Human genetics

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Human genetics is the study of inheritance as it occurs in human beings. Human genetics encompasses a variety of overlapping fields including: classical genetics, cytogenetics, molecular genetics, biochemical genetics, genomics, population genetics, developmental genetics, clinical genetics, and genetic counseling.

Contents

Genes are the common factor of the qualities of most human-inherited traits. Study of human genetics can answer questions about human nature, can help understand diseases and the development of effective treatment and help us to understand the genetics of human life. This article describes only basic features of human genetics; for the genetics of disorders please see: medical genetics.

Representation of the double helix structure of human DNA Genetica Humana - py5aal.jpg
Representation of the double helix structure of human DNA

Genetic differences and inheritance patterns

Autosomal dominant pattern, a 50/50 chance Autosomal dominant - en.svg
Autosomal dominant pattern, a 50/50 chance

Inheritance of traits for humans are based upon Gregor Mendel's model of inheritance. Mendel deduced that inheritance depends upon discrete units of inheritance, called factors or genes. [1]

Autosomal dominant inheritance

Autosomal traits are associated with a single gene on an autosome (non-sex chromosome)—they are called "dominant" because a single copy—inherited from either parent—is enough to cause this trait to appear. This often means that one of the parents must also have the same trait, unless it has arisen due to an unlikely new mutation. Examples of autosomal dominant traits and disorders are Huntington's disease and achondroplasia.

Autosomal recessive inheritance

Autosomal recessive inheritance, a 25% chance Autorecessive.svg
Autosomal recessive inheritance, a 25% chance

Autosomal recessive traits is one pattern of inheritance for a trait, disease, or disorder to be passed on through families. For a recessive trait or disease to be displayed two copies of the trait or disorder needs to be presented. The trait or gene will be located on a non-sex chromosome. Because it takes two copies of a trait to display a trait, many people can unknowingly be carriers of a disease. From an evolutionary perspective, a recessive disease or trait can remain hidden for several generations before displaying the phenotype. Examples of autosomal recessive disorders are albinism, cystic fibrosis.

X-linked and Y-linked inheritance

X-linked genes are found on the sex X chromosome. X-linked genes just like autosomal genes have both dominant and recessive types. Recessive X-linked disorders are rarely seen in females and usually only affect males. This is because males inherit their X chromosome and all X-linked genes will be inherited from the maternal side. Fathers only pass on their Y chromosome to their sons, so no X-linked traits will be inherited from father to son. Men cannot be carriers for recessive X linked traits, as they only have one X chromosome, so any X linked trait inherited from the mother will show up.

Females express X-linked disorders when they are homozygous for the disorder and become carriers when they are heterozygous. X-linked dominant inheritance will show the same phenotype as a heterozygote and homozygote. Just like X-linked inheritance, there will be a lack of male-to-male inheritance, which makes it distinguishable from autosomal traits. One example of an X-linked trait is Coffin–Lowry syndrome, which is caused by a mutation in ribosomal protein gene. This mutation results in skeletal, craniofacial abnormalities, mental retardation, and short stature.

X chromosomes in females undergo a process known as X inactivation. X inactivation is when one of the two X chromosomes in females is almost completely inactivated. It is important that this process occurs otherwise a woman would produce twice the amount of normal X chromosome proteins. The mechanism for X inactivation will occur during the embryonic stage. For people with disorders like trisomy X, where the genotype has three X chromosomes, X-inactivation will inactivate all X chromosomes until there is only one X chromosome active. Males with Klinefelter syndrome, who have an extra X chromosome, will also undergo X inactivation to have only one completely active X chromosome.

Y-linked inheritance occurs when a gene, trait, or disorder is transferred through the Y chromosome. Since Y chromosomes can only be found in males, Y linked traits are only passed on from father to son. The testis determining factor, which is located on the Y chromosome, determines the maleness of individuals. Besides the maleness inherited in the Y-chromosome there are no other found Y-linked characteristics.

