paternal chromosomal complement will lead to a Prader Willi syndrome different from the Angelman syndrome observed if the deletion involves the maternal chromosome.
- In some diseases the sex of the affected parent can influence the degree of severity of the disease in the individual to whom the mutant gene has been transmitted.
- In myotonic dystrophy the disease will be more severe, even often congenital, if the mother is the affected parent who transmitted the disease.
- In Huntington disease the age of onset may be earlier and the severity more pronounced if the father transmitted the disease.
In those two examples it has not been demonstrated beyond doubt that the phenomenon is due to parental imprinting, triplet amplification or a mitochondrial mutation.
--->Fertilization of an ovum without a nucleus by a sperm cell that has undergone a duplication of its haploid set or a dispermy could lead to a hydatiform mole.
1.5.8 Gene interaction / Co-factors
Gene action is sometimes regulated by more than one gene acting as regulator. A gene may have a normal structure but other genes in the metabolic chain or the absence of co-factor(s) may be responsible for the inhibition of a protein activity and the production of a genetic disease.
- For some individuals rickets is due to a vitamin D deficiency that will be corrected by the addition of a vitamin supplement in the diet. For others the disease due to the absence of the active form of Vitamin D, an autosomal recessive disease, or several other mutations regulating the vitamin D metabolism.
- Mutations of cancer suppressors, protein regulators ( enzymes) or DNA repair genes have been identified. For example those mutations can induce metabolic diseases like mucopolysaccharidoses, ovary and colon cancers and DNA repair defects like Ataxia telangiectasia.
1.5.9 Genes susceptibility to cancer and malformations
A number of genes susceptible to be at the origin of a cancer can simultaneouly cause a malformation syndrome.
- If a deletion occurs in gene WT1 located on chromosome 11 in region 11p13, it will lead to a Wilms tumor and a nephropathy. Syndrome WAGR ( W:: Wilms; A: aniridia, G: genito-urinary malformations, R: mental retardation) would result from the deletion of this and other contiguous genes located in region 11p13-11p14.
- Another example is Beckwith-Wiedemann syndrome also located on chromosome 11, in region 11p15.5, that would imply several contiguous genes. The syndrome manifests with obesity, macroglossia, nephroblastoma ( hepatoblastoma, neuroblastoma) gigantism and omphalocele. Growth factor IGF-2 (insulin-like growth factor 2) a paternally expressed gene would be responsible for the pathogenesis of macrosomia; mutation of other genes like CDKNIC ( p57K1P2) ( maternal expression), may be responsible for other aspects of the phenotype.
---> Other case reports and molecular studies are essential to circumvene etiological mechanisms in those malformation syndromes with susceptibility to cancer.
A false paternity may sometimes be at the origin of an incomplete or incorrect family history. Doubt may arise about the paternity of an individual if ongoing molecular studies do not find in the suspected father the presence of one or more DNA sequences.
1.5.11 Diagnostic error / classification
Difficulties encountered sometime in the evaluation of a pattern of transmission of a disease may be due to diagnostic or classification errors. Several groups of diseases like glycogenoses and mucopolysaccharidoses often have a similar phenotype but a different enzymatic deficiency confirmed by the identification of a specific mutation for each one of them.
II MUTIFACTORIAL INHERITANCE
1. Continuous quantitative heredity
Distribution of the population on a Gauss model curve ( ex:
Threshold model often arbitrary.
2. Discontinued quantitative heredity
Examples of multifactorial diseases
- Cleft palate
- Hare lip and cleft palate
- Cardio-vascular disesases
- Hip dislocation
- Psoriasis etc etc
III MITOCHONDRIAL INHERITANCE
Mitochondrias come from ancestor anareobic bacterias ;---> they have their own DNA. We then have extranuclear DNA in our cells.
MITOCHONDRIAL DNA :
A mitochondrial gene disease is transmitted :
The term mitochondrial cytopathy may be ambiguous : the mitochondrial cytopathies include not only the pathologies due to mitochondrial gene mutations but also those due to nuclear genes coding for proteins invoved in the mitochondrial metabolism (enzymes of the respiratoiry chain).
Examples of of mitochondrial hereditary diseases :
|Written||2002-12||Louis Dallaire, Jean-Loup Huret|
|Centre de Recherche, Hôpital Ste-Justine, Montréal, Canada (LD); Genetics, Dept Medical Information, UMR 8125 CNRS, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers France (JLH)|
|© Atlas of Genetics and Cytogenetics in Oncology and Haematology||indexed on : Mon Sep 18 16:46:54 CEST 2017|
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