Medical genetics

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Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from human genetics in that human genetics is a field of scientific research that may or may not apply to medicine, while medical genetics refers to the application of genetics to medical care. 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 counselling people with genetic disorders would be considered part of medical genetics.

Contents

In contrast, the study of typically non-medical phenotypes such as the genetics of eye color would be considered part of human genetics, but not necessarily relevant to medical genetics (except in situations such as albinism). Genetic medicine is a newer term for medical genetics and incorporates areas such as gene therapy, personalized medicine, and the rapidly emerging new medical specialty, predictive medicine.

Autosomal dominant and autosomal recessive inheritance, the two most common Mendelian inheritance patterns. An autosome is any chromosome other than a sex chromosome. Autosomal dominant and recessive.svg
Autosomal dominant and autosomal recessive inheritance, the two most common Mendelian inheritance patterns. An autosome is any chromosome other than a sex chromosome.

Scope

Medical genetics encompasses many different areas, including clinical practice of physicians, genetic counselors, and nutritionists, clinical diagnostic laboratory activities, and research into the causes and inheritance of genetic disorders. Examples of conditions that fall within the scope of medical genetics include birth defects and dysmorphology, intellectual disabilities, autism, mitochondrial disorders, skeletal dysplasia, connective tissue disorders, cancer genetics, and prenatal diagnosis. Medical genetics is increasingly becoming relevant to many common diseases. Overlaps with other medical specialties are beginning to emerge, as recent advances in genetics are revealing etiologies for morphologic, endocrine, cardiovascular, pulmonary, ophthalmologist, renal, psychiatric, and dermatologic conditions. The medical genetics community is increasingly involved with individuals who have undertaken elective genetic and genomic testing.

Subspecialties

In some ways, many of the individual fields within medical genetics are hybrids between clinical care and research. This is due in part to recent advances in science and technology (for example, see the Human Genome Project) that have enabled an unprecedented understanding of genetic disorders.

Clinical genetics

Clinical genetics a medical specialty with particular attention to hereditary disorders. Branches of clinical genetics include:

1. Prenatal genetics
  • Couples at risk of having a child with a genetic disorder preconception or while pregnant
  • High risk prenatal screening results
  • Abnormal fetal ultrasound
2. Pediatric genetics
3. Adult genetics
4. Cancer genetics

Examples of genetic syndromes that are commonly seen in the genetics clinic include chromosomal rearrangements (e.g. Down syndrome, 22q11.2 deletion syndrome, Turner syndrome, Williams syndrome), Fragile X syndrome, Marfan syndrome, neurofibromatosis, Huntington disease, familial adenomatous polyposis, and many more.

Training and qualification

In the United States, physicians who practice clinical genetics are accredited by the American Board of Medical Genetics and Genomics (ABMGG). [1] In order to become a board-certified practitioner of Clinical Genetics, a physician must complete a minimum of 24 months of training in a program accredited by the ABMGG. Individuals seeking acceptance into clinical genetics training programs must hold an M.D. or D.O. degree (or their equivalent) and have completed a minimum of 12 months of training in an ACGME-accredited residency program in internal medicine, pediatrics, obstetrics and gynecology, or other medical specialty. [2]

In Australia and New Zealand, clinical genetics is a three-year advanced training program for those who already have their primary medical qualification (MBBS or MD) and have successfully completed basic training in either paediatric medicine or adult medicine. Training is overseen by the Royal Australasian College of Physicians with the Australasian Association of Clinical Geneticists contributing to authorship of the curriculum via their parent organization, the Human Genetics Society of Australasia. [3]

Metabolic/biochemical genetics

Metabolic (or biochemical) genetics involves the diagnosis and management of inborn errors of metabolism in which patients have enzymatic deficiencies that perturb biochemical pathways involved in metabolism of carbohydrates, amino acids, and lipids. Examples of metabolic disorders include galactosemia, glycogen storage disease, lysosomal storage disorders, metabolic acidosis, peroxisomal disorders, phenylketonuria, and urea cycle disorders.

Cytogenetics

Cytogenetics is the study of chromosomes and chromosome abnormalities. While cytogenetics historically relied on microscopy to analyze chromosomes, new molecular technologies such as array comparative genomic hybridization are now becoming widely used. Examples of chromosome abnormalities include aneuploidy, chromosomal rearrangements, and genomic deletion/duplication disorders.

Molecular genetics

Molecular genetics involves the discovery of and laboratory testing for DNA mutations that underlie many single gene disorders. Examples of single gene disorders include achondroplasia, cystic fibrosis, Duchenne muscular dystrophy, hereditary breast cancer (BRCA1/2), Huntington disease, Marfan syndrome, Noonan syndrome, and Rett syndrome. Molecular tests are also used in the diagnosis of syndromes involving epigenetic abnormalities, such as Angelman syndrome, Beckwith-Wiedemann syndrome, Prader-willi syndrome, and uniparental disomy.

