39
Genetic diseases
39 Genetic diseases
Klaus Huber
39.1 Introduction
Molecular genetics has made significant progress in recent years, not only in the understanding of the underlying causes of disease but also by providing new insights into particular disease entities. The introduction of the polymerase chain reaction (PCR) was an important development that allowed clinical laboratories to perform diagnostic testing using molecular genetics. Equally important are the new sequencing technologies that are summarized under the term next-generation sequencing. As a result of these innovations, it is highly likely that the mutations responsible for the vast majority of Mendelian diseases will be known soon. The introduction of these methods to the laboratory represents a further technological boost, the effects of which are on a par with the introduction of PCR. The ”$1,000 genome” was announced in 2015. This catchphrase refers to the cost of sequencing an individual’s entire genome, which will bring truly individualized medicine within reach.
This opens up the possibility of:
- Performing individual genome sequencing
- Re sequencing large fragments
- Analyzing the set of all messenger RNA molecules in one cell or a population of cells (transcriptome) using RNA sequencing
- Performing exome sequencing in complex disease. An exome includes only those RNA molecules found in a specified cell population, and usually includes the amount or concentration of each RNA molecule in addition to the molecular identities.
- Analyzing epigenetic changes. These changes modify the activation of certain genes, but not the genetic code sequence of DNA.
- Performing mutation analysis in infectious disease to guide individual therapy decisions. Mutation analysis investigates mutations (e.g., the permanent alteration of the nucleotide sequence of the genome of an organism).
The starting point for all of these developments was the Human Genome Project, which was started in 1988 with the goal of sequencing the entire human genome and was completed successfully in 2003. Approximately 95% of all bases had already been sequenced by 2001; it took two more years to completely sequence the more difficult fragments that remained. The human genome is made up of 30,000–40,000 genes, not all of which have been assigned a function to date. Many new explanations have been found for diseases whose mode of inheritance deviates from Mendelian principles. The last edition of McKusick’s ”Mendelian Inheritance in Man” contains approximately 18,000 listings. The following chapter describes a wide range of genetic diseases for which laboratories offer diagnostic tests.
However, a complete list of all genetic diseases that can be diagnosed in European laboratories would be beyond the scope of this chapter. The diagnosing physician should therefore make use of the many available online databases as a search tool:
- Database of genetic diseases: OMIM (Online Mendelian Inheritance in Man: www.ncbi.nlm.nih.gov/omim, compiled by Prof. Victor McKusick)
- ORPHANET: www.orpha.net/consor/cgi-bin/index.php?lng=EN (an overview of the diagnosis of genetic diseases)
- Various mutation-specific databases (can be found via NCBI: www.ncbi.nlm.nih.gov/)
- Single Nucleotide Polymorphism database (dbSNP): www.ncbi.nlm.nih.gov/snp/ (collection of single nucleotide polymorphisms)
- MITOMAP: www.mitomap.org/MITOMAP (mitochondrial database)
- The useful and informative GeneCards database: www.genecards.org (integrates a wide range of information about disease genes)
- Country specific home pages of various expert associations and self help organizations in the area of human genetics.
The corresponding Mendelian Inheritance in Man (MIM) number is provided for each disease listed and can be used in the Online Mendelian Inheritance in Man (OMIM) to search directly for further information and literature.
39.2 Terminology
39.2.1 Monogenic diseases
Monogenic diseases are caused by mutations affecting only one gene and have a dominant, recessive, or X-linked mode of inheritance. A dominant mode of inheritance leads to clinical manifestation of the disease if one of the two corresponding chromosomes (autosomes: chromosomes 1–22; sex chromosomes: X,Y) carries a mutated gene; clinical manifestation of disorders with recessive inheritance occurs only if both genes are mutated. Disease loci on the X chromosomes are passed on via an X-linked inheritance mode. Usually, only male offspring, who have only one X chromosome per cell, are affected. However, females are also affected by diseases with a dominant X-linked inheritance pattern.
Many deviations from this Mendelian inheritance pattern can be found:
- In triplet repeat expansion diseases, the underlying defect involves multiple repetitions of base triplets in certain genes; uncontrolled replication leads to clinical expression. These diseases exhibit the phenomenon of anticipation, whereby the severity of the clinical course increases from generation to generation.
- In diseases triggered by uniparental disomy; the corresponding genes are inherited from one parent only
- The modification of some genes may depend on their origin (paternal/maternal) (imprinting).
The causes of monogenic diseases include:
- Point mutations (missense mutations: exchange of an amino acid within the corresponding protein
- Nonsense mutations: introduction of a stop codon
- Deletions and insertions involving bases and larger gene fragments with resultant shifts in the reading frame during translation (the amino acid sequence is altered from the mutation site onward)
- Mutations of control regions; alteration in poly adenylation or the correct assembly of RNA (splice mutants); and other mechanisms. Poly adenylation is the addition of a poly(A) tail (adenine nucleotides) to an RNA molecule.
39.2.2 Multifactorial genetic diseases
Multifactorial genetic diseases are the result of disturbed interaction between many genes and/or environmental factors. Their mode of inheritance is much more complex, but the probability of offspring being affected by the disease is generally lower than for monogenic diseases. Chromosomal alterations influencing many genes result from losses, excesses, or new arrangements of chromosomes or chromosome segments.
39.2.3 Epigenetics
Epigenetic changes refer to acquired cellular traits that, although they may be heritable, are not caused by changes in the DNA sequence. These changes in DNA or chromosomes influence the activity of chromosomes or chromosome segments. The changes are functional rather than structural; for example, the covalent binding of chemical groups to DNA or histones without alteration in the DNA sequence.
Epigenetic changes are continuous and quantitative. For instance, the ratio of hypo- to hyper methylated DNA sequences influences tumor growth. These changes, which may be reversible, operate at the interface between genes and environment.
39.3 Indication
- Diagnostic evaluation and differential diagnosis of manifest disease
- Predictive diagnosis of disease in family constellations
- Prenatal diagnostics
- Family testing.
39.4 Diagnostic procedures
Depending on the size of the affected gene and the frequency of individual mutations of this gene, different diagnostic methods are employed:
- Direct mutation detection: these methods can be used in those instances where one or a few mutations within a gene are responsible for most cases of a disease. The affected gene sequence is usually examined using, e.g. real-time PCR. For large genes or alterations that affect entire gene fragments and in diseases caused by many individual mutations of one gene, direct (sequencing) and, occasionally, indirect mutation detection methods are used.
- Indirect mutation detection: these methods include chemical or enzymatic mismatch cleavage [CCMD, chemical cleavage mutation detection] and special techniques such as single strand conformational polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), and temperature gradient gel electrophoresis (TGGE). These methods can be used alternately.
The Southern blot method (Section 52.1.10.1 – Immunoblotting) examines genes for the presence of larger deletions or insertions as well as alterations in restriction enzyme sites. Alternatively, comparative genomic hybridization (CGH) can be used. In CGH, DNA from a test sample and DNA from a control sample are labeled with two different fluorophores and cohybridized to an array of gene probes that represents a large part of the human genome. The hybridization pattern shows the variations between the sample and control DNA (virtual karyotype). However, due to the availability of automated sequencing methods, gene or gene fragment sequencing is now performed by many clinical laboratories. Even if the actual gene involved is not yet known, the mode of inheritance of the disease can be determined by linkage analysis (i.e., the analysis of markers that are associated with the disease). Ultimately, cytogenetics, with all of its different techniques, is the basis for all tests in human genetics laboratories.
References
ScienceDirect: Genetic testing. www.sciencedirect.com/topics/medicine-and-dentistry/genetic-screening
Brusick DJ. Principles of GeneticToxicology. Springer Link. https://www.springer.com/gp/book/9780306425325
39.5 Specimen
- 2 to 3 EDTA blood count tubes (non heparinized blood)
- Cheek swab
- Amniotic fluid.
39.6 Clinical significance
Homozygous and compound heterozygous mutations lead to a loss of function of the corresponding gene on both chromosomes. Compound heterozygosity is the condition of having two heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state. Thus, homozygous and compound heterozygous mutations explain the cause of disease at the molecular level. In the case of two mutated alleles, however, it is often difficult to determine whether there is one mutation on each gene or there are two mutations on the same gene, and therefore, whether one or both genes are non functional. These mutations should therefore be demonstrated in one or both parents of the affected individual. However, this is often not possible. In such cases, the answer is determined by the clinical picture.
