Genetic disorder Classification and external resources MeSH D030342
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions.
A genetic disorder may or may not be a heritable disorder. Some genetic disorders are passed down from the parents' genes, but others are always or almost always caused by new mutations or changes to the DNA. In other cases, the same disease, such as some forms of cancer, may be caused by an inherited genetic condition in some people, by new mutations in other people, and by non-genetic causes in still other people.
Single gene disorder
Prevalence of some single gene disorders Disorder Prevalence (approximate) Autosomal dominant Familial hypercholesterolemia 1 in 500 Polycystic kidney disease 1 in 1250 Neurofibromatosis Type I 1 in 2,500 Hereditary spherocytosis 1 in 5,000 Marfan syndrome 1 in 4,000  Huntington's disease 1 in 15,000  Autosomal recessive Sickle cell anemia 1 in 625
Cystic fibrosis 1 in 2,000
Lysosomal Acid Lipase (LAL) Deficiency 1 in 40,000 Tay-Sachs disease 1 in 3,000
Phenylketonuria 1 in 12,000 Mucopolysaccharidoses 1 in 25,000 Glycogen storage diseases 1 in 50,000 Galactosemia 1 in 57,000 X-linked Duchenne muscular dystrophy 1 in 7,000 Hemophilia 1 in 10,000 Values are for liveborn infants
A single gene disorder is the result of a single mutated gene. There are estimated to be over 4000 human diseases caused by single gene defects. Single gene disorders can be passed on to subsequent generations in several ways. Genomic imprinting and uniparental disomy, however, may affect inheritance patterns. The divisions between recessive and dominant types are not "hard and fast" although the divisions between autosomal and X-linked types are (since the latter types are distinguished purely based on the chromosomal location of the gene). For example, achondroplasia is typically considered a dominant disorder, but children with two genes for achondroplasia have a severe skeletal disorder that achondroplasics could be viewed as carriers of. Sickle-cell anemia is also considered a recessive condition, but heterozygous carriers have increased resistance to malaria in early childhood, which could be described as a related dominant condition. When a couple where one partner or both are sufferers or carriers of a single gene disorder and wish to have a child they can do so through IVF which means they can then have PGD (pre-implantation genetic diagnosis) to check whether the fertilised egg has had the genetic disorder passed on.
Only one mutated copy of the gene will be necessary for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. There is a 50% chance that a child will inherit the mutated gene. Conditions that are autosomal dominant sometimes have reduced penetrance, which means that although only one mutated copy is needed, not all individuals who inherit that mutation go on to develop the disease. Examples of this type of disorder are Huntington's disease, neurofibromatosis type 1, neurofibromatosis type 2, Marfan syndrome, hereditary nonpolyposis colorectal cancer, and hereditary multiple exostoses, which is a highly penetrant autosomal dominant disorder. Birth defects are also called congenital anomalies.
Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Two unaffected people who each carry one copy of the mutated gene have a 25% chance with each pregnancy of having a child affected by the disorder. Examples of this type of disorder are cystic fibrosis, sickle-cell disease, Tay-Sachs disease, Niemann-Pick disease, spinal muscular atrophy, and Roberts syndrome. Certain other phenotypes, such as wet versus dry earwax, are also determined in an autosomal recessive fashion.
X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern, with a prime example being X-linked hypophosphatemic rickets. Males and females are both affected in these disorders, with males typically being more severely affected than females. Some X-linked dominant conditions such as Rett syndrome, incontinentia pigmenti type 2 and Aicardi syndrome are usually fatal in males either in utero or shortly after birth, and are therefore predominantly seen in females. Exceptions to this finding are extremely rare cases in which boys with Klinefelter syndrome (47,XXY) also inherit an X-linked dominant condition and exhibit symptoms more similar to those of a female in terms of disease severity. The chance of passing on an X-linked dominant disorder differs between men and women. The sons of a man with an X-linked dominant disorder will all be unaffected (since they receive their father's Y chromosome), and his daughters will all inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an affected fetus with each pregnancy, although it should be noted that in cases such as incontinentia pigmenti only female offspring are generally viable. In addition, although these conditions do not alter fertility per se, individuals with Rett syndrome or Aicardi syndrome rarely reproduce.
X-linked recessive conditions are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. A woman who is a carrier of an X-linked recessive disorder (XRXr) has a 50% chance of having sons who are affected and a 50% chance of having daughters who carry one copy of the mutated gene and are therefore carriers. X-linked recessive conditions include the serious diseases Hemophilia A, Duchenne muscular dystrophy, and Lesch-Nyhan syndrome as well as common and less serious conditions such as male pattern baldness and red-green color blindness. X-linked recessive conditions can sometimes manifest in females due to skewed X-inactivation or monosomy X (Turner syndrome).