Pedigrees analysis

An example of a family pedigree displaying an autosomal recessive trait Autosomal Recessive Pedigree Chart.svg
An example of a family pedigree displaying an autosomal recessive trait

A pedigree is a diagram showing the ancestral relationships and transmission of genetic traits over several generations in a family. Square symbols are almost always used to represent males, whilst circles are used for females. Pedigrees are used to help detect many different genetic diseases. A pedigree can also be used to help determine the chances for a parent to produce an offspring with a specific trait.

Four different traits can be identified by pedigree chart analysis: autosomal dominant, autosomal recessive, x-linked, or y-linked. Partial penetrance can be shown and calculated from pedigrees. Penetrance is the percentage expressed frequency with which individuals of a given genotype manifest at least some degree of a specific mutant phenotype associated with a trait.

Inbreeding, or mating between closely related organisms, can clearly be seen on pedigree charts. Pedigree charts of royal families often have a high degree of inbreeding, because it was customary and preferable for royalty to marry another member of royalty. Genetic counselors commonly use pedigrees to help couples determine if the parents will be able to produce healthy children.

Karyotype

Micrographic karyogram of a human male, showing 46 chromosomes including XY sex chromosomes Human male karyotype.gif
Micrographic karyogram of a human male, showing 46 chromosomes including XY sex chromosomes
Schematic karyogram of a human, with annotated bands and sub-bands. It shows dark and white regions on G banding. It shows 22 homologous chromosomes, both the male (XY) and female (XX) versions of the sex chromosome (bottom right), as well as the mitochondrial genome (at bottom left). Further information: Karyotype Human karyotype with bands and sub-bands.png
Schematic karyogram of a human, with annotated bands and sub-bands. It shows dark and white regions on G banding. It shows 22 homologous chromosomes, both the male (XY) and female (XX) versions of the sex chromosome (bottom right), as well as the mitochondrial genome (at bottom left).

A karyotype is a very useful tool in cytogenetics. A karyotype is picture of all the chromosomes in the metaphase stage arranged according to length and centromere position. A karyotype can also be useful in clinical genetics, due to its ability to diagnose genetic disorders. On a normal karyotype, aneuploidy can be detected by clearly being able to observe any missing or extra chromosomes. [1]

Giemsa banding, g-banding, of the karyotype can be used to detect deletions, insertions, duplications, inversions, and translocations. G-banding will stain the chromosomes with light and dark bands unique to each chromosome. A FISH, fluorescent in situ hybridization, can be used to observe deletions, insertions, and translocations. FISH uses fluorescent probes to bind to specific sequences of the chromosomes that will cause the chromosomes to fluoresce a unique color. [1]

Genomics

Genomics is the field of genetics concerned with structural and functional studies of the genome. [1] A genome is all the DNA contained within an organism or a cell including nuclear and mitochondrial DNA. The human genome is the total collection of genes in a human being contained in the human chromosome, composed of over three billion nucleotides. [2] In April 2003, the Human Genome Project was able to sequence all the DNA in the human genome, and to discover that the human genome was composed of around 20,000 protein coding genes.

Medical genetics

Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics is the application of genetics to medical care. It overlaps human genetics, for example, research on the causes and inheritance of genetic disorders would be considered within both human genetics and medical genetics, while the diagnosis, management, and counseling of individuals with genetic disorders would be considered part of medical genetics.

Population genetics

Population genetics is the branch of evolutionary biology responsible for investigating processes that cause changes in allele and genotype frequencies in populations based upon Mendelian inheritance. [3] Four different forces can influence the frequencies: natural selection, mutation, gene flow (migration), and genetic drift. A population can be defined as a group of interbreeding individuals and their offspring. For human genetics the populations will consist only of the human species. The Hardy–Weinberg principle is a widely used principle to determine allelic and genotype frequencies.

Mitochondrial DNA

In addition to nuclear DNA, humans (like almost all eukaryotes) have mitochondrial DNA. Mitochondria, the "power houses" of a cell, have their own DNA. Mitochondria are inherited from one's mother, and their DNA is frequently used to trace maternal lines of descent (see mitochondrial Eve). Mitochondrial DNA is only 16kb in length and encodes for 62 genes.

