Genetic disorder

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Genetic disorder
A boy with Down syndrome using cordless drill to assemble a book case.jpg
A boy with Down syndrome, one of the most common genetic disorders
Specialty Medical genetics
Diagram featuring examples of a disease located on each chromosome Human chromosome diseases set en.svg
Diagram featuring examples of a disease located on each chromosome

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. [1] [2] The mutation responsible can occur spontaneously before embryonic development (a de novo mutation), or it can be inherited from two parents who are carriers of a faulty gene (autosomal recessive inheritance) or from a parent with the disorder (autosomal dominant inheritance). 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 (due to their size). [3]

Contents

There are well over 6,000 known genetic disorders, [4] and new genetic disorders are constantly being described in medical literature. [5] More than 600 genetic disorders are treatable. [6] Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder. [7] Around 65% of people have some kind of health problem as a result of congenital genetic mutations. [7] Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare" (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves. [5] [8]

Genetic disorders are present before birth, and some genetic disorders produce birth defects, but birth defects can also be developmental rather than hereditary. The opposite of a hereditary disease is an acquired disease. Most cancers, although they involve genetic mutations to a small proportion of cells in the body, are acquired diseases. Some cancer syndromes, however, such as BRCA mutations, are hereditary genetic disorders. [9]

Single-gene

Prevalence of some single-gene disorders [10]
Disorder prevalence (approximate)
Autosomal dominant
Familial hypercholesterolemia 1 in 500 [11]
Myotonic dystrophy type 1 1 in 2,100 [12]
Neurofibromatosis type I 1 in 2,500 [13]
Hereditary spherocytosis 1 in 5,000
Marfan syndrome 1 in 4,000 [14]
Huntington's disease 1 in 15,000 [15]
Autosomal recessive
Sickle cell anaemia 1 in 625 [16]
Cystic fibrosis 1 in 2,000
Tay–Sachs disease 1 in 3,000
Phenylketonuria 1 in 12,000
Autosomal recessive polycystic kidney disease 1 in 20,000 [17]
Mucopolysaccharidoses 1 in 25,000
Lysosomal acid lipase deficiency 1 in 40,000
Glycogen storage diseases 1 in 50,000
Galactosemia 1 in 57,000
X-linked
Duchenne muscular dystrophy 1 in 5,000
Hemophilia 1 in 10,000
Values are for liveborn infants

A single-gene disorder (or monogenic disorder) is the result of a single mutated gene. 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, the common form of dwarfism, achondroplasia, is typically considered a dominant disorder, but children with two genes for achondroplasia have a severe and usually lethal skeletal disorder, one that achondroplasics could be considered carriers for. 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. [18] When a couple where one partner or both are affected or carriers of a single-gene disorder wish to have a child, they can do so through in vitro fertilization, which enables preimplantation genetic diagnosis to occur to check whether the embryo has the genetic disorder. [19]

Most congenital metabolic disorders known as inborn errors of metabolism result from single-gene defects. Many such single-gene defects can decrease the fitness of affected people and are therefore present in the population in lower frequencies compared to what would be expected based on simple probabilistic calculations. [20]

Autosomal dominant

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. [21] : 57  The chance a child will inherit the mutated gene is 50%. Autosomal dominant conditions sometimes have reduced penetrance, which means 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, [21] : 58  neurofibromatosis type 1, neurofibromatosis type 2, Marfan syndrome, hereditary nonpolyposis colorectal cancer, hereditary multiple exostoses (a highly penetrant autosomal dominant disorder), tuberous sclerosis, Von Willebrand disease, and acute intermittent porphyria. Birth defects are also called congenital anomalies.[ citation needed ]

Autosomal recessive

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 genetic carriers. Each parent with a defective gene normally do not have symptoms. [22] Two unaffected people who each carry one copy of the mutated gene have a 25% risk with each pregnancy of having a child affected by the disorder. Examples of this type of disorder are albinism, medium-chain acyl-CoA dehydrogenase deficiency, 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. [23] [24] Some autosomal recessive disorders are common because, in the past, carrying one of the faulty genes led to a slight protection against an infectious disease or toxin such as tuberculosis or malaria. [25] Such disorders include cystic fibrosis, [26] sickle cell disease, [27] phenylketonuria [28] and thalassaemia. [29]