Y-linked disorders are caused by mutations on the Y chromosome. Because males inherit a Y chromosome from their fathers, every son of an affected father will be affected. Because females inherit an X chromosome from their fathers, female offspring of affected fathers are never affected.
Since the Y chromosome is relatively small and contains very few genes, there are relatively few Y-linked disorders. Often the symptoms include infertility, which may be circumvented with the help of some fertility treatments. Examples are male infertility and hypertrichosis pinnae.
This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Because only egg cells contribute mitochondria to the developing embryo, only mothers can pass on mitochondrial conditions to their children. An example of this type of disorder is Leber's hereditary optic neuropathy.
Multifactorial and polygenic (complex) disorders
Genetic disorders may also be complex, multifactorial, or polygenic, meaning that they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. Multifactorial disorders include heart disease and diabetes. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified.
On a pedigree, polygenic diseases do tend to “run in families”, but the inheritance does not fit simple patterns as with Mendelian diseases. But this does not mean that the genes cannot eventually be located and studied. There is also a strong environmental component to many of them (e.g., blood pressure).
- autoimmune diseases such as multiple sclerosis
- cleft palate
- heart disease
- inflammatory bowel disease
- mental retardation
- mood disorder
- refractive error
Prognosis and treatment of genetic disorders
- Gauchers disease is a genetic disease affecting metabolism. It is more treatable then most other genetic diseases, and can be treated with enzyme replacement therapy, medication miglustat, and bone marrow transplantion.
- Genetic epidemiology
- Inborn errors of metabolism
- List of genetic disorders
- Medical genetics
- Population groups in biomedicine
- ^ WGBH Educational Foundation
- ^ Keane MG, Pyeritz RE (May 2008). "Medical management of Marfan syndrome". Circulation 117 (21): 2802–13. doi:10.1161/CIRCULATIONAHA.107.693523. PMID 18506019. http://circ.ahajournals.org/cgi/content/full/117/21/2802.
- ^ Walker FO (2007). "Huntington's disease". Lancet 369 (9557): 218–28. doi:10.1016/S0140-6736(07)60111-1. PMID 17240289.
- ^ Kuliev A, Verlinsky Y (2005). "Preimplantation diagnosis: A realistic option for assisted reproduction and genetic practice". Curr. Opin. Obstet. Gynecol. 17 (2): 179–83. doi:10.1097/01.gco.0000162189.76349.c5. PMID 15758612. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1040-872X&volume=17&issue=2&spage=179. Retrieved 2009-04-01.
- ^ Wade, Nicholas (January 29, 2006). "Japanese Scientists Identify Ear Wax Gene". New York Times.
- ^ Yoshiura K, Kinoshita A, Ishida T, et al. (March 2006). "A SNP in the ABCC11 gene is the determinant of human earwax type". Nat. Genet. 38 (3): 324–30. doi:10.1038/ng1733. PMID 16444273.
- ^ Retinitis Pigmentosa: Treatment & Medication~treatment at eMedicine
- ^ Gaucher's disease:Treatments and drugs, eMedicine WebMD, 2009-07-11, accessed 2010-03-31.