XY Chromosomes A region in the pseudoautosomal region of the short arms of the X- and Y-chromosome.jpg
XY Chromosomes

Genes and sex

The XY sex-determination system is the sex-determination system found in humans, most other mammals, some insects ( Drosophila ), and some plants ( Ginkgo ). In this system, the sex of an individual is determined by a pair of sex chromosomes (gonosomes). Females have two of the same kind of sex chromosome (XX), and are called the homogametic sex. Males have two distinct sex chromosomes (XY), and are called the heterogametic sex.

X-linked traits

Sex linkage is the phenotypic expression of an allele related to the chromosomal sex of the individual. This mode of inheritance is in contrast to the inheritance of traits on autosomal chromosomes, where both sexes have the same probability of inheritance. Since humans have many more genes on the X than the Y, there are many more X-linked traits than Y-linked traits. However, females carry two or more copies of the X chromosome, resulting in a potentially toxic dose of X-linked genes. [4]

To correct this imbalance, mammalian females have evolved a unique mechanism of dosage compensation. In particular, by way of the process called X-chromosome inactivation (XCI), female mammals transcriptionally silence one of their two Xs in a complex and highly coordinated manner. [4]

X-link dominantX-link recessiveReferences
Alport syndrome Absence of blood in urine
Coffin–Lowry syndrome No cranial malformations
Colour vision Colour blindness
Normal clotting factor Haemophilia A & B
Strong muscle tissue Duchenne muscular dystrophy
fragile X syndrome Normal X chromosome
Aicardi syndrome Absence of brain defects
Absence of autoimmunity IPEX syndrome
Xg blood type Absence of antigen
Production of GAGs Hunter syndrome
Normal muscle strength Becker's Muscular Dystrophy
Unaffected body Fabry's disease
No progressive blindness Choroideremia
No kidney damage Dent's disease
Rett syndrome No microcephaly
Production of HGPRT Lesch–Nyhan syndrome
High levels of copper Menkes disease
Normal immune levels Wiskott–Aldrich syndrome
Focal dermal hypoplasia Normal pigmented skin
Normal pigment in eyes Ocular albinism
Vitamin D resistant rickets Absorption of Vitamin D
Synesthesia Non colour perception

Human traits with possible monogenic or oligogenic inheritance patterns

DominantRecessiveReferences
Low heart rate High heart rate [5]
Widow's peak straight hair line [6] [7]
ocular hypertelorism Hypotelorism
Normal digestive muscle POLIP syndrome
Facial dimples *No facial dimples [8] [9]
Able to taste PTC Unable to taste PTC [10]
Unattached (free) earlobe Attached earlobe [8] [11] [12]
Clockwise hair direction (left to right) Counter-Clockwise hair direction (right to left) [13]
Cleft chin smooth chin [14]
No progressive nerve damage Friedreich's ataxia
Ability to roll tongue (Able to hold tongue in a U shape)No ability to roll tongue
extra finger or toe Normal five fingers and toes
Straight Thumb Hitchhiker's Thumb
Freckles No freckles [8] [15]
Wet-type earwax Dry-type earwax [11] [16]
Normal flat palm Cenani Lenz syndactylism
shortness in fingers Normal finger length
Webbed fingers Normal separated fingers
Roman nose No prominent bridge [17]
Marfan's syndrome Normal body proportions [18]
Huntington's disease No nerve damage [19]
Normal mucus lining Cystic fibrosis [20]
Photic sneeze reflex No ACHOO reflex [21]
Forged chinReceding chin [17]
White ForelockDark Forelock [22]
Ligamentous angustus Ligamentous Laxity [23]
Ability to eat sugar Galactosemia [24]
Total leukonychia and Bart pumphrey syndromepartial leukonychia [25]
Absence of fish-like body odour Trimethylaminuria [26]
Primary Hyperhidrosis little sweating in hands [27]
Lactose persistence * Lactose intolerance * [28]
Prominent chin (V-shaped)less prominent chin (U-shaped) [29]
Acne prone Clear complexion [30]
Normal height Cartilage–hair hypoplasia