X-linked dominant

Schematic karyogram showing an overview of the human genome. It shows annotated bands and sub-bands as used in the nomenclature of genetic disorders. It shows 22 homologous chromosomes, both the female (XX) and male (XY) versions of the sex chromosome (bottom right), as well as the mitochondrial genome (to scale at bottom left) . Further information: Karyotype Human karyotype with bands and sub-bands.png
Schematic karyogram showing an overview of the human genome. It shows annotated bands and sub-bands as used in the nomenclature of genetic disorders. It shows 22 homologous chromosomes, both the female (XX) and male (XY) versions of the sex chromosome (bottom right), as well as the mitochondrial genome (to scale at bottom left) .

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 (44+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), but 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 in cases such as incontinentia pigmenti, only female offspring are generally viable.

X-linked recessive

X-linked recessive conditions are also caused by mutations in genes on the X chromosome. Males are much more frequently affected than females, because they only have the one X chromosome necessary for the condition to present. 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 (since they receive their father's Y chromosome), but his daughters will be carriers of 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 are carriers of one copy of the mutated gene. 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).[ citation needed ]

Y-linked

Y-linked disorders are caused by mutations on the Y chromosome. These conditions may only be transmitted from the heterogametic sex (e.g. male humans) to offspring of the same sex. More simply, this means that Y-linked disorders in humans can only be passed from men to their sons; females can never be affected because they do not possess Y-allosomes.[ citation needed ]

Y-linked disorders are exceedingly rare but the most well-known examples typically cause infertility. Reproduction in such conditions is only possible through the circumvention of infertility by medical intervention.

Mitochondrial

This type of inheritance, also known as maternal inheritance, is the rarest and applies to the 13 genes encoded by mitochondrial DNA. Because only egg cells contribute mitochondria to the developing embryo, only mothers (who are affected) can pass on mitochondrial DNA conditions to their children. An example of this type of disorder is Leber's hereditary optic neuropathy.[ citation needed ]

It is important to stress that the vast majority of mitochondrial diseases (particularly when symptoms develop in early life) are actually caused by a nuclear gene defect, as the mitochondria are mostly developed by non-mitochondrial DNA. These diseases most often follow autosomal recessive inheritance. [30]

Multifactorial disorder

Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely associated with the effects of multiple genes in combination with lifestyles 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. Studies that aim to identify the cause of complex disorders can use several methodological approaches to determine genotype–phenotype associations. One method, the genotype-first approach, starts by identifying genetic variants within patients and then determining the associated clinical manifestations. This is opposed to the more traditional phenotype-first approach, and may identify causal factors that have previously been obscured by clinical heterogeneity, penetrance, and expressivity.[ citation needed ]

On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit simple patterns as with Mendelian diseases. 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). Other factors include:

Chromosomal disorder

Chromosomes in Down syndrome, the most common human condition due to aneuploidy. There are three chromosomes 21 (in the last row). Down Syndrome Karyotype.png
Chromosomes in Down syndrome, the most common human condition due to aneuploidy. There are three chromosomes 21 (in the last row).

A chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. [31] It can be from an atypical number of chromosomes or a structural abnormality in one or more chromosomes. An example of these disorders is Trisomy 21 (the most common form of Down syndrome), in which there is an extra copy of chromosome 21 in all cells. [32]

Diagnosis

Due to the wide range of genetic disorders that are known, diagnosis is widely varied and dependent of the disorder. Most genetic disorders are diagnosed pre-birth, at birth, or during early childhood however some, such as Huntington's disease, can escape detection until the patient begins exhibiting symptoms well into adulthood. [33]

The basic aspects of a genetic disorder rests on the inheritance of genetic material. With an in depth family history, it is possible to anticipate possible disorders in children which direct medical professionals to specific tests depending on the disorder and allow parents the chance to prepare for potential lifestyle changes, anticipate the possibility of stillbirth, or contemplate termination. [34] Prenatal diagnosis can detect the presence of characteristic abnormalities in fetal development through ultrasound, or detect the presence of characteristic substances via invasive procedures which involve inserting probes or needles into the uterus such as in amniocentesis. [35]

Prognosis

Not all genetic disorders directly result in death; however, there are no known cures for genetic disorders. Many genetic disorders affect stages of development, such as Down syndrome, while others result in purely physical symptoms such as muscular dystrophy. Other disorders, such as Huntington's disease, show no signs until adulthood. During the active time of a genetic disorder, patients mostly rely on maintaining or slowing the degradation of quality of life and maintain patient autonomy. This includes physical therapy and pain management.