Heterozygous mutations with a dominant mode of inheritance lead to disease, depending on the penetrance of the respective mutation. Heterozygous mutations with a recessive mode of inheritance can also lead to symptoms; however, these are usually attenuated or have a different course.
In the case of triplet repeat disorders, the anticipation phenomenon must be kept in mind; this can lead to earlier onset and more severe symptoms in successive generations.
For affected gene regions in genetic diseases refer to
- OMIM®, Online Mendelian Inheritance in Man®. An online catalog of human genes and genetic disorders. Updated June 6, 2019.
- Tab. 39-1 – Gene regions in genetic diseases (eye diseases – selection)
- Tab. 39-2 – Gene regions in genetic diseases (disorders of connective tissue and bone formation – selection)
- Tab. 39-3 – Gene regions in genetic diseases (diseases involving oncogenes – selection)
- Tab. 39-4 – Gene regions in genetic diseases (developmental disorders – selection)
- Tab. 39-5 – Gene regions in genetic diseases (disorders of hemostasis – selection)
- Tab. 39-6 – Gene regions in genetic diseases (skin diseases – selection)
- Tab. 39-7 – Gene regions in genetic diseases (immunodeficiencies – selection)
- Tab. 39-8 – Gene regions in genetic diseases (muscle disorders – selection)
- Tab. 39-9 – Gene regions in genetic diseases (neurodegenerative diseases – selection)
- Tab. 39-10 – Gene regions in genetic diseases (kidney disorders – selection)
- Tab. 39-11 – Gene regions in genetic diseases (impaired oxygen transport – selection)
- Tab. 39-12 – Gene regions in genetic diseases (metabolic diseases – selection)
- Tab. 39-13 – Gene regions in genetic diseases (metabolic diseases – selection)
39.7 Comments and problems
It is generally easy to obtain DNA from a wide range of specimens. Contamination by foreign genetic material or amplified fragments from previous tests must be avoided by implementing measures such as physically separating sample preparation areas and analysis areas. The quality of analyses must be systematically checked by testing positive and negative controls and participating in inter laboratory surveys (EMQN European Molecular Genetics Quality Network: www.emqn.org).
Laboratories that perform genetic investigations must also be fully aware of the legal considerations. It is also important to remember that genetic diagnoses have implications for family members. Before embarking on a genetic diagnosis, in-depth genetic counseling and a comprehensive family history must always be carried out. Patients have the right not to be informed of findings, in Huntington’s disease, for example, even though a full genetic diagnosis may have been made.
Possible social disadvantages associated with the diagnosis of a genetic disease (loss of insurance/employment) must be prevented by rigorous data security measures.
39.8 Explanation of terms
- Anticipation: this term describes the worsening of the clinical phenotype with each successive generation.
- Compound heterozygote: this term describes the condition of having two heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state.
- Dominant: clinical symptoms occur even with heterozygotic mutations.
- Exon: protein producing part of a gene.
- Exome: includes only those RNA molecules found in a specified cell population.
- Frame shift mutation: a genetic mutation caused by a deletion or insertion in a DNA sequence that shifts the way the sequence is read.
- Heterozygote: sequence alteration in one gene only
- Homozygote: sequence alteration in both genes of a gene pair.
- Imprinting: is the epigenetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner.
- Intron: the part of a gene that does not encode a protein.
- Shift of the reading frame: refer to ”Frame shift mutation” above.
- Missense mutation: refers to a change in one amino acid in a protein, arising from a point mutation in a single nucleotide.
- Monogenic disease: is caused by a single gene.
- Nonsense mutation: is a genetic mutation in a DNA sequence that results in a shorter, unfinished protein.
- Polyadenylation: addition of adenosine groups to RNA.
- Rearrangements: rearrangement of chromosome segments.
- Recessive: clinical symptoms occur only with homozygous mutations.
- Splice-junction mutation: error in the assembly of exon products (RNA) of a gene.
- Transcriptome: the entire transcribed (DNA → RNA) area of the genome.
- Triplet repeat expansion: the genetic code contains regions of triplet repeats (CAG, CTG, CGG, or CAA). These regions of triplet repeats have a normal number of repetitions and can be located before, after, or within a gene. Triplet repeat disorders are caused by genes that have an expansion in the number of trinucleotides.
- Uniparental disomy: active gene is inherited from one parent only.
- X-linked: genes are inherited on the X chromosome.
References
- Erlich HA. PCR technology. New York; McMillan Publishers, Stockton Press 1989.
- Haselberger AG, Gressler S. Epigenetics and human health. Weinheim, Wiley-VCH Verlag GmbH & Co. 2010.
- Keller GH, Manak MM. DNA probes. London, Nature Publishing Group 1993.
- Lewis R. Human Genetics. New York, McGraw-Hill 2005
- McKusick V. Mendelian inheritance in man (XI edition). Baltimore; John Hopkins University Press 1998.
- Milunsky A, Milunsky JM. Genetic disorders and the fetus. Chichester, Wiley Blackwell 2010.
- Passarge E. Taschenatlas der Genetik. Stuttgart; Thieme 2008.
- Runge MS, Patterson C. Principles of molecular medicine. Humana Press, Totowa, New Jersey 2006
- Scriver CR. Beaudet AL, Sly WS, Valle D. The metabolic and molecular bases of inherited disease (VIII edition). New York; McGraw-Hill 2000.
- Smith CUM. Elements of molecular neurobiology. Chichester; John Wiley & Sons 2002.
- Strachan T, Matthes TJ. Human molecular genetics. London; Garland Science 2003.
- Strachan T, Read AP. Molekulare Humangenetik. Heidelberg: Spektrum Akademischer Verlag 2005.
- Taylor GR, Day IN, Human Genome Organization (HUGO). Guide to mutation detection. Chichester, John Wiley & Sons 2005
- Terwilliger JD, Ott J: Handbook of genetic linkage. Baltimore; John Hopkins University Press 1994.
- Weatherall DJ, Ledingham JGG, Warell DA. Oxford textbook of medicine (4th edition). Oxford; Oxford University Press 2003.
- Blau N, Duran M, Baskovics ME, Gibson KM. Physician’s guide to the laboratory diagnosis of metabolic diseases. New York; Springer 2004.