Disabling conditions

Genetic
Chromosomal

EffectSourceReferences
Down syndrome Additional 21st chromosome [31]
Cri du chat syndrome Partial deletion of a chromosome in the B Group [32]
Klinefelter syndrome One or more extra sex chromosome(s) [33]
Turner syndrome Rearrangement of one or both X chromosomes, deletion of part of the second X chromosome, presence of part of a Y chromosome [34]

[35]

See also

Related Research Articles

An allele, or allelomorph, is a variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule.

<span class="mw-page-title-main">Autosome</span> Any chromosome other than a sex chromosome

An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal pairs, which may have different structures. The DNA in autosomes is collectively known as atDNA or auDNA.

<span class="mw-page-title-main">Genetic disorder</span> Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a specific gene depends on the number of copies of each chromosome found in that species, also referred to as ploidy. In diploid species like humans, two full sets of chromosomes are present, meaning each individual has two alleles for any given gene. If both alleles are the same, the genotype is referred to as homozygous. If the alleles are different, the genotype is referred to as heterozygous.

<span class="mw-page-title-main">Heredity</span> Passing of traits to offspring from the species parents or ancestor

Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic information of their parents. Through heredity, variations between individuals can accumulate and cause species to evolve by natural selection. The study of heredity in biology is genetics.

Online Mendelian Inheritance in Man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits, with a particular focus on the gene-phenotype relationship. As of 28 June 2019, approximately 9,000 of the over 25,000 entries in OMIM represented phenotypes; the rest represented genes, many of which were related to known phenotypes.

<span class="mw-page-title-main">Immunodeficiency–centromeric instability–facial anomalies syndrome</span> Medical condition

ICF syndrome is a very rare autosomal recessive immune disorder.

<span class="mw-page-title-main">X-linked recessive inheritance</span> Mode of inheritance

X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males and in females who are homozygous for the gene mutation, see zygosity. Females with one copy of the mutated gene are carriers.

<span class="mw-page-title-main">Sex linkage</span> Sex-specific patterns of inheritance

Sex linked describes the sex-specific reading patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, X-linked dominant and Y-linked. The inheritance and presentation of all three differ depending on the sex of both the parent and the child. This makes them characteristically different from autosomal dominance and recessiveness.

<span class="mw-page-title-main">Non-Mendelian inheritance</span> Type of pattern of inheritance

Non-Mendelian inheritance is any pattern in which traits do not segregate in accordance with Mendel's laws. These laws describe the inheritance of traits linked to single genes on chromosomes in the nucleus. In Mendelian inheritance, each parent contributes one of two possible alleles for a trait. If the genotypes of both parents in a genetic cross are known, Mendel's laws can be used to determine the distribution of phenotypes expected for the population of offspring. There are several situations in which the proportions of phenotypes observed in the progeny do not match the predicted values.

Genetics, a discipline of biology, is the science of heredity and variation in living organisms.

<span class="mw-page-title-main">Genetic analysis</span>

Genetic analysis is the overall process of studying and researching in fields of science that involve genetics and molecular biology. There are a number of applications that are developed from this research, and these are also considered parts of the process. The base system of analysis revolves around general genetics. Basic studies include identification of genes and inherited disorders. This research has been conducted for centuries on both a large-scale physical observation basis and on a more microscopic scale. Genetic analysis can be used generally to describe methods both used in and resulting from the sciences of genetics and molecular biology, or to applications resulting from this research.

<span class="mw-page-title-main">X-linked dominant inheritance</span> Mode of inheritance

X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome. As an inheritance pattern, it is less common than the X-linked recessive type. In medicine, X-linked dominant inheritance indicates that a gene responsible for a genetic disorder is located on the X chromosome, and only one copy of the allele is sufficient to cause the disorder when inherited from a parent who has the disorder. In this case, someone who expresses an X-linked dominant allele will exhibit the disorder and be considered affected.