- Public Health Genomics at CDC
- OMIM — Online Mendelian Inheritance in Man, a catalog of human genes and genetic disorders
- Genetic and Rare Diseases Information Center (GARD) Office of Rare Diseases (ORD), National Institutes of Health (NIH)
- CDC’s National Center on Birth Defects and Developmental Disabilities
- Genetic Disease Information from the Human Genome Project
Genetic disorder, protein biosynthesis: Transcription factor/coregulator deficiencies (1) Basic domains (2) Zinc finger
2.1 (Intracellular receptor): Thyroid hormone resistance · Androgen insensitivity syndrome (PAIS, MAIS, CAIS) · Kennedy's disease · PHA1AD pseudohypoaldosteronism · Estrogen insensitivity syndrome · X-linked adrenal hypoplasia congenita · MODY 1 · Familial partial lipodystrophy 3 · SF1 XY gonadal dysgenesis
2.2: Barakat syndrome · Tricho–rhino–phalangeal syndrome
2.3: Greig cephalopolysyndactyly syndrome/Pallister-Hall syndrome · Denys–Drash syndrome · Duane-radial ray syndrome · MODY 7 · MRX 89 · Townes–Brocks syndrome · Acrocallosal syndrome · Myotonic dystrophy 22.5: Autoimmune polyendocrine syndrome type 1
(3) Helix-turn-helix domains
3.1: ARX (Ohtahara syndrome, Lissencephaly X2) · HLXB9 (Currarino syndrome) · HOXD13 (SPD1 Synpolydactyly) · IPF1 (MODY 4) · LMX1B (Nail–patella syndrome) · MSX1 (Tooth and nail syndrome, OFC5) · PITX2 (Axenfeld syndrome 1) · POU4F3 (DFNA15) · POU3F4 (DFNX2) · ZEB1 (Posterior polymorphous corneal dystrophy 3, Fuchs' dystrophy 3) · ZEB2 (Mowat-Wilson syndrome)
3.3: FOXC1 (Axenfeld syndrome 3, Iridogoniodysgenesis, dominant type) · FOXC2 (Lymphedema–distichiasis syndrome) · FOXE1 (Bamforth–Lazarus syndrome) · FOXE3 (Anterior segment mesenchymal dysgenesis) · FOXF1 (ACD/MPV) · FOXI1 (Enlarged vestibular aqueduct) · FOXL2 (Premature ovarian failure 3) · FOXP3 (IPEX)3.5: IRF6 (Van der Woude syndrome, Popliteal pterygium syndrome)
(4) β-Scaffold factors
with minor groove contacts
4.2: Hyperimmunoglobulin E syndrome
4.3: Holt-Oram syndrome · Li-Fraumeni syndrome · Ulnar–mammary syndromeCleidocranial dysostosis
(0) Other transcription factors0.6: Kabuki syndrome Ungrouped Transcription coregulators Genetic disorder, membrane: Solute carrier disorders 1-10SLC1A3 (Episodic ataxia 6) · SLC2A1 (De Vivo disease) · SLC2A5 (Fructose malabsorption) · SLC2A10 (Arterial tortuosity syndrome) · SLC3A1 (Cystinuria) · SLC4A1 (Hereditary spherocytosis 4/Hereditary elliptocytosis 4) · SLC4A11 (Congenital endothelial dystrophy type 2, Fuchs' dystrophy 4) · SLC5A1 (Glucose-galactose malabsorption) · SLC5A2 (Renal glycosuria) · SLC5A5 (Thyroid dyshormonogenesis type 1) · SLC6A19 (Hartnup disease) · SLC7A7 (Lysinuric protein intolerance) · SLC7A9 (Cystinuria) 11-20 21-40 Genetic disorder, membrane: cell surface receptor deficiencies G protein-coupled receptor
(including hormone)Class AClass BClass CCASR (Familial hypocalciuric hypercalcemia)Class FFZD4 (Familial exudative vitreoretinopathy 1)
growth factor)ROR2 (Robinow syndrome) · FGFR1 (Pfeiffer syndrome, KAL2 Kallmann syndrome) · FGFR2 (Apert syndrome, Antley-Bixler syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson-Weiss syndrome) · FGFR3 (Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Muenke syndrome) · INSR (Donohue syndrome · Rabson–Mendenhall syndrome) · NTRK1 (Congenital insensitivity to pain with anhidrosis) · KIT (KIT Piebaldism, Gastrointestinal stromal tumor)
JAK-STAT TNF receptor Lipid receptor Other/ungroupedEDAR (EDAR Hypohidrotic ectodermal dysplasia) · PTCH1 (Nevoid basal cell carcinoma syndrome) · BMPR1A (BMPR1A Juvenile polyposis syndrome) · IL2RG (X-linked severe combined immunodeficiency) Genetic disorder, organelle: Peroxisomal disorders and lysosomal structural disorders (E80.3, 277.86) Peroxisome biogenesis disorder Enzyme-related Transporter-related Lysosomal Genetic disorder, organelle: Ciliopathy Structural Signaling Other/ungrouped Genetic disorder, extracellular: scleroprotein disease (excluding laminin and keratin) Collagen disease
COL2: Hypochondrogenesis · Achondrogenesis type 2 · Stickler syndrome · Marshall syndrome · Spondyloepiphyseal dysplasia congenita · Spondyloepimetaphyseal dysplasia, Strudwick type · Kniest dysplasia (see also C2/11)
COL3: Ehlers–Danlos syndrome, types 3 & 4 (Sack–Barabas syndrome)
COL4: Alport syndrome
COL7: Epidermolysis bullosa dystrophica · Recessive dystrophic epidermolysis bullosa · Bart syndrome · Transient bullous dermolysis of the newborn
COL8: Fuchs' dystrophy 1
COL10: Schmid metaphyseal chondrodysplasiaBullous pemphigoid
LamininJunctional epidermolysis bullosa · Laryngoonychocutaneous syndrome Other
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