Mitochondrial genetics

Mitochondrial genetics concerns the diagnosis and management of mitochondrial disorders, which have a molecular basis but often result in biochemical abnormalities due to deficient energy production.

There exists some overlap between medical genetic diagnostic laboratories and molecular pathology.

Genetic counseling

Genetic counseling is the process of providing information about genetic conditions, diagnostic testing, and risks in other family members, within the framework of nondirective counseling. Genetic counselors are non-physician members of the medical genetics team who specialize in family risk assessment and counseling of patients regarding genetic disorders. The precise role of the genetic counselor varies somewhat depending on the disorder. When working alongside geneticists, genetic counselors normally specialize in pediatric genetics which focuses on developmental abnormalities present in newborns, infants or children. The major goal of pediatric counseling is attempting to explain the genetic basis behind the child's developmental concerns in a compassionate and articulated manner that allows the potentially distressed or frustrated parents to easily understand the information. As well, genetic counselors normally take a family pedigree, which summarizes the medical history of the patient's family. This then aids the clinical geneticist in the differential diagnosis process and help determine which further steps should be taken to help the patient. [4]

History

Although genetics has its roots back in the 19th century with the work of the Bohemian monk Gregor Mendel and other pioneering scientists, human genetics emerged later. It started to develop, albeit slowly, during the first half of the 20th century. Mendelian (single-gene) inheritance was studied in a number of important disorders such as albinism, brachydactyly (short fingers and toes), and hemophilia. Mathematical approaches were also devised and applied to human genetics. Population genetics was created.

Medical genetics was a late developer, emerging largely after the close of World War II (1945) when the eugenics movement had fallen into disrepute. [5] The Nazi misuse of eugenics sounded its death knell. [6] Shorn of eugenics, a scientific approach could be used and was applied to human and medical genetics. Medical genetics saw an increasingly rapid rise in the second half of the 20th century and continues in the 21st century.

Current practice

The clinical setting in which patients are evaluated determines the scope of practice, diagnostic, and therapeutic interventions. For the purposes of general discussion, the typical encounters between patients and genetic practitioners may involve:

Diagnostic evaluation

Each patient will undergo a diagnostic evaluation tailored to their own particular presenting signs and symptoms. The geneticist will establish a differential diagnosis and recommend appropriate testing. These tests might evaluate for chromosomal disorders, inborn errors of metabolism, or single gene disorders.

Chromosome studies

Schematic karyogram of a human, with annotated bands and sub-bands as used in the International System for Human Cytogenomic Nomenclature for chromosomal abnormalities. 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 as used in the International System for Human Cytogenomic Nomenclature for chromosomal abnormalities. 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).

Chromosome studies are used in the general genetics clinic to determine a cause for developmental delay or intellectual disability, birth defects, dysmorphic features, or autism.[ citation needed ] Chromosome analysis is also performed in the prenatal setting to determine whether a fetus is affected with aneuploidy or other chromosome rearrangements. Finally, chromosome abnormalities are often detected in cancer samples. A large number of different methods have been developed for chromosome analysis:

  • Chromosome analysis using a karyotype involves special stains that generate light and dark bands, allowing identification of each chromosome under a microscope.
  • Fluorescence in situ hybridization (FISH) involves fluorescent labeling of probes that bind to specific DNA sequences, used for identifying aneuploidy, genomic deletions or duplications, characterizing chromosomal translocations and determining the origin of ring chromosomes.
  • Chromosome painting is a technique that uses fluorescent probes specific for each chromosome to differentially label each chromosome. This technique is more often used in cancer cytogenetics, where complex chromosome rearrangements can occur.
  • Array comparative genomic hybridization is a newer molecular technique that involves hybridization of an individual DNA sample to a glass slide or microarray chip containing molecular probes (ranging from large ~200kb bacterial artificial chromosomes to small oligonucleotides) that represent unique regions of the genome. This method is particularly sensitive for detection of genomic gains or losses across the genome but does not detect balanced translocations or distinguish the location of duplicated genetic material (for example, a tandem duplication versus an insertional duplication).