Table 39-1 Gene regions in genetic diseases (eye diseases – selection)
|
Affected organs |
Eye diseases |
|
Disease |
Choiroideremia (hemeralopia) |
|
Frequency |
1 : 100,000 |
|
MIM |
303100 |
|
Inheritance |
X-linked |
|
Chromosomal location |
Xq21 |
|
Type of mutation |
Deletions, translocations, point mutations |
|
Mutant gene product |
Decreased/absent activity of the choroideremia (CHM) gene product (REP1 protein, geranylgeranyltransferase); may be substituted in part by choroideremia-like (CHML) gene products with similar activity |
|
Clinical features |
Progressive degeneration of the choroid and retina; atrophy of the pigment epithelium, choroid, and retina; night blindness from adolescence, complete blindness in middle age |
|
Detection method |
Western blot with anti-REP1 antibody, PCR |
|
Disease |
Color blindness: Blue monochromasy, red-green color blindness |
|
Frequency |
1 : 100,000 (blue monochromasy), 1 : 13 (red-green) in male Caucasians |
|
MIM |
303900 |
|
Inheritance |
X-linked |
|
Chromosomal location |
Xq28 |
|
Type of mutation |
Deletions, missense mutations |
|
Mutant gene product |
Absence of the respective opsins, fusion products with altered spectral qualities |
|
Clinical features |
Color blindness |
|
Detection method |
SSCP, Southern blot, Sequencing |
|
Disease |
Retinoschisis |
|
Frequency |
1 : 10,000–100,000 |
|
MIM |
312700 |
|
Inheritance |
X-linked |
|
Chromosomal location |
Xp22.2–22.1 |
|
Type of mutation |
Nonsense, missense, and frame shift mutations |
|
Mutant gene product |
Mutated XLRS1 gene product (retinoschisin), which is important for cellular adhesion during retinal development |
|
Clinical features |
Splitting and rupture of retinal cell layers |
|
Detection method |
Clinical evidence of macular lesions; sequencing |
|
Disease |
Retinitis pigmentosa |
|
Frequency |
1 : 10,000 |
|
MIM |
180380, 600105, 608133, 312600, 600059, 600105, Usher syndrome: 276900, and others |
|
Inheritance |
X-linked, autosomal dominant, autosomal recessive |
|
Chromosomal location |
Xp11, Xp21,1q31–q32.1 3q21–24, 6p21.1-cen, and other loci |
|
Type of mutation |
Point mutations |
|
Mutant gene product |
RP1–RP15: abnormal cellular localization or defective glycosylation or altered function of rhodopsin; mutant peripherin |
|
Clinical features |
Degeneration of photo receptors, loss of vision (autosomal dominant and recessive: at around 60 yrs.; X-linked: at around 45 yrs.) |
|
Detection method |
Molecular diagnostics, depending on the gene affected |
Table 39-2 Gene regions in genetic diseases (disorders of connective tissue and bone formation – selection)
|
Affected organs |
Disorders of connective tissue and bone formation |
|
Disease |
Achondrogenesis/hypochondrogenesis |
|
Frequency |
Rare |
|
MIM |
200600, 200610, 600972 |
|
Inheritance |
Type II: new dominant mutations; type 1: autosomal recessive |
|
Chromosomal location |
Type II: 12q14.3, type IB: 6q32–33.1 |
|
Type of mutation |
Deletion, insertion, missense mutations in COL2A1 or DTDST gene |
|
Mutant gene product |
Type II: altered type II collagen, type IB: diastrophic dysplasia sulfate transporter gene |
|
Clinical features |
Most severe form of the chondroplasty; short-limbed dwarfism; lethal during early childhood or in utero |
|
Detection method |
Direct detection for known mutations, linkage analysis, sequencing |
|
Disease |
Achondroplasia |
|
Frequency |
1 : 15,000 |
|
MIM |
100800 |
|
Inheritance |
Autosomal dominant; new dominant mutations |
|
Chromosomal location |
4p16.3 |
|
Type of mutation |
> 95% of all cases caused by one point mutation |
|
Mutant gene product |
Loss of function of fibroblast growth factor receptor 3 |
|
Clinical features |
Most common form of dwarfism, short extremities |
|
Detection method |
Direct detection of mutation |
|
Disease |
Anhidrotic ectodermal dysplasia (Christ-Siemens-Touraine syndrome) |
|
Frequency |
Rare |
|
MIM |
305100 |
|
Inheritance |
X-linked |
|
Chromosomal location |
Xq12.2–q13.1 |
|
Type of mutation |
Deletions, transitions, transversions |
|
Mutant gene product |
Reduced EGR receptor expression due to mutations in the gene for EDA (ectodysplasin A) |
|
Clinical features |
Anhidrosis (absent sweat glands), hypotrichosis, abnormal tooth development (few teeth) |
|
Detection method |
Sequencing, direct detection of mutation |
|
Disease |
Crouzon syndrome (dysostosis craniofacialis hereditaria) |
|
Frequency |
1 : 10,000–100,000 |
|
MIM |
123500 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
10q26 |
|
Type of mutation |
Point mutations |
|
Mutant gene product |
Decreased function or absent fibroblast growth factor receptor 2 |
|
Clinical features |
Craniosynostosis, hypertelorism, strabismus, exophthalmos |
|
Detection method |
Direct detection of mutation, sequencing |
|
Disease |
Ehlers-Danlos syndrome type IV (vascular type) |
|
Frequency |
1 : 10,000–100,000 |
|
MIM |
130050 |
|
Inheritance |
Autosomal dominant; new dominant mutations |
|
Chromosomal location |
2q31–2q32.3 |
|
Type of mutation |
Deletions, insertions, point mutations in the Col3A1 gene |
|
Mutant gene product |
Defective secretion or abnormal structure or unstable type III pro collagen |
|
Clinical features |
Tissues containing mutant type III collagen are fragile; thin, parchment skin; intestinal, uterine, arterial ruptures |
|
Detection method |
Direct detection for known mutations, DGGE, sequencing |
|
Disease |
Ehlers-Danlos syndrome type VII |
|
Frequency |
Rare |
|
MIM |
130060 |
|
Inheritance |
Autosomal dominant; new dominant mutations |
|
Chromosomal location |
17q21.3–q22 in CoI1A1, 7q21.3–q22.1 in CoI1A2 |
|
Type of mutation |
Deletion of exon 6 by splice-junction mutations in the CoI1A2 or CoI1A1 gene |
|
Mutant gene product |
Impaired conversion of type I pro collagen to collagen |
|
Clinical features |
EDS type VII presents with joint problems (hyper mobility) and hip dislocations |
|
Detection method |
Sequencing, Southern blot, linkage analysis |
|
Disease |
Kniest syndrome |
|
Frequency |
Rare |
|
MIM |
156550 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
12q13.1–q13.2 |
|
Type of mutation |
Deletions |
|
Mutant gene product |
Impaired processing of type II collagen C-propeptide (CoI2A1 gene) |
|
Clinical features |
Short stature, craniofacial anomalies, myopia, cataracts, dislocated lenses |
|
Detection method |
Direct detection of mutation, DGGE |
|
Disease |
Congenital spondyloepiphyseal dysplasia |
|
Frequency |
Rare |
|
MIM |
Autosomal dominant: 183900, recessive: 6000093, X-linked: 313400 |
|
Inheritance |
Autosomal dominant/recessive, X-linked |
|
Chromosomal location |
12q13.1–q13.2, Xp22.2–p22.1 |
|
Type of mutation |
Exon duplications, deletions, point mutations, splice-junction mutations |
|
Mutant gene product |
Decreased or altered type II collagen (CoI2A1 gene) or mutations in SEDL gene (X chromosome) |
|
Clinical features |
Variable growth retardation, abnormal epiphyses, myopia, retinal degeneration |
|
Detection method |
Direct detection of mutation, DGGE |
|
Disease |
Metaphyseal dysplasia type Schmid |
|
Frequency |
Rare |
|
MIM |
156500 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
6q21–q22.3 |
|
Type of mutation |
Point mutations, small deletions |
|
Mutant gene product |
Altered type X collagen (Col10A1 gene) |
|
Clinical features |
Irregularities of the metaphyseal ends of bones with resultant genu varum |
|
Detection method |
PCR, SSCP |
|
Disease |
Osteogenesis imperfecta (brittle bone disease) |
|
Frequency |
1 : 20,000–40,000 for type I, II, and IV; rare for type III |
|
MIM |
166200, 166210, 166220, 259420, and others |
|
Inheritance |