<span class="mw-page-title-main">Sex chromosome</span> Chromosome that differs from an ordinary autosome in form, size, and behavior

Sex chromosomes are chromosomes that carry the genes that determine the sex of an individual. The human sex chromosomes are a typical pair of mammal allosomes. They differ from autosomes in form, size, and behavior. Whereas autosomes occur in homologous pairs whose members have the same form in a diploid cell, members of an allosome pair may differ from one another.

The following outline is provided as an overview of and topical guide to genetics:

Pseudodominance is the situation in which the inheritance of a recessive trait mimics a dominant pattern.

<span class="mw-page-title-main">Hereditary carrier</span> Organism with a recessive genetic allele that does not display the recessive trait

A hereditary carrier, is a person or other organism that has inherited a recessive allele for a genetic trait or mutation but usually does not display that trait or show symptoms of the disease. Carriers are, however, able to pass the allele onto their offspring, who may then express the genetic trait.

An obligate carrier is an individual who may be clinically unaffected but who must carry a gene mutation based on analysis of the family history; usually applies to disorders inherited in an autosomal recessive and X-linked recessive manner.

Oligogenic inheritance describes a trait that is influenced by a few genes. Oligogenic inheritance represents an intermediate between monogenic inheritance in which a trait is determined by a single causative gene, and polygenic inheritance, in which a trait is influenced by many genes and often environmental factors.

Mendelian traits behave according to the model of monogenic or simple gene inheritance in which one gene corresponds to one trait. Discrete traits with simple Mendelian inheritance patterns are relatively rare in nature, and many of the clearest examples in humans cause disorders. Discrete traits found in humans are common examples for teaching genetics.