Basic metabolic studies

Biochemical studies are performed to screen for imbalances of metabolites in the bodily fluid, usually the blood (plasma/serum) or urine, but also in cerebrospinal fluid (CSF). Specific tests of enzyme function (either in leukocytes, skin fibroblasts, liver, or muscle) are also employed under certain circumstances. In the US, the newborn screen incorporates biochemical tests to screen for treatable conditions such as galactosemia and phenylketonuria (PKU). Patients suspected to have a metabolic condition might undergo the following tests:

  • Quantitative amino acid analysis is typically performed using the ninhydrin reaction, followed by liquid chromatography to measure the amount of amino acid in the sample (either urine, plasma/serum, or CSF). Measurement of amino acids in plasma or serum is used in the evaluation of disorders of amino acid metabolism such as urea cycle disorders, maple syrup urine disease, and PKU. Measurement of amino acids in urine can be useful in the diagnosis of cystinuria or renal Fanconi syndrome as can be seen in cystinosis.
  • Urine organic acid analysis can be either performed using quantitative or qualitative methods, but in either case the test is used to detect the excretion of abnormal organic acids. These compounds are normally produced during bodily metabolism of amino acids and odd-chain fatty acids, but accumulate in patients with certain metabolic conditions.
  • The acylcarnitine combination profile detects compounds such as organic acids and fatty acids conjugated to carnitine. The test is used for detection of disorders involving fatty acid metabolism, including MCAD.
  • Pyruvate and lactate are byproducts of normal metabolism, particularly during anaerobic metabolism. These compounds normally accumulate during exercise or ischemia, but are also elevated in patients with disorders of pyruvate metabolism or mitochondrial disorders.
  • Ammonia is an end product of amino acid metabolism and is converted in the liver to urea through a series of enzymatic reactions termed the urea cycle. Elevated ammonia can therefore be detected in patients with urea cycle disorders, as well as other conditions involving liver failure.
  • Enzyme testing is performed for a wide range of metabolic disorders to confirm a diagnosis suspected based on screening tests.

Molecular studies

Treatments

Each cell of the body contains the hereditary information (DNA) wrapped up in structures called chromosomes. Since genetic syndromes are typically the result of alterations of the chromosomes or genes, there is no treatment currently available that can correct the genetic alterations in every cell of the body. Therefore, there is currently no "cure" for genetic disorders. However, for many genetic syndromes there is treatment available to manage the symptoms. In some cases, particularly inborn errors of metabolism, the mechanism of disease is well understood and offers the potential for dietary and medical management to prevent or reduce the long-term complications. In other cases, infusion therapy is used to replace the missing enzyme. Current research is actively seeking to use gene therapy or other new medications to treat specific genetic disorders.

Management of metabolic disorders

In general, metabolic disorders arise from enzyme deficiencies that disrupt normal metabolic pathways. For instance, in the hypothetical example:

A ---> B ---> C ---> D AAAA ---> BBBBBB ---> CCCCCCCCCC ---> (no D) X Y Z X Y | (no or insufficient Z) EEEEE

Compound "A" is metabolized to "B" by enzyme "X", compound "B" is metabolized to "C" by enzyme "Y", and compound "C" is metabolized to "D" by enzyme "Z". If enzyme "Z" is missing, compound "D" will be missing, while compounds "A", "B", and "C" will build up. The pathogenesis of this particular condition could result from lack of compound "D", if it is critical for some cellular function, or from toxicity due to excess "A", "B", and/or "C", or from toxicity due to the excess of "E" which is normally only present in small amounts and only accumulates when "C" is in excess. Treatment of the metabolic disorder could be achieved through dietary supplementation of compound "D" and dietary restriction of compounds "A", "B", and/or "C" or by treatment with a medication that promoted disposal of excess "A", "B", "C" or "E". Another approach that can be taken is enzyme replacement therapy, in which a patient is given an infusion of the missing enzyme "Z" or cofactor therapy to increase the efficacy of any residual "Z" activity.

  • Diet

Dietary restriction and supplementation are key measures taken in several well-known metabolic disorders, including galactosemia, phenylketonuria (PKU), maple syrup urine disease, organic acidurias and urea cycle disorders. Such restrictive diets can be difficult for the patient and family to maintain, and require close consultation with a nutritionist who has special experience in metabolic disorders. The composition of the diet will change depending on the caloric needs of the growing child and special attention is needed during a pregnancy if a woman is affected with one of these disorders.

  • Medication

Medical approaches include enhancement of residual enzyme activity (in cases where the enzyme is made but is not functioning properly), inhibition of other enzymes in the biochemical pathway to prevent buildup of a toxic compound, or diversion of a toxic compound to another form that can be excreted. Examples include the use of high doses of pyridoxine (vitamin B6) in some patients with homocystinuria to boost the activity of the residual cystathione synthase enzyme, administration of biotin to restore activity of several enzymes affected by deficiency of biotinidase, treatment with NTBC in Tyrosinemia to inhibit the production of succinylacetone which causes liver toxicity, and the use of sodium benzoate to decrease ammonia build-up in urea cycle disorders.

Certain lysosomal storage diseases are treated with infusions of a recombinant enzyme (produced in a laboratory), which can reduce the accumulation of the compounds in various tissues. Examples include Gaucher disease, Fabry disease, Mucopolysaccharidoses and Glycogen storage disease type II. Such treatments are limited by the ability of the enzyme to reach the affected areas (the blood brain barrier prevents enzyme from reaching the brain, for example), and can sometimes be associated with allergic reactions. The long-term clinical effectiveness of enzyme replacement therapies vary widely among different disorders.