Autosomal dominant, rarely autosomal recessive, new dominant mutations |
|
Chromosomal location |
17q21.3–q22 in Col1A1, 7q21.3–q22.1 in Col1A2 |
|
Type of mutation |
Missense, deletion, insertion, frameshift, splice-junction, and nonsense mutations in the Col1A1 or Col1A2 gene |
|
Mutant gene product |
Reduced production of type I collagen, reduced secretion or thermal lability of type I procollagen |
|
Clinical features |
Osteogenesis imperfecta, a heterogeneous group of diseases characterized by bone fragility and most commonly caused by mutations of type I collagen |
|
Detection method |
Clinical diagnosis (battered child syndrome is often suspected); direct detection for known mutations |
|
Disease |
Hereditary osteoarthritis |
|
Frequency |
Rare |
|
MIM |
604864 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
12q13.11–q13.2 |
|
Type of mutation |
Point mutations |
|
Mutant gene product |
Altered type II collagen (Col2A1) |
|
Clinical features |
Joint disorder with inflammatory and non-inflammatory components; progressive cartilage and bone destruction |
|
Detection method |
Direct detection of mutation |
|
Disease |
Stickler syndrome (arthro-ophthalmo-dystrophy) |
|
Frequency |
1 : 10,000 |
|
MIM |
108300, 184840, 604841, 609508 |
|
Inheritance |
Autosomal dominant, autosomal recessive |
|
Chromosomal location |
12q13.11–q13.2, 6p21.3 |
|
Type of mutation |
Nonsense, missense mutations in the Col2A1 or Col11A2 gene |
|
Mutant gene product |
Decreased production of type II collagen, vitreous body degeneration |
|
Clinical features |
Vitreoretinopathy, degenerative joint disorder, myopia |
|
Detection method |
Direct detection for known mutations, sequencing tection of mutation |
Table 39-3 Gene regions in genetic diseases (diseases involving oncogenes – selection)
|
Affected organs |
Diseases involving oncogenes |
|
Disease |
Multiple endocrine neoplasia type 2a |
|
Frequency |
Rare |
|
MIM |
171400, 162300 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
10q11.2 |
|
Type of mutation |
Missense mutations |
|
Mutant gene product |
Mutant RET oncogene |
|
Clinical features |
Medullary thyroid cancers with pheochromocytomas and parathyroid tumors |
|
Detection method |
Biochemical analysis of calcitonin and catecholamines, Sequenching |
|
Disease |
Neurofibromatosis type 1 (von Recklinghausen neurofibromatosis) |
|
Frequency |
1 : 3,500 |
|
MIM |
162200, 162210 |
|
Inheritance |
Autosomal dominant, many new mutations |
|
Chromosomal location |
17q11.2 |
|
Type of mutation |
Point mutations, deletions, insertions |
|
Mutant gene product |
Absent tumor suppressor neurofibromin (regulator of ras protein) |
|
Clinical features |
Café au lait spots, Lisch nodules of the iris, multiple neurofibromas; in addition: scoliosis (30%), tumors of the nervous system (5%) |
|
Detection method |
Clinical features, Sequenching |
|
Disease |
Neurofibromatosis type 2 |
|
Frequency |
1 : 100,000 |
|
MIM |
101000 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
22q12.2 |
|
Type of mutation |
Point mutations, deletions |
|
Mutant gene product |
Mutant tumor suppressor schwannomin |
|
Clinical features |
Deafness caused by vestibular schwannomas, occasionally cataracts, café au lait spots, other tumors |
|
Detection method |
Family history, clinical features (MRI), linkage analysis |
|
Disease |
Polyposis coli |
|
Frequency |
1 : 25,000 |
|
MIM |
175100 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
5q21–q22 |
|
Type of mutation |
Point mutations, deletions, insertions |
|
Mutant gene product |
Loss of function of tumor suppressor gene APC (adenomatous polyposis coli) |
|
Clinical features |
Development of thousands of adenomatous polyps in the colon and rectum; 100% risk of cancer |
|
Detection method |
DGGE, sequencing |
|
Disease |
Retinoblastoma |
|
Frequency |
1 : 10,000–100,000 |
|
MIM |
180200 |
|
Inheritance |
Autosomal dominant (60% of cases due to new mutations) |
|
Chromosomal location |
13q14.1–q14.2 |
|
Type of mutation |
Point mutations, deletions |
|
Mutant gene product |
Loss of function of tumor suppressor gene RB1 |
|
Clinical features |
Unilateral and bilateral retinoblastomas (in inherited type, usually bilateral) |
|
Detection method |
Ophthalmological examination, linkage analysis, DGGE, sequencing, Southern blot |
|
Disease |
Tuberous sclerosis |
|
Frequency |
1 : 10,000–100,000 |
|
MIM |
191100, 613354 |
|
Inheritance |
Autosomal dominant, mostly new mutations |
|
Chromosomal location |
TSC1: 9q34, TSC2: 16p13.3 |
|
Type of mutation |
Translocations, TSC2: frameshift and splice mutations |
|
Mutant gene product |
Loss of function of tumor suppressor hamartin (TSC1) or tuberin (TSC2) |
|
Clinical features |
Phakomatosis, proliferation of glial cells, depigmentation, facial angiofibromas, adenoma sebaceum, epilepsy, hamartomas, lipomas, occasionally cardiac myomas |
|
Detection method |
Clinical features, Sequenching, Southern blot, SSCP |
|
Disease |
WAGR syndrome (Wilms tumor, aniridia, genitourinary malformations, mental retardation) |
|
Frequency |
1 : 100,000 |
|
MIM |
194072, 612469 |
|
Inheritance |
Mostly new mutations, some cases autosomal dominant |
|
Chromosomal location |
11p13, 11p15, and other loci |
|
Type of mutation |
Deletions, point mutations, translocations |
|
Mutant gene product |
Altered or absent transcription factor WT1 (tumor suppressor gene) |
|
Clinical features |
Kidney tumors (Wilms tumor), mental/psychomotor retardation, genitourinary anomalies (Denys-Drash syndrome), absent or malformed iris |
|
Detection method |
Chromosomal analysis, direct detection of mutation, linkage analysis |
Table 39-4 Gene regions in genetic diseases (developmental disorders – selection)
|
Affected organs |
Developmental disorders |
|
Disease |
DiGeorge (CATCH 22) syndrome |
|
Frequency |
1 : 10,000 |
|
MIM |
188400, 192430, 274210 |
|
Inheritance |
Autosomal dominant, mostly new mutations |
|
Chromosomal location |
22q11 |
|
Type of mutation |
Deletions causing functional monosomy |
|
Mutant gene product |
Possible loss of function of transcription regulator protein TUPLE1 |
|
Clinical features |
Cardiac, abnormal facies, thymic hypoplasia, hypocalcemia (CATCH 22) Cardiac and cranial malformations, cleft palate, hypocalcemia, absent parathyroid glands and thymus |
|
Detection method |
Array CGH (comparative genomic hybridization), sequencing, Southern blot, karyotyping |
|
Disease |
Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome) |
|
Frequency |
Rare |
|
MIM |
150230 |
|
Inheritance |
Autosomal dominant, many new mutations |
|
Chromosomal location |
8q23.3–q24.13 |
|
Type of mutation |
Deletions, translocations, inversions, insertions |
|
Mutant gene product |
Possible gene dosage effects caused by deletion of several genes (TRPS1 and EXT1) |
|
Clinical features |
Characteristic facial features (pear-shaped nose, extended ears), cone-shaped epiphyses, mental retardation, redundant skin, short stature |
|
Detection method |
Array CGH, sequencing, Southern blot, cytogenetic analysis |
|
Disease |
Lowe syndrome (oculo-cerebro-renal syndrome) |
|
Frequency |
Rare |
|
MIM |
309000 |
|
Inheritance |
X-linked |
|
Chromosomal location |
Xq26.1 |
|
Type of mutation |
Translocations, nonsense mutations |
|
Mutant gene product |
Absent OCRL-1 (oculocerebrorenal transcript 1) gene product (may be involved in inositol metabolism) |
|
Clinical features |
Congenital cataracts, hypotonia, cognitive impairment, renal tubular defects, often cryptorchidism |
|
Detection method |
Ophthalmological examination, direct detection of mutation, linkage analysis |
|
Disease |
Norrie disease |
|
Frequency |
Rare |
|
MIM |