References

  1. 1 2 3 4 Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. (2007). Genetics in Medicine (7th ed.). Philadelphia: Saunders.
  2. ↑ "Glossary". Genetics Home Reference. U.S. National Library of Medicine. 14 March 2008.
  3. ↑ Freeman, Scott; Jon C., Herron (2007). "Evolutionary Analysis" (4th ed.). Upper Saddle River: Pearson:Prentice Hall.
  4. 1 2 Ahn, J.; Lee, J. (2008). "X Chromosome Inactivation". SciTable. Nature Education.
  5. ↑ Calkins, Hugh. "Can Sinus Bradycardia Be Inherited?" . NEJM Journal Watch. Massachusetts Medical Society.
  6. ↑ Campbell, Neil; Reece, Jane (2005). Biology. San Francisco: Benjamin Cummings. p. 265. ISBN   0-07-366175-9.
  7. ↑ McKusick, Victor A. (10 February 2009). "Widow's Peak". Online Mendelian Inheritance in Man. Johns Hopkins University. 194000. Archived from the original on 9 December 2015.
  8. 1 2 3 "Genetics/Reproduction". ScienceNet – Life Science. Singapore Science Centre. Archived from the original on 2003-09-25.
  9. ↑ McKusick, Victor A. (25 June 1994). "Dimples, Facial". Online Mendelian Inheritance in Man. Johns Hopkins University. 126100. Archived from the original on 9 April 2019.
  10. ↑ Wooding, Stephen (28 June 2004). "Natural selection at work in genetic variation to taste". Medical News Today. Archived from the original on 2007-12-13.
  11. 1 2 Cruz-Gonzalez, L.; Lisker, R. (1982). "Inheritance of ear wax types, ear lobe attachment and tongue rolling ability". Acta Anthropogenet. 6 (4): 247–54. PMID   7187238.
  12. ↑ McKusick, Victor A.; Lopez, A (30 July 2010). "Earlobe Attachment, Attached vs. Unattached". Online Mendelian Inheritance in Man. Johns Hopkins University. 128900.[ permanent dead link ]
  13. ↑ McDonald, John H. (8 December 2011). "Hair Whorl". Myths of Human Genetics. University of Delaware.
  14. ↑ McKusick, Victor A. (23 March 2013). "Cleft Chin". Online Mendelian Inheritance in Man. Johns Hopkins University. 119000. Archived from the original on 29 April 2017.
  15. ↑ Xue-Jun Zhang; et al. (2004). "A Gene for Freckles Maps to Chromosome 4q32–q34". Journal of Investigative Dermatology. 122 (2): 286–290. doi: 10.1046/j.0022-202x.2004.22244.x . PMID   15009706.
  16. ↑ McKusick, Victor A.; O'Neill, Marla J. F. (22 November 2010). "Apocrine Gland Secretion, Variation in". Online Mendelian Inheritance in Man. Johns Hopkins University. 117800. Archived from the original on 30 April 2017.
  17. 1 2 "Mendelian Traits in Humans" (PDF). Human Genetics. San Diego Supercomputer Center (SDSC).
  18. ↑ Chen, Harold (2019-03-08). Buehler, Bruce (ed.). "Genetics of Marfan Syndrome". Medscape. WebMD LLC.
  19. ↑ Stafford, Kate; Mannor, Michael. "Mutations and Genetic Disease". Genetic Diseases. ThinkQuest. Archived from the original on 2007-01-03.
  20. ↑ "Autosomal Recessive: Cystic Fibrosis, Sickle Cell Anemia, Tay Sachs Disease". Medical Genetics. Children's Hospital of Pittsburgh. 3 February 2008. Archived from the original on 24 August 2009. Retrieved 28 September 2011.
  21. ↑ Schrock, Karen (10 January 2008). "Looking at the Sun Can Trigger a Sneeze". Scientific American. Archived from the original on 2011-03-19.
  22. ↑ "Inherited Human Traits". EdQuest. Archived from the original on 2012-02-01.
  23. ↑ Scott, C. I. (1971). "Unusual facies, joint hypermobility, genital anomaly and short stature: A new dysmorphic syndrome". Birth Defects Original Article Series. 7 (6): 240–246. PMID   5173168.
  24. ↑ Fankhauser, D. B. (2 Feb 2006). "Human Heritable Traits". University of Cincinnati Clermont College. Archived from the original on 2012-02-23.
  25. ↑ Tüzün, Yalçın; Karaku, Özge (2009). "Leukonychia" (PDF). Journal of the Turkish Academy of Dermatology. JTAD. Archived from the original (PDF) on 2016-03-03. Retrieved 2012-03-03.
  26. ↑ "Learning About Trimethylaminuria". genome.gov. National Human Genome Research Institute.
  27. ↑ Kaufmann, Horacio; et al. (April 2003). "Primary hyperhidrosis – Evidence for autosomal dominant inheritance" (PDF). Clinical Autonomic Research. 13 (2): 96–98. doi:10.1007/s10286-003-0082-x. PMID   12720093. S2CID   37824317.
  28. ↑ Bowen, R. (25 April 2009). "Lactose Intolerance (Lactase Non-Persistence)". Colorado State University.
  29. ↑ Jablecki, Donna Mae. "Variations on a Human Face" (PDF). Science Experiments on File. Facts on File.
  30. ↑ Strickland, Barbara. "Acne is a Four Letter Word". Sage Advice. Barbara Strickland. Archived from the original on 2006-02-07.
  31. ↑ "Down Syndrome". Mosby's Dictionary of Medicine, Nursing & Health Professions . Elsevier Health Sciences. Retrieved 27 September 2013.
  32. ↑ "Cri Du Chat Syndrome (Cat Cry Syndrome)". Encyclopedia of Special Education. Wiley. Retrieved 27 September 2013.
  33. ↑ "Klinefelter Syndrome". Encyclopedia of Special Education. Wiley. Retrieved 27 September 2013.
  34. ↑ Tager-Flusberg, Helen (1999). Neurodevelopmental Disorders. Massachusetts: Massachusetts Institute of Technology. p. 227. ISBN   0-262-20116-X.
  35. ↑ "Etiology". Encyclopedia of Special Education. Wiley. Retrieved 27 September 2013.

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