Other examples

  • Angiotensin receptor blockers in Marfan syndrome & Loeys-Dietz
  • Bone marrow transplantation
  • Gene therapy

Career paths and training

Geneticist working with a pedigree ScientistPedigree.JPG
Geneticist working with a pedigree

There are a variety of career paths within the field of medical genetics, and naturally the training required for each area differs considerably. The information included in this section applies to the typical pathways in the United States and there may be differences in other countries. US practitioners in clinical, counseling, or diagnostic subspecialties generally obtain board certification through the American Board of Medical Genetics.

CareerDegreeDescriptionTraining
Clinical geneticist MBBS, MD, DO, or MD-PhD A clinical geneticist is typically a physician who evaluates patients in the office or as a hospital consultation. This process includes a medical history, family history (pedigree), a detailed physical examination, reviewing objective data such as imaging and test results, establishing a differential diagnosis, and recommending appropriate diagnostic tests.College (4 yrs) → Medical school (4 yrs) → Primary residency (1 yr) → Residency in Clinical genetics (2 yrs). Some Clinical geneticists also obtain a PhD degree (4-7 yrs). A new residency track offers a 4 yr primary residency in Clinical genetics immediately after finishing Medical school.[ citation needed ]
Genetic counselorMSA genetic counselor specializes in communication of genetic information to patients and families. Genetic counselors often work closely with Clinical geneticists or other physicians (such as Obstetricians or Oncologists) and often convey the results of the recommended tests.College (4 yrs) → Graduate program in Genetic counseling (2 yrs).
Metabolic nurse and/or nutritionistBA/BS, MS, RNOne of the critical aspects of the management of patients with metabolic disorders is the appropriate nutritional intervention (either restricting the compound that cannot be metabolized, or supplementing compounds that are deficient as the result of an enzyme deficiency). The metabolic nurse and nutritionist play important roles in coordinating the dietary management.College (4 yrs) → Nursing school or graduate training in nutrition.
Biochemical diagnosticsBS, MS, PhD, MBBS, MD, DO, MD-PhDIndividuals who specialize in Biochemical genetics typically work in the diagnostic laboratory, analyzing and interpreting specialized biochemical tests that measure amino acids, organic acids, and enzyme activity. Some Clinical Geneticists are also board certified in Biochemical Genetics.College (4 yrs) → Graduate school (PhD, usually 4–7 years) and/or Medical school (4 years)
Cytogenetic diagnosticsBS, MS, PhD, MBBS, MD, DO, MD-PhDIndividuals who specialize in Cytogenetics typically work in the diagnostic laboratory, analyzing and interpreting karyotypes, FISH, and comparative genomic hybridization tests. Some Clinical Geneticists are also board certified in Cytogenetics.College (4 yrs) → Graduate school (PhD, usually 4–7 years) and/or Medical school (4 years)
Molecular geneticsBS, MS, PhD, MBBS, MD, DO, MD-PhDIndividuals who specialize in Molecular genetics typically work in the diagnostic laboratory, analyzing and interpreting specialized genetic tests that look for disease-causing changes (mutations) in the DNA. Some examples of molecular diagnostic tests include DNA sequencing and Southern blotting.College (4 yrs) → Graduate school (PhD, usually 4–7 years) and/or Medical school (4 years)
Research geneticistBS, MS, PhD, MBBS, MD, DO, MD-PhDAny researcher who studies the genetic basis of human disease or uses model organisms to study disease mechanisms could be considered a Research Geneticist. Many of the clinical career paths also include basic or translational research, and thus individuals in the field of medical genetics often participate in some form of research.College (4 yrs) → Graduate school (PhD, usually 4–7 years) and/or Medical school (4 years) → Post-doctoral research training (usually 3+ years)
Laboratory technicianAS, BS, MSTechnicians in the diagnostic or research labs handle samples and run the assays at the bench.College (4 yrs), may have higher degree (MS, 2+ years)

Genetic information provides a unique type of knowledge about an individual and his/her family, fundamentally different from a typically laboratory test that provides a "snapshot" of an individual's health status. The unique status of genetic information and inherited disease has a number of ramifications with regard to ethical, legal, and societal concerns.