310600 |
|
Inheritance |
X-linked, new mutations |
|
Chromosomal location |
Xp11.4 |
|
Type of mutation |
Large deletions, point mutations |
|
Mutant gene product |
Loss of norrin (NDP gene product), which is involved in vessel development via the Wnt signal cascade |
|
Clinical features |
Atrophy of the eyeball, sometimes hearing loss |
|
Detection method |
SSCP, sequencing, linkage analysis |
|
Disease |
Prader-Willi syndrome |
|
Frequency |
1 : 10,000 |
|
MIM |
176270, 601491 |
|
Inheritance |
Mostly new mutations, autosomal dominant with imprinting |
|
Chromosomal location |
15q11–q13 |
|
Type of mutation |
Loss of function (due to deletion) of the paternal chromosome fragment or uniparental disomy |
|
Mutant gene product |
Absent small nuclear ribonucleoprotein-associated peptide N and possibly other gene products (necedin gene) |
|
Clinical features |
Oligophrenia, obesity, scoliosis, hypogenitalism, short stature |
|
Detection method |
PCR analysis of microsatellite polymorphisms, methylation pattern, Southern blot |
|
Disease |
Waardenburg syndrome type III |
|
Frequency |
1 : 300,000 |
|
MIM |
148820 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
2q35 |
|
Type of mutation |
Deletions, missense mutations |
|
Mutant gene product |
Altered transcription factor PAX3 protein |
|
Clinical features |
Commonest form of congenital deafness, depigmented hair, iris heterochromy, broad nasal bridge |
|
Detection method |
Direct detection of mutation |
|
Disease |
Beckwith-Wiedemann syndrome |
|
Frequency |
1 : 15,000 |
|
MIM |
130650 |
|
Inheritance |
Mostly new mutations, autosomal dominant |
|
Chromosomal location |
11p15.5 |
|
Type of mutation |
Loss of function (due to deletion) of the maternal chromosome fragment or uniparental disomy |
|
Mutant gene product |
Loss of function of tumor suppressor genes and other genes |
|
Clinical features |
Growth anomalies such as macroglossia, organomegaly, and gigantism; neonatal hypoglycemia; increased risk of adrenal carcinoma and hepatoblastoma |
|
Detection method |
PCR analysis of microsatellite polymorphisms, methylation pattern, Southern blot |
|
Disease |
Williams syndrome |
|
Frequency |
1 : 10,000 |
|
MIM |
194050 |
|
Inheritance |
Sporadic |
|
Chromosomal location |
7q11.2 and other loci |
|
Type of mutation |
Large gene deletions |
|
Mutant gene product |
Hemizygosity at the elastin locus and loss of other genes |
|
Clinical features |
Supravalvular aortic stenosis, peripheral pulmonary artery stenosis, infantile hypercalcemia, mental retardation, growth retardation, ”elfin” facies |
|
Detection method |
Gene dosage PCR, quantitative Southern blot, FISH |
Table 39-5 Gene regions in genetic diseases (disorders of hemostasis – selection)
|
Affected organs |
Disorders of hemostasis |
|
Disease |
APC resistance/factor V Leiden |
|
Frequency |
Europe: 2–7% of the population are heterozygous and 0.1% are homozygous |
|
MIM |
227400, 188050, 188055 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
1q23 |
|
Type of mutation |
> 90% of all cases caused by one point mutation |
|
Mutant gene product |
Mutant activated factor V cannot be inactivated |
|
Clinical features |
Increased thromboembolic risk, especially in combination with oral contraceptive use |
|
Detection method |
Coagulation tests, direct detection of mutation |
|
Disease |
Hemophilia A |
|
Frequency |
1 : 5,000–10,000 |
|
MIM |
306700 |
|
Inheritance |
X-linked |
|
Chromosomal location |
Xq28 |
|
Type of mutation |
Deletions, insertions, point mutations, inversions |
|
Mutant gene product |
Reduced, absent, or non-functional anti-hemophilic factor (factor VIII) |
|
Clinical features |
Hemophilia, hemorrhage |
|
Detection method |
Coagulation tests, sequencing |
|
Disease |
Hemophilia B |
|
Frequency |
1 : 70,000 |
|
MIM |
306900 |
|
Inheritance |
X-linked |
|
Chromosomal location |
Xq27.1–q27.2 |
|
Type of mutation |
Deletions, insertions, point mutations |
|
Mutant gene product |
Reduced, absent, or non-functional Christmas factor (factor IX, β-prothromboplastin) |
|
Clinical features |
Hemophilia, hemorrhage |
|
Detection method |
Coagulation tests, sequencing, direct detection of mutation |
|
Affected organs |
Protease inhibitors |
|
Disease |
Alpha1-antitrypsin deficiency |
|
Frequency |
1 : 7,000; heterozygosity in the % range |
|
MIM |
613490 |
|
Inheritance |
Autosomal recessive |
|
Chromosomal location |
14q32.1 |
|
Type of mutation |
Missense mutations in the SERPINA1 gene |
|
Mutant gene product |
Decreased serum α1-antitrypsin |
|
Clinical features |
Emphysema caused by unopposed leukocyte elastase activity; chronic liver injury |
|
Detection method |
Biochemical analysis of antitrypsin, electrophoretic separation of structural variants, PCR, sequenching |
Table 39-6 Gene regions in genetic diseases (skin diseases – selection)
|
Affected organs |
Skin diseases |
|
Disease |
Ichthyosis (X) |
|
Frequency |
1 : 2,000–6,000 |
|
MIM |
308100 |
|
Inheritance |
X-linked |
|
Chromosomal location |
Xp22.32 |
|
Type of mutation |
Large deletions, point mutations |
|
Mutant gene product |
Steroid sulfatase (STS) deficiency |
|
Clinical features |
Hyperkeratosis, thickened stratum corneum, with onset up to 4 months postpartum |
|
Detection method |
STS enzyme assay, analysis of cholesterol sulfate, Southern blot, multiplex PCR |
Table 39-7 Gene regions in genetic diseases (immunodeficiencies – selection)
|
Affected organs |
Immunodeficiencies |
|
Disease |
Adenosine deaminase deficiency |
|
Frequency |
Rare |
|
MIM |
102700 |
|
Inheritance |
Autosomal recessive |
|
Chromosomal location |
20q13.11 |
|
Type of mutation |
Missense mutations |
|
Mutant gene product |
Reduced or absent ADA activity |
|
Clinical features |
Life-threatening bacterial, fungal, viral, and protozoal infections Abnormal development of B and T lymphocytes; thymus and lymph node deficiency, mostly lethal |
|
Detection method |
Serological and immunological assays |
|
Disease |
Bruton type agammaglobulinemia |
|
Frequency |
1 : 100,000 |
|
MIM |
300755, 300310 |
|
Inheritance |
X-linked |
|
Chromosomal location |
Xq21.2–q22 |
|
Type of mutation |
Missense mutations in the BTK gene |
|
Mutant gene product |
Reduced production of Bruton’s tyrosine kinase (ATK) or B-cell progenitor kinase (BPK) |
|
Clinical features |
Impaired maturation of B lymphocytes, Ig heavy chain rearrangement, and antibody production; recurrent bacterial infections |
|
Detection method |
Serological and immunological assays, linkage analysis, Sequenching |
|
Disease |
Wiskott-Aldrich syndrome |
|
Frequency |
1 : 500,000 |
|
MIM |
301000, (600903) |
|
Inheritance |
X-linked recessive, (autosomal dominant) |
|
Chromosomal location |
Xp11.23–p11.22 |
|
Type of mutation |
Missense, nonsense, frameshift, and splice mutations; deletions; insertions |
|
Mutant gene product |
Mutant WASP gene product |
|
Clinical features |
Immunodeficiency, thrombocytopenia, recurrent severe infections, increased risk for non hodgkin lymphoma |
|
Detection method |
Sequencing, flow cytometry |
Table 39-8 Gene regions in genetic diseases (muscle disorders – selection)
|
Affected organs |
Muscle disorders |
|
Disease |
Central core disease |
|
Frequency |
Rare |
|
MIM |
117000 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
19q13.1 |
|
Type of mutation |
Point mutations |
|
Mutant gene product |
Altered or missing calcium channel: ryanodine ”receptor” |
|
Clinical features |
Non-progressive myopathy, degenerated core muscles, increased urinary creatine excretion, ”floppy infant” syndrome |
|
Detection method |
Creatine analysis, creatine kinase, DGGE, direct detection of mutation |
|
Disease |
Duchenne muscular dystrophy (DMD)/Becker muscular dystrophy (BMD) |
|
Frequency |
1 : 3,500 (DMD), 1 : 20,000 (BMD) |
|
MIM |
310200, 300376 |
|
Inheritance |
X-linked, new mutations for DMD |
|
Chromosomal location |
Xp21.2 |
|
Type of mutation |
Deletions with (DMD) or without (BMD) frameshifts, duplications, point mutations |
|
Mutant gene product |
Absent (DMD) or altered (BMD) dystrophin |
|
Clinical features |
Progressive muscle degeneration, complete wheelchair-dependence at around age 12 (DMD) or age 16 (BMD) |
|
Detection method |
Serum creatine kinase assay, analysis of dystrophin in muscle, Southern blot, multiplex PCR, linkage analysis |
|
Disease |
EMD (Emery-Dreifuss muscular dystrophy), X-linked (also autosomal forms) |
|
Frequency |
Rare |
|
MIM |
310300 |
|
Inheritance |
X-linked |
|
Chromosomal location |
Xq28 |
|
Type of mutation |
Point mutations |
|
Mutant gene product |
Absent nuclear membrane protein ”emerin” |
|
Clinical features |
Relatively mild X-linked muscular dystrophy but cardiac conduction defects that require pacemaker; impaired extension of neck and spine; slight increase in creatine kinase |
|
Detection method |
Linkage analysis, direct detection of mutation |
|
Disease |
Hyperkalemic periodic paralysis (adynamia periodica) |
|
Frequency |
Rare |
|
MIM |
170500 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
17q23.1–q25.3 |
|
Type of mutation |
Point mutations |
|
Mutant gene product |
Mutant skeletal muscle sodium channel (SCN4); possibly other mutant gene products; allelic variant of paramyotonia congenita |
|
Clinical features |
Episodic muscle weakness |
|
Detection method |
Linkage analysis, direct detection of mutation |
|
Disease |
Malignant hyperthermia |
|
Frequency |
1 : 1,000–10,000; anesthesia incidents: 1 : 15,000 for children, 1 : 100,000 for adults |
|
MIM |
145600 and 8 additional loci |
|
Inheritance |
Mostly autosomal dominant, some recessive and new mutations |
|
Chromosomal location |
19q13.1 and other loci |
|
Type of mutation |
Point mutations |
|
Mutant gene product |
Altered ”ryanodine receptor” (RYR1) and other gene products |
|
Clinical features |
Crisis: tachycardia, muscle spasm, and increased temperature due to increased intramuscular calcium ion concentration |
|
Detection method |
Caffeine-halothane contracture test on muscle biopsies, mutation analysis on the RYR gene, sequencing |
|
Disease |
Myoadenylate deaminase deficiency |
|
Frequency |
High (1 : 500), but minor clinical features |
|
MIM |
102770 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
1p21–p13 |
|
Type of mutation |
Missense mutations |
|
Mutant gene product |
Inactive adenosine monophosphate deaminase (AMPD1 gene) |
|
Clinical features |
Early skeletal muscle fatigue, cramps, myalgia |
|
Detection method |
Direct detection of mutation |
|
Disease |
Myotonic dystrophy |
|
Frequency |
1 : 50,000–10,000 |
|
MIM |
160900 |
|
Inheritance |
Autosomal dominant (anticipation) |
|
Chromosomal location |
19q13.2–q13.3 |
|
Type of mutation |
Triplet repeat expansion |
|
Mutant gene product |
DMPK gene: myotonin protein kinase |
|
Clinical features |
Muscle atrophy with myotonia; other manifestations such as diabetes and cataracts |
|
Detection method |
PCR and electrophoresis |
|
Disease |
Paramyotonia congenita |
|
Frequency |
Rare |
|
MIM |
168300 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
17q23.3 |
|
Type of mutation |
Point mutations |
|
Mutant gene product |
(Temperature-sensitive?) mutations in the skeletal muscle sodium channel (SCN4); possibly other mutant gene products; allelic variant of hyperkalemic periodic paralysis |
|
Clinical features |
Muscle weakness after cooling or exercise |
|
Detection method |
Sequencing |
Table 39-9 Gene regions in genetic diseases (neurodegenerative diseases – selection)
|
Affected organs |
Neurodegenerative diseases |
|
Disease |
Alzheimer’s disease |
|
Frequency |
1 : 5,000 |
|
MIM |
104300, 104760, 107741, 104311, and others |
|
Inheritance |
Complex, autosomal dominant |
|
Chromosomal location |
20p, 17q23, 1q31–q42, 10q24, and other loci |
|
Type of mutation |
Point mutations, missense mutations |
|
Mutant gene product |
Apolipoprotein E, presenilin I and II, amyloid precursor protein, alpha-synuclein, mitochondrial transcripts, STM2 |
|
Clinical features |
Progressive diffuse brain atrophy, dementia |
|
Detection method |
Linkage analysis, direct detection of mutation, sequencing, psychological testing |
|
Disease |
CADASIL (hereditary multi-infarct dementia) |
|
Frequency |
Rare |
|
MIM |
125310 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
19p13.2–p13.1 |
|
Type of mutation |
Point mutations |
|
Mutant gene product |
Mutations in the NOTCH3 gene |
|
Clinical features |
Multiple infarcts, hemiplegia, intellectual deterioration, structural anomalies of the nervous system, speech difficulties |
|
Detection method |
Immunostaining, sequencing |
|
Disease |
Angelman syndrome |
|
Frequency |
1 : 10,000–20,000 |
|
MIM |
105830 |
|
Inheritance |
Mostly new mutations, autosomal dominant with imprinting |
|
Chromosomal location |
15q11–q13 |
|
Type of mutation |
Loss of function (due to deletion) of the maternal chromosome fragment or uniparental disomy |
|
Mutant gene product |
Absent small nuclear ribonucleoprotein polypeptide N or UBE3A (ubiquitin protein ligase) gene |
|
Clinical features |
Mental retardation, seizures, impaired speech development, protruding tongue, episodic laughter |
|
Detection method |
PCR analysis of microsatellite polymorphisms, methylation pattern, Southern blot |
|
Disease |
Huntington’s disease |
|
Frequency |
1 : 20,000 |
|
MIM |
143100 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
4p16.3 |
|
Type of mutation |
Triplet repeat expansion (anticipation) |
|
Mutant gene product |
Altered protein ”huntingtin” |
|
Clinical features |
Coordination problems, cognitive and behavioral impairment, chorea, dystonia |
|
Detection method |
PCR and electrophoresis |
|
Disease |
CMT (Charcot-Marie-Tooth disease), many types |
|
Frequency |
Type 1A: 1 : 4,000; 1B: 1 : 5,000–10,000; 1X: 1 : 25,000 |
|
MIM |
1A: 118220, 1B: 118200, 1X: 302800, and others |
|
Inheritance |
Autosomal dominant or X-linked |
|
Chromosomal location |
1A: 17p11.2; 1B: 1q22–p23; 1X: Xq13.1, and others |
|
Type of mutation |
1A: duplications; 1B, X: point mutations |
|
Mutant gene product |
Dosage effect (duplication) of PMP22 (peripheral myelin protein 22) for type 1 A; mutant myelin protein zero (P0) or gene product for Cx32 (connexin) gene product for type 1B and 1X |
|
Clinical features |
Muscle weakness and atrophy; segment demyelination with peripheral neuropathy; deletion of PMP22 causes HNPP (hereditary neuropathy with pressure palsies) |
|
Detection method |
Southern blot, sequencing |
|
Disease |
Dentatorubral pallidoluysian atrophy |
|
Frequency |
Rare outside Japan |
|
MIM |
125370 |
|
Inheritance |
Autosomal dominant (anticipation) |
|
Chromosomal location |
12p13.31 |
|
Type of mutation |
Triplet repeat expansion |
|
Mutant gene product |
DRPL gene with unknown function |
|
Clinical features |
Myoclonic epilepsy, dementia, ataxia, degeneration of the dentatorubral and pallidoluysian system. DD: Huntington’s disease |
|
Detection method |
PCR, Southern blot |
|
Disease |
Dopa-responsive dystonia (DRD) |
|
Frequency |
Rare |
|
MIM |
128230, 605407 |
|
Inheritance |
Autosomal dominant, autosomal recessive |
|
Chromosomal location |
14q22.1–q22.2, 11p15.5 |
|
Type of mutation |
Splice mutations, missense mutations |
|
Mutant gene product |
Loss of function of GTP cyclohydrolase I leads to lack of tetrahydrobiopterin (BH4) |
|
Clinical features |
Progressive dystonia, parkinsonism with dramatic response to levodopa therapy |
|
Detection method |
PCR, sequencing, linkage analysis |
|
Disease |
Dystonia-parkinsonism syndrome (X-linked), torsion dystonia |
|
Frequency |
Relatively high in the Philippines |
|
MIM |
314250 |
|
Inheritance |
X-linked |
|
Chromosomal location |
Xq13.1 |
|
Type of mutation |
Mutations in the DYT3 gene TAF1 |
|
Mutant gene product |
Dystonia torsion 3 (DYT3) gene product |
|
Clinical features |
Progressive dystonia, sometimes with parkinsonism |
|
Detection method |
Linkage analysis |
|
Disease |
Fragile X (FraX A) syndrome |
|
Frequency |
1 : 2,000 (men), 1 : 4,000 (women) |
|
MIM |
309550 |
|
Inheritance |
X-linked semi-dominant (anticipation) |
|
Chromosomal location |
Xq27.3 |
|
Type of mutation |
Triplet repeat expansion |
|
Mutant gene product |
FMR1 gene |
|
Clinical features |
Mental retardation, characteristic facies, macroorchidism |
|
Detection method |
PCR, Southern blot |
|
Disease |
Friedreich’s ataxia |
|
Frequency |
1 : 50,000 |
|
MIM |
229300, 601992 |
|
Inheritance |
Autosomal recessive |
|
Chromosomal location |
9q13, 9p23-p11 |
|
Type of mutation |
Triplet repeat expansion |
|
Mutant gene product |
Reduced amount of X25 gene product ”frataxin” |
|
Clinical features |
Cerebellar ataxia with speech impairment, pes cavus caused by muscle weakness, scoliosis, cardiomyopathy. DD: abetalipoproteinemia |
|
Detection method |
PCR, Southern blot |
|
Disease |
Kallmann syndrome |
|
Frequency |
1 : 10,000 (but 5% of all ichthyosis X patients) |
|
MIM |
308700, 147950, 244200 |
|
Inheritance |
X-linked; also autosomal dominant and autosomal recessive forms |
|
Chromosomal location |
Xp22.3, autosomal dominant: 8p11.2–p11.1 |
|
Type of mutation |
Translocations, deletions |
|
Mutant gene product |
Defective KAL1, FGR1, FGF8, PROKR2, PROK2, and others |
|
Clinical features |
Reduced secretion of gonadotropin-releasing hormone resulting in hypogonadism; anosmia (agenesis of olfactory bulb) |
|
Detection method |
Quantitative sex hormone determination, tests of olfactory function, Southern blot, PCR |
|
Disease |
Lissencephaly, isolated |
|
Frequency |
Rare |
|
MIM |
607432 |
|
Inheritance |
Mostly new mutations |
|
Chromosomal location |
17p13.3 |
|
Type of mutation |
Mostly large deletions |
|
Mutant gene product |
Gene dosage effect due to deletion of LIS1 gene (role in signal transduction?, involved in cerebral development) |
|
Clinical features |
”Smooth brain”, agyria, pachygyria, severe retardation, characteristic facies |
|
Detection method |
Direct detection of the gene deletion by PCR and VNTRs, FISH |
|
Disease |
Machado-Joseph disease (spinocerebellar ataxia 3, SCA 3) |
|
Frequency |
Rare, but the most common autosomal dominant degenerative disorder |
|
MIM |
109150 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
14q24.3–q32 |
|
Type of mutation |
Triplet repeat expansion |
|
Mutant gene product |
Polyglutamine induced neurotoxicity |
|
Clinical features |
(Parkinson-like) ataxia, reduced eye mobility, neuronal degeneration |
|
Detection method |
Electrooculogram, PCR and gel electrophoresis |
|
Disease |
Miller-Dieker syndrome |
|
Frequency |
Rare |
|
MIM |
247200 |
|
Inheritance |
Mostly new mutations |
|
Chromosomal location |
17p13.3 |
|
Type of mutation |
Mostly large deletions |
|
Mutant gene product |
Gene dosage effect due to deletion of LIS1 gene (role in signal transduction?, involved in cerebral development) |
|
Clinical features |
Lissencephaly (see above) with characteristic facial features (prominent forehead, short nose, small jaw) |
|
Detection method |
PCR, FISH |
|
Disease |
Spinal muscular atrophy (autosomal recessive) (SMA 1) |
|
Frequency |
1 : 10,000 |
|
MIM |
253300 |
|
Inheritance |
Autosomal recessive |
|
Chromosomal location |
5q11.2–q13.3 |
|
Type of mutation |
Large deletions |
|
Mutant gene product |
Loss of function of SMN (survival motor neuron) and NAIP (neuronal apoptosis inhibitory protein) gene products |
|
Clinical features |
Progressive atrophy, beginning with pelvis, thigh, and trunk muscles; death from respiratory paralysis in early childhood |
|
Detection method |
Detection of deletions with PCR |
|
Disease |
Spinal and bulbar muscular atrophy (Kennedy’s disease, SMAX 1) |
|
Frequency |
1 : 50,000 (men only) |
|
MIM |
313200 |
|
Inheritance |
X-linked recessive |
|
Chromosomal location |
Xq11.2–q12 |
|
Type of mutation |
Triplet repeat expansion |
|
Mutant gene product |
Mutant androgen receptor |
|
Clinical features |
Bulbar atrophic paresis (atrophy of the tongue), gynecomastia, often diabetes mellitus, disorders of lipid metabolism, testicular atrophy |
|
Detection method |
PCR and gel electrophoresis |
|
Disease |
Spinocerebellar ataxias (SCA1, SCA2, SCA3/Machado-Joseph disease, SCA4, SCA5, and others (up to SCA41) |
|
Frequency |
1 : 10,000–100,000 |
|
MIM |
164400, 183090, 109150, 600223, 600224 |
|
Inheritance |
Autosomal dominant (anticipation) |
|
Chromosomal location |
SCA1: 6p23; SCA2: 12q24; SCA3: 14q24.3–q31; SCA4: 16q22.1; SCA5: 11p11-q11 |
|
Type of mutation |
Triplet repeat expansions |
|
Mutant gene product |
Altered gene products |
|
Clinical features |
Variable neurological manifestations: late-onset cerebellar ataxia, muscle rigidity, bradykinesia, dysarthria, muscle atrophy, and dementia |
|
Detection method |
PCR and gel electrophoresis |
Table 39-10 Gene regions in genetic diseases (kidney disorders – selection)
|
Affected organs |
Kidney disorders |
|
Disease |
Polycystic kidney disease |
|
Frequency |
1 : 1,250 |
|
MIM |
PKD1: 173900, 601313; PKD2: 173910; PKD3: 600666 |
|
Inheritance |
PKD1: autosomal recessive; PKD2, PKD3: autosomal dominant |
|
Chromosomal location |
PKD1: 16p13.3–p13.12; PKD2: 4q21–q23; PKD3: ? |
|
Type of mutation |
Deletions, insertions, rearrangements |
|
Mutant gene product |
PKD1: altered membrane protein polycystin (binds to PKD2) |
|
Clinical features |
Bilateral kidney cysts, significant renal enlargement |
|
Detection method |
Sequencing, linkage analysis, DGGE |
|
Disease |
Nephrogenic diabetes insipidus |
|
Frequency |
Rare |
|
MIM |
304800 |
|
Inheritance |
X-linked (also autosomal dominant and autosomal recessive forms) |
|
Chromosomal location |
Xq28 |
|
Type of mutation |
Frameshift mutations, deletions |
|
Mutant gene product |
Mutant vasopressin (V2) receptor; no activation of adenylate cyclase; mutant aquaporin |
|
Clinical features |
Tubular cells are insensitive to vasopressin, resulting in polyuria, hyposthenuria, and polydipsia |
|
Detection method |
History, linkage analysis, direct detection of mutation |
Table 39-11 Gene regions in genetic diseases (impaired oxygen transport – selection)
|
Affected organs |
Impaired oxygen transport |
|
Disease |
Hb defects: structural variants of globin, thalassemias |
|
Frequency |
Africa: Carrier rate (CR) for HbS up to 20%; CR for HbC up to 3%; CR for HbE up to 20%; CR for α-thalassemia up to 30%. Asia: CR for HbD up to 20%. Europe: CR for β-thalassemia up to 10%. |
|
MIM |
Beta locus: 141900; alpha locus: 141800 |
|
Inheritance |
Autosomal recessive |
|
Chromosomal location |
α globin: 16pter-p13.3; β globin: 11p15.5 |
|
Type of mutation |
Deletions, point mutations, mutations in control regions, splice mutations, and more |
|
Mutant gene product |
Altered or decreased α or β globin |
|
Clinical features |
α-thal.: hemolytic anemia; β-thal.: impaired erythrocyte maturation and function, hemolytic anemia; HbS: sickle cell anemia; HbC, HbE: mild hemolytic anemia; HbD: hemolytic tendency |
|
Detection method |
Direct detection of mutation |