Treatment

From personal genomics to gene therapy Personal genomics gene therapy flowchart.png
From personal genomics to gene therapy

The treatment of genetic disorders is an ongoing battle, with over 1,800 gene therapy clinical trials having been completed, are ongoing, or have been approved worldwide. [36] Despite this, most treatment options revolve around treating the symptoms of the disorders in an attempt to improve patient quality of life.

Gene therapy refers to a form of treatment where a healthy gene is introduced to a patient. This should alleviate the defect caused by a faulty gene or slow the progression of the disease. A major obstacle has been the delivery of genes to the appropriate cell, tissue, and organ affected by the disorder. Researchers have investigated how they can introduce a gene into the potentially trillions of cells that carry the defective copy. Finding an answer to this has been a roadblock between understanding the genetic disorder and correcting the genetic disorder. [37]

Epidemiology

Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder. [7] Around 65% of people have some kind of health problem as a result of congenital genetic mutations. [7] Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare" (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves. [5] [8] There are well over 6,000 known genetic disorders, [4] and new genetic disorders are constantly being described in medical literature. [5]

History

The earliest known genetic condition in a hominid was in the fossil species Paranthropus robustus, with over a third of individuals displaying amelogenesis imperfecta. [38]

See also

Related Research Articles

<span class="mw-page-title-main">Joubert syndrome</span> Medical condition

Joubert syndrome is a rare autosomal recessive genetic disorder that affects the cerebellum, an area of the brain that controls balance and coordination.

<span class="mw-page-title-main">Waardenburg syndrome</span> Genetic condition involving hearing loss and depigmentation

Waardenburg syndrome is a group of rare genetic conditions characterised by at least some degree of congenital hearing loss and pigmentation deficiencies, which can include bright blue eyes, a white forelock or patches of light skin. These basic features constitute type 2 of the condition; in type 1, there is also a wider gap between the inner corners of the eyes called telecanthus, or dystopia canthorum. In type 3, which is rare, the arms and hands are also malformed, with permanent finger contractures or fused fingers, while in type 4, the person also has Hirschsprung's disease. There also exist at least two types that can result in central nervous system (CNS) symptoms such as developmental delay and muscle tone abnormalities.

<span class="mw-page-title-main">Alport syndrome</span> Medical condition

Alport syndrome is a genetic disorder affecting around 1 in 5,000-10,000 children, characterized by glomerulonephritis, end-stage kidney disease, and hearing loss. Alport syndrome can also affect the eyes, though the changes do not usually affect vision, except when changes to the lens occur in later life. Blood in urine is universal. Proteinuria is a feature as kidney disease progresses.

<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">Alagille syndrome</span> Medical condition

Alagille syndrome (ALGS) is a genetic disorder that affects primarily the liver and the heart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 30,000 to 1 in every 40,000 live births. It is named after the French pediatrician Daniel Alagille, who first described the condition in 1969.

<span class="mw-page-title-main">Human genetics</span> Study of inheritance as it occurs in human beings

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.

Severe congenital neutropenia (SCN), also often known as Kostmann syndrome or disease, is a group of rare disorders that affect myelopoiesis, causing a congenital form of neutropenia, usually without other physical malformations. SCN manifests in infancy with life-threatening bacterial infections. It causes severe pyogenic infections. It can be caused by autosomal dominant inheritance of the ELANE gene, autosomal recessive inheritance of the HAX1 gene. There is an increased risk of leukemia and myelodysplastic cancers.

Hereditary inclusion body myopathies (HIBM) are a group of rare genetic disorders which have different symptoms. Generally, they are neuromuscular disorders characterized by muscle weakness developing in young adults. Hereditary inclusion body myopathies comprise both autosomal recessive and autosomal dominant muscle disorders that have a variable expression (phenotype) in individuals, but all share similar structural features in the muscles.