On 19 March 2015, scientists urged a worldwide ban on clinical use of methods, particularly the use of CRISPR and zinc finger, to edit the human genome in a way that can be inherited. [7] [8] [9] [10] In April 2015 and April 2016, Chinese researchers reported results of basic research to edit the DNA of non-viable human embryos using CRISPR. [11] [12] [13] In February 2016, British scientists were given permission by regulators to genetically modify human embryos by using CRISPR and related techniques on condition that the embryos were destroyed within seven days. [14] In June 2016 the Dutch government was reported to be planning to follow suit with similar regulations which would specify a 14-day limit. [15]

Societies

The more empirical approach to human and medical genetics was formalized by the founding in 1948 of the American Society of Human Genetics. The Society first began annual meetings that year (1948) and its international counterpart, the International Congress of Human Genetics, has met every 5 years since its inception in 1956. The Society publishes the American Journal of Human Genetics on a monthly basis.

Medical genetics is recognized as a distinct medical specialty. In the U.S., medical genetics has its own approved board (the American Board of Medical Genetics) and clinical specialty college (the American College of Medical Genetics). The college holds an annual scientific meeting, publishes a monthly journal, Genetics in Medicine , and issues position papers and clinical practice guidelines on a variety of topics relevant to human genetics.

In Australia and New Zealand, medical geneticists are trained and certified under the auspices of the Royal Australasian College of Physicians, but professionally belong to the Human Genetics Society of Australasia and its special interest group, the Australasian Association of Clinical Geneticists, for ongoing education, networking and advocacy.

bioethics

[16]


Research

The broad range of research in medical genetics reflects the overall scope of this field, including basic research on genetic inheritance and the human genome, mechanisms of genetic and metabolic disorders, translational research on new treatment modalities, and the impact of genetic testing

Basic genetics research

Basic research geneticists usually undertake research in universities, biotechnology firms and research institutes.

Allelic architecture of disease

Sometimes the link between a disease and an unusual gene variant is more subtle. The genetic architecture of common diseases is an important factor in determining the extent to which patterns of genetic variation influence group differences in health outcomes. [17] [18] [19] According to the common disease/common variant hypothesis, common variants present in the ancestral population before the dispersal of modern humans from Africa play an important role in human diseases. [20] Genetic variants associated with Alzheimer disease, deep venous thrombosis, Crohn disease, and type 2 diabetes appear to adhere to this model. [21] However, the generality of the model has not yet been established and, in some cases, is in doubt. [18] [22] [23] Some diseases, such as many common cancers, appear not to be well described by the common disease/common variant model. [24]

Another possibility is that common diseases arise in part through the action of combinations of variants that are individually rare. [25] [26] Most of the disease-associated alleles discovered to date have been rare, and rare variants are more likely than common variants to be differentially distributed among groups distinguished by ancestry. [24] [27] However, groups could harbor different, though perhaps overlapping, sets of rare variants, which would reduce contrasts between groups in the incidence of the disease.

The number of variants contributing to a disease and the interactions among those variants also could influence the distribution of diseases among groups. The difficulty that has been encountered in finding contributory alleles for complex diseases and in replicating positive associations suggests that many complex diseases involve numerous variants rather than a moderate number of alleles, and the influence of any given variant may depend in critical ways on the genetic and environmental background. [22] [28] [29] [30] If many alleles are required to increase susceptibility to a disease, the odds are low that the necessary combination of alleles would become concentrated in a particular group purely through drift. [31]

Population substructure in genetics research

One area in which population categories can be important considerations in genetics research is in controlling for confounding between population substructure, environmental exposures, and health outcomes. Association studies can produce spurious results if cases and controls have differing allele frequencies for genes that are not related to the disease being studied, [32] although the magnitude of this problem in genetic association studies is subject to debate. [33] [34] Various methods have been developed to detect and account for population substructure, [35] [36] but these methods can be difficult to apply in practice. [37]

Population substructure also can be used to advantage in genetic association studies. [38] For example, populations that represent recent mixtures of geographically separated ancestral groups can exhibit longer-range linkage disequilibrium between susceptibility alleles and genetic markers than is the case for other populations. [39] [40] [41] [42] Genetic studies can use this admixture linkage disequilibrium to search for disease alleles with fewer markers than would be needed otherwise. Association studies also can take advantage of the contrasting experiences of racial or ethnic groups, including migrant groups, to search for interactions between particular alleles and environmental factors that might influence health. [43] [44]

See also

Related Research Articles

<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.

<span class="mw-page-title-main">Tay–Sachs disease</span> Human medical condition

Tay–Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent around the age of three to six months of age, with the baby losing the ability to turn over, sit, or crawl. This is then followed by seizures, hearing loss, and inability to move, with death usually occurring by the age of three to five. Less commonly, the disease may occur later in childhood, adolescence, or adulthood. These forms tend to be less severe, but the juvenile form typically results in death by age 15.

<span class="mw-page-title-main">Hereditary haemochromatosis</span> Medical condition

Hereditary haemochromatosis type 1 is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, have no mechanism to regulate excess iron, simply losing a limited amount through various means like sweating or menstruating.

<span class="mw-page-title-main">Methylmalonic acidemia</span> Medical condition

Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism. It is a classical type of organic acidemia. The result of this condition is the inability to properly digest specific fats and proteins, which in turn leads to a buildup of a toxic level of methylmalonic acid in the blood.

<span class="mw-page-title-main">Lesch–Nyhan syndrome</span> Rare genetic disorder

Lesch–Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This deficiency occurs due to mutations in the HPRT1 gene located on the X chromosome. LNS affects about 1 in 380,000 live births. The disorder was first recognized and clinically characterized by American medical student Michael Lesch and his mentor, pediatrician William Nyhan, at Johns Hopkins.

Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or due to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are often referred to as congenital metabolic diseases or inherited metabolic disorders. Another term used to describe these disorders is "enzymopathies". This term was created following the study of biodynamic enzymology, a science based on the study of the enzymes and their products. Finally, inborn errors of metabolism were studied for the first time by British physician Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism, was published in 1923.

<span class="mw-page-title-main">Maple syrup urine disease</span> Autosomal recessive metabolic disorder

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder affecting branched-chain amino acids. It is one type of organic acidemia. The condition gets its name from the distinctive sweet odor of affected infants' urine and earwax, particularly prior to diagnosis and during times of acute illness. It was described by John Menkes in the 1950s.

<span class="mw-page-title-main">X-linked ichthyosis</span> Medical condition

X-linked ichthyosis is a skin condition caused by the hereditary deficiency of the steroid sulfatase (STS) enzyme that affects 1 in 2000 to 1 in 6000 males. XLI manifests with dry, scaly skin and is due to deletions or mutations in the STS gene. XLI can also occur in the context of larger deletions causing contiguous gene syndromes. Treatment is largely aimed at alleviating the skin symptoms. The term is from the Ancient Greek 'ichthys' meaning 'fish'.

Pantothenate kinase-associated neurodegeneration (PKAN), formerly called Hallervorden–Spatz syndrome, is a genetic degenerative disease of the brain that can lead to parkinsonism, dystonia, dementia, and ultimately death. Neurodegeneration in PKAN is accompanied by an excess of iron that progressively builds up in the brain.

Pyruvate dehydrogenase deficiency is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism. PDCD is a genetic disease resulting from mutations in one of the components of the pyruvate dehydrogenase complex (PDC). The PDC is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria. The disorder shows heterogeneous characteristics in both clinical presentation and biochemical abnormality.

<span class="mw-page-title-main">CYP2C19</span> Mammalian protein found in humans

Cytochrome P450 2C19 is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some proton pump inhibitors and antiepileptic drugs. In humans, it is the CYP2C19 gene that encodes the CYP2C19 protein. CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use, most notably the antiplatelet treatment clopidogrel (Plavix), drugs that treat pain associated with ulcers, such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.

In medical genetics, compound heterozygosity is the condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state; that is, an organism is a compound heterozygote when it has two recessive alleles for the same gene, but with those two alleles being different from each other. Compound heterozygosity reflects the diversity of the mutation base for many autosomal recessive genetic disorders; mutations in most disease-causing genes have arisen many times. This means that many cases of disease arise in individuals who have two unrelated alleles, who technically are heterozygotes, but both the alleles are defective.

<span class="mw-page-title-main">MTRR (gene)</span> Protein-coding gene in the species Homo sapiens

Methionine synthase reductase, also known as MSR, is an enzyme that in humans is encoded by the MTRR gene.

<span class="mw-page-title-main">Neutral lipid storage disease</span> Congenital autosomal recessive disorder

Neutral lipid storage disease is a congenital autosomal recessive disorder characterized by accumulation of triglycerides in the cytoplasm of leukocytes, muscle, liver, fibroblasts, and other tissues. It commonly occurs as one of two subtypes, cardiomyopathic neutral lipid storage disease (NLSD-M), or ichthyotic neutral lipid storage disease (NLSD-I) which is also known as Chanarin–Dorfman syndrome), which are characterized primarily by myopathy and ichthyosis, respectively. Normally, the ichthyosis that is present is typically non-bullous congenital ichthyosiform erythroderma which appears as white scaling.

Congenital generalized lipodystrophy is an extremely rare autosomal recessive condition, characterized by an extreme scarcity of fat in the subcutaneous tissues. It is a type of lipodystrophy disorder where the magnitude of fat loss determines the severity of metabolic complications. Only 250 cases of the condition have been reported, and it is estimated that it occurs in 1 in 10 million people worldwide.

DECIPHER is a web-based resource and database of genomic variation data from analysis of patient DNA. It documents submicroscopic chromosome abnormalities and pathogenic sequence variants, from over 25000 patients and maps them to the human genome using Ensembl or UCSC Genome Browser. In addition it catalogues the clinical characteristics from each patient and maintains a database of microdeletion/duplication syndromes, together with links to relevant scientific reports and support groups.

Non-allelic homologous recombination (NAHR) is a form of homologous recombination that occurs between two lengths of DNA that have high sequence similarity, but are not alleles.

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

Donohue syndrome is an extremely rare and severe genetic disorder. Leprechaunism derives its name from the hallmark elvish features exhibited by the affected individuals. The disease is caused by a mutation in the INSR gene, which contains the genetic information for the formation of insulin receptors. As a result, affected individuals have either a decreased number of insulin receptors, or insulin receptor with greatly impaired functionality. The lack and impairment of insulin receptor functionality leads to an inability to regulate blood glucose levels through severe insulin resistance. This will ultimately lead to affected development of tissues and organs throughout the body. In addition to the physical abnormalities, leprechaunism is also characterized by endocrine system abnormalities that can lead to conditions such as hyperglycemia, hypoglycemia, hyperinsulemia, and the enlargement of certain sex organs such as the penis in males, and the clitoris in females.

Autism spectrum disorder (ASD) refers to a variety of conditions typically identified by challenges with social skills, communication, speech, and repetitive sensory-motor behaviors. The 11th International Classification of Diseases (ICD-11), released in January 2021, characterizes ASD by the associated deficits in the ability to initiate and sustain two-way social communication and restricted or repetitive behavior unusual for the individual's age or situation. Although linked with early childhood, the symptoms can appear later as well. Symptoms can be detected before the age of two and experienced practitioners can give a reliable diagnosis by that age. However, official diagnosis may not occur until much older, even well into adulthood. There is a large degree of variation in how much support a person with ASD needs in day-to-day life. This can be classified by a further diagnosis of ASD level 1, level 2, or level 3. Of these, ASD level 3 describes people requiring very substantial support and who experience more severe symptoms. ASD-related deficits in nonverbal and verbal social skills can result in impediments in personal, family, social, educational, and occupational situations. This disorder tends to have a strong correlation with genetics along with other factors. More research is identifying ways in which epigenetics is linked to autism. Epigenetics generally refers to the ways in which chromatin structure is altered to affect gene expression. Mechanisms such as cytosine regulation and post-translational modifications of histones. Of the 215 genes contributing, to some extent in ASD, 42 have been found to be involved in epigenetic modification of gene expression. Some examples of ASD signs are specific or repeated behaviors, enhanced sensitivity to materials, being upset by changes in routine, appearing to show reduced interest in others, avoiding eye contact and limitations in social situations, as well as verbal communication. When social interaction becomes more important, some whose condition might have been overlooked suffer social and other exclusion and are more likely to have coexisting mental and physical conditions. Long-term problems include difficulties in daily living such as managing schedules, hypersensitivities, initiating and sustaining relationships, and maintaining jobs.

<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.

References

  1. "American Board of Medical Genetics and Genomics". abmgg.org.
  2. "Training Options - ABMGG". abmgg.org.
  3. RACP. "Clinical Genetics". Royal Australasian College of Physicians.
  4. Resta, Robert (19 May 2006). "A new definition of genetic counseling: national society of genetic counselors' task force report". Journal of Genetic Counseling. 15 (2): 77–83. doi: 10.1007/s10897-005-9014-3 . PMID   16761103. S2CID   25809385.
  5. Rose, Nikolas. (2009). The Politics of Life Itself : Biomedicine, Power, and Subjectivity in the Twenty-First Century. Princeton University Press. ISBN   978-0-691-12190-1. OCLC   995257497.
  6. KOCH, TOM (2011-03-25). "Eugenics and the Genetic Challenge, Again: All Dressed Up and Just Everywhere to Go". Cambridge Quarterly of Healthcare Ethics. 20 (2): 191–203. doi:10.1017/s0963180110000848. ISSN   0963-1801. PMC   3535762 . PMID   21435294.
  7. Wade, Nicholas (19 March 2015). "Scientists Seek Ban on Method of Editing the Human Genome". New York Times . Retrieved 20 March 2015.
  8. Pollack, Andrew (3 March 2015). "A Powerful New Way to Edit DNA". New York Times . Retrieved 20 March 2015.
  9. Baltimore, David; Berg, Paul; Botchan, Dana; Charo, R. Alta; Church, George; Corn, Jacob E.; Daley, George Q.; Doudna, Jennifer A.; Fenner, Marsha; Greely, Henry T.; Jinek, Martin; Martin, G. Steven; Penhoet, Edward; Puck, Jennifer; Sternberg, Samuel H.; Weissman, Jonathan S.; Yamamoto, Keith R. (19 March 2015). "A prudent path forward for genomic engineering and germline gene modification". Science . 348 (6230): 36–8. Bibcode:2015Sci...348...36B. doi:10.1126/science.aab1028. PMC   4394183 . PMID   25791083.
  10. Lanphier, Edward; Urnov, Fyodor; Haecker, Sarah Ehlen; Werner, Michael; Smolenski, Joanna (26 March 2015). "Don't edit the human germ line". Nature . 519 (7544): 410–411. Bibcode:2015Natur.519..410L. doi: 10.1038/519410a . PMID   25810189.
  11. Kolata, Gina (23 April 2015). "Chinese Scientists Edit Genes of Human Embryos, Raising Concerns". New York Times . Retrieved 24 April 2015.
  12. Liang, Puping; Xu, Yanwen; Zhang, Xiya; Ding, Chenhui; Huang, Rui; Zhang, Zhen; Lv, Jie; Xie, Xiaowei; Chen, Yuxi; Li, Yujing; Sun, Ying; Bai, Yaofu; Songyang, Zhou; Ma, Wenbin; Zhou, Canquan; Huang, Junjiu (18 April 2015). "CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes". Protein & Cell . 6 (5): 363–72. doi:10.1007/s13238-015-0153-5. PMC   4417674 . PMID   25894090.
  13. Regalado, Antonio (2016-05-08). "Chinese Researchers Experiment with Making HIV-Proof Embryos". MIT Technology Review. Retrieved 2016-06-10.
  14. Gallagher, James (1 February 2016). "Scientists get 'gene editing' go-ahead". BBC News . BBC. Retrieved 10 June 2016.
  15. Amjad, Anneesa (2016-06-06). "Dutch government seeks to allow creation of human embryos for research". BioNews. Retrieved 2016-06-10.
  16. D. Bonneau, S. Marlin, D. Sanlaville, J.-M. Dupont, H. Sobol, M. Gonzales, M. Le Merrer, P. Malzac, F. Razavi, S. Manouvrier, S. Odent, D. Stoppa-Lyonnet, Les tests génétiques à l’heure de la deuxième révision des lois de bioéthique, Pathologie Biologie, Volume 58, Issue 5, 2010, Pages 396-401
  17. Reich DA, Lander ES (2001). "On the allelic spectrum of human disease". Trends Genet. 17 (9): 502–510. doi:10.1016/s0168-9525(01)02410-6. PMID   11525833.
  18. 1 2 Pritchard JK (2002). "The allelic architecture of human disease genes: common disease-common variant...or not?". Hum Mol Genet. 11 (20): 2417–2423. doi: 10.1093/hmg/11.20.2417 . PMID   12351577.
  19. Smith DJ, Lusis AJ (2002). "The allelic structure of common disease". Hum Mol Genet. 11 (20): 2455–2461. CiteSeerX   10.1.1.497.3708 . doi:10.1093/hmg/11.20.2455. PMID   12351581.
  20. Goldstein DB, Chikhi L (2002). "Human migrations and population structure: what we know and why it matters". Annu Rev Genom Hum Genet. 3: 129–152. doi:10.1146/annurev.genom.3.022502.103200. PMID   12142358.
  21. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN (2003). "Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease". Nat Genet. 33 (2): 177–182. doi:10.1038/ng1071. PMID   12524541. S2CID   6850292.
  22. 1 2 Weiss KM, Terwilliger JD (2000). "How many diseases does it take to map a gene with SNPs?". Nat Genet. 26 (2): 151–157. doi:10.1038/79866. PMID   11017069. S2CID   685795.
  23. Cardon LR, Abecasis GR (2003). "Using haplotype blocks to map human complex trait loci". Trends Genet. 19 (3): 135–140. CiteSeerX   10.1.1.398.8937 . doi:10.1016/s0168-9525(03)00022-2. PMID   12615007.
  24. 1 2 Kittles RA, Weiss KM (2003). "Race, ancestry, and genes: implications for defining disease risk". Annu Rev Genom Hum Genet. 4: 33–67. doi:10.1146/annurev.genom.4.070802.110356. PMID   14527296.
  25. Pritchard JK (2001). "Are rare variants responsible for susceptibility to complex diseases?". Am J Hum Genet. 69 (1): 124–137. doi:10.1086/321272. PMC   1226027 . PMID   11404818.
  26. Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH (2004). "Multiple rare alleles contribute to low plasma levels of HDL cholesterol". Science. 305 (5685): 869–872. Bibcode:2004Sci...305..869C. doi:10.1126/science.1099870. PMID   15297675. S2CID   39429794.
  27. Risch N, Burchard E, Ziv E, Tang H, "Categorization of humans in biomedical research: genes, race and disease", Genome Biol (2002) 3 (http://genomebiology.com/2002/3/7/comment/2007 Archived 2006-06-24 at the Wayback Machine ) (electronically published July 1, 2002; accessed August 25, 2005)
  28. Risch N (2