Table 39-12 Gene regions in genetic diseases (metabolic diseases – selection)
|
Affected organs |
Metabolic diseases |
|
Disease |
Thyroid hormone resistance |
|
Frequency |
Rare |
|
MIM |
145650 |
|
Inheritance |
Autosomal dominant, autosomal recessive |
|
Chromosomal location |
3p24.3 |
|
Type of mutation |
Point mutations |
|
Mutant gene product |
Mutant thyroid hormone receptor β (TRβ, ERBA) |
|
Clinical features |
Psychomotor retardation, possibly goiter |
|
Detection method |
Serum level of T3 and T4, direct detection of mutation |
|
Affected organs |
Metabolic diseases – Enzymes |
|
Disease |
Lesch-Nyhan syndrome |
|
Frequency |
Rare |
|
MIM |
300322 |
|
Inheritance |
X-linked recessive |
|
Chromosomal location |
Xq26–q27.2 |
|
Type of mutation |
Deletions, point mutations, splice-junction mutations |
|
Mutant gene product |
Absent or defective hypoxanthine-guanine phosphoribosyltransferase (HGPRT) |
|
Clinical features |
Abnormal dopaminergic function, hyperuricemia, choreoathetosis, mental retardation, self-mutilation |
|
Detection method |
HGPRT assay, Southern blot, sequencing |
|
Disease |
Ornithine transcarbamylase (OTC) deficiency |
|
Frequency |
1 : 100,000 |
|
MIM |
311250 |
|
Inheritance |
X-linked |
|
Chromosomal location |
Xp21.1 |
|
Type of mutation |
Gene deletions, missense and nonsense mutations |
|
Mutant gene product |
Absent OTC activity prevents the production of citrulline from ornithine |
|
Clinical features |
Reduced urea production, hyperammonemia, ammonia intoxication |
|
Detection method |
Mass spectrometry, Cytogenetics |
|
Disease |
PKU (phenylketonuria) |
|
Frequency |
1 : 10,000–100,000 |
|
MIM |
261600 |
|
Inheritance |
Autosomal recessive |
|
Chromosomal location |
12q24.1 |
|
Type of mutation |
Various mutations |
|
Mutant gene product |
Absent enzyme activity (phenylalanine hydroxylase) leading to insufficient tyrosine production |
|
Clinical features |
Elevated phenylalanine levels resulting in cognitive impairment, demyelination |
|
Detection method |
Screening: plasma concentration of phenylalanine; diagnosis: detection of mutation |
|
Affected organs |
Metabolic diseases – Hormones |
|
Disease |
Congenital adrenal hyperplasia describes a group of diseases |
|
Frequency |
1 : 5,000 |
|
MIM |
201910 and others |
|
Inheritance |
Autosomal recessive |
|
Chromosomal location |
6p21.3 and others |
|
Type of mutation |
Point mutations, deletions |
|
Mutant gene product |
Absent or altered steroid hydroxylases, resulting in reduced amounts of deoxycortisol and increased amounts of progesterone |
|
Clinical features |
Virilization, severe forms present with salt wasting (cortisol deficiency), hyperplasia of the adrenal cortex |
|
Detection method |
Gas chromatography, Southern blot, PCR, Sequenching |
|
Disease |
Androgen insensitivity (testicular feminization) |
|
Frequency |
1 : 10,000 |
|
MIM |
300068 |
|
Inheritance |
X-linked, recessive |
|
Chromosomal location |
Xq1.1–q1.2 |
|
Type of mutation |
Point mutations, gene deletions |
|
Mutant gene product |
Absent or mutant androgen receptor |
|
Clinical features |
Male pseudohermaphroditism with variable female phenotype and XY karyotype |
|
Detection method |
Karyotyping, analysis of plasma steroids, evaluation of the genitourinary tract, possibly molecular biological methods (linkage analysis, direct detection of mutation) |
|
Affected organs |
Metabolic diseases – Lipids |
|
Disease |
Apolipoprotein B deficiency (abetalipoproteinemia) |
|
Frequency |
1 : 3,000 |
|
MIM |
107730 |
|
Inheritance |
Autosomal dominant |
|
Chromosomal location |
2p24 |
|
Type of mutation |
Nonsense mutations, deletions, mutations in regulatory sequences |
|
Mutant gene product |
Decreased production of apolipoprotein B-100 |
|
Clinical features |
Heterozygotes mildly affected; homozygotes show fat malabsorption, chronic diarrhea, neurological defects, retinitis pigmentosa, low plasma concentrations of VLDL and chylomicrons |
|
Detection method |
Biochemical assays, direct detection of mutation |
Table 39-13 Gene regions in genetic diseases (metabolic diseases – selection)
|
Affected organs |
Metabolic diseases – Lysosome function |
|
Disease |
Hunter syndrome – mucopolysaccharidosis type II |
|
Frequency |
1 : 100,000 |
|
MIM |
309900 |
|
Inheritance |
X-linked recessive |
|
Chromosomal location |
Xq28 |
|
Type of mutation |
Point mutations, large deletions |
|
Mutant gene product |
Loss of function of iduronate sulfatase |
|
Clinical features |
Defective breakdown of dermatan sulfate and heparan sulfate; progressive disorder affecting nearly all organs; growth disorders (dysostosis multiplex), retardation, hydrocephalus of varying degree; life expectancy in the most severe form approx. 15 years |
|
Detection method |
Sequencing |
|
Affected organs |
Metabolic diseases – Membrane transport |
|
Disease |
Cystic fibrosis |
|
Frequency |
Caucasians: 1 : 2,500; others, rare |
|
MIM |
219700 |
|
Inheritance |
Autosomal recessive |
|
Chromosomal location |
7q31.2 |
|
Type of mutation |
Point mutations, small deletions |
|
Mutant gene product |
Defective cAMP dependent chloride channel (CFTR, cystic fibrosis transmembrane conductance regulator) |
|
Clinical features |
Severe respiratory complications, pulmonary infections, pancreatic insufficiency, vas deferens defects |
|
Detection method |
Direct detection of mutations, sequencing |
|
Affected organs |
Metabolic diseases – Mitochondrial function |
|
Disease |
MCAD (medium-chain acyl-CoA dehydrogenase) deficiency |
|
Frequency |
1 : 2,000–20,000 |
|
MIM |
201450, (short chain: 606885) |
|
Inheritance |
Autosomal recessive |
|
Chromosomal location |
1p31, (12q22-qter) |
|
Type of mutation |
Point mutations (> 90% of all cases are caused by one mutation) |
|
Mutant gene product |
Absent medium-chain acyl-CoA dehydrogenase (β-oxidation of fatty acids) |
|
Clinical features |
Hypoketosis, hypoglycemia after fasting; first episode often fatal (DD: sudden infant death syndrome, Reye syndrome); accumulation of fatty acid intermediates in plasma and urine |
|
Detection method |
Biochemical analysis of plasma acylcarnitine or urinary acylglycine, direct detection of mutation |
|
Affected organs |
Metabolic diseases – Peroxisome function |
|
Disease |
Adrenoleukodystrophy (ALD) Two forms exist: neonatal ALD (N-ALD), X-linked ALD (X-ALD) |
|
Frequency |
1 : 100,000 |
|
MIM |
N-ALD: 202370; X-ALD: 300100 |
|
Inheritance |
Autosomal recessive or X-linked |
|
Chromosomal location |
Xq28 and several other gene loci |
|
Type of mutation |
?, X: small deletions and point mutations in the ABCD1 gene |
|
Mutant gene product |
Various genes, X: very-long-chain fatty acid (VLCFA)-CoA synthetase |
|
Clinical features |
Lack of peroxisomes in liver cells; severely reduced plasmalogen synthesis; increased bile acid intermediaries for N-ALD; accumulation of long-chain fatty acids for both N-ALD and X-ALD; pathological changes in the brain, kidneys, adrenals, liver, eyes, bones, and other organs |
|
Detection method |
Biochemical analysis of VLCFA, sequencing |
|
Affected organs |
Metabolic diseases – Protease inhibitors |
|
Disease |
Alpha1-antitrypsin deficiency |
|
Frequency |
1 : 7,000; heterozygosity in the % range |
|
MIM |
613490 |
|
Inheritance |
Autosomal recessive |
|
Chromosomal location |
14q32.1 |
|
Type of mutation |
Missense mutations in the SERPINA1 gene |
|
Mutant gene product |
Decreased serum α1-antitrypsin |
|
Clinical features |
Emphysema caused by unopposed leukocyte elastase activity; chronic liver injury |
|
Detection method |
Biochemical analysis of antitrypsin, electrophoretic separation of structural variants, PCR, sequenching |