<span class="mw-page-title-main">SCARF syndrome</span> Medical condition

SCARF syndrome is a rare syndrome characterized by skeletal abnormalities, cutis laxa, craniostenosis, ambiguous genitalia, psychomotor retardation, and facial abnormalities. These characteristics are what make up the acronym SCARF. It shares some features with Lenz-Majewski hyperostotic dwarfism. It is a very rare disease with an incidence rate of approximately one in a million newborns. It has been clinically described in two males who were maternal cousins, as well as a 3-month-old female. Babies affected by this syndrome tend to have very loose skin, giving them an elderly facial appearance. Possible complications include dyspnea, abdominal hernia, heart disorders, joint disorders, and dislocations of multiple joints. It is believed that this disease's inheritance is X-linked recessive.

<span class="mw-page-title-main">Gray platelet syndrome</span> Medical condition

Gray platelet syndrome (GPS), or platelet alpha-granule deficiency, is a rare congenital autosomal recessive bleeding disorder caused by a reduction or absence of alpha-granules in blood platelets, and the release of proteins normally contained in these granules into the marrow, causing myelofibrosis. The name derives from the initial observation of gray appearance of platelets with a paucity of granules on blood films from a patient with a lifelong bleeding disorder.

<span class="mw-page-title-main">Naegeli–Franceschetti–Jadassohn syndrome</span> Medical condition

Naegeli–Franceschetti–Jadassohn syndrome (NFJS), also known as chromatophore nevus of Naegeli and Naegeli syndrome, is a rare autosomal dominant form of ectodermal dysplasia, characterized by reticular skin pigmentation, diminished function of the sweat glands, the absence of teeth and hyperkeratosis of the palms and soles. One of the most striking features is the absence of fingerprint lines on the fingers.

<span class="mw-page-title-main">Rosselli–Gulienetti syndrome</span> Medical condition

Rosselli–Gulienetti syndrome, also known as Zlotogora–Ogur syndrome and Bowen–Armstrong syndrome, is a type of congenital ectodermal dysplasia syndrome. The syndrome is relatively rare and has only been described in a few cases.

<span class="mw-page-title-main">Uncombable hair syndrome</span> Rare scalp hair shaft dysplasia

Uncombable hair syndrome (UHS) is a rare structural anomaly of the hair with a variable degree of effect. It is characterized by hair that is silvery, dry, frizzy, wiry, and impossible to comb. It was first reported in the early 20th century. It typically becomes apparent between the ages of 3 months and 12 years. UHS has several names, including pili trianguli et canaliculi (Latin), cheveux incoiffables (French), and "spun-glass hair". This disorder is believed to be autosomal recessive in most instances, but there are a few documented cases where multiple family members display the trait in an autosomal dominant fashion. Based on the current scientific studies related to the disorder, the three genes that have been causally linked to UHS are PADI3, TGM3, and TCHH. These genes encode proteins important for hair shaft formation. Clinical symptoms of the disorder arise between 3 months and 12 years of age. The quantity of hair on the head does not change, but hair starts to grow more slowly and becomes increasingly "uncombable". To be clinically apparent, 50% of all scalp hair shafts must be affected by UHS. This syndrome only affects the hair shaft of the scalp and does not influence hair growth in terms of quantity, textural feel, or appearance on the rest of the body.

<span class="mw-page-title-main">Rothmund–Thomson syndrome</span> Rare autosomal recessive skin condition.

Rothmund–Thomson syndrome (RTS) is a rare autosomal recessive skin condition.

<span class="mw-page-title-main">Gillespie syndrome</span> Medical condition

Gillespie syndrome, also called aniridia, cerebellar ataxia and mental deficiency, is a rare genetic disorder. The disorder is characterized by partial aniridia, ataxia, and, in most cases, intellectual disability. It is heterogeneous, inherited in either an autosomal dominant or autosomal recessive manner. Gillespie syndrome was first described by American ophthalmologist Fredrick Gillespie in 1965.

Nasodigitoacoustic syndrome, also called Keipert syndrome, is a rare congenital syndrome first described by J.A. Keipert and colleagues in 1973. The syndrome is characterized by a misshaped nose, broad thumbs and halluces, brachydactyly, sensorineural hearing loss, facial features such as hypertelorism, and developmental delay.

<span class="mw-page-title-main">Hereditary cancer syndrome</span> Inherited genetic condition that predisposes a person to cancer

A hereditary cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancer and may also cause early onset of these cancers. Hereditary cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.

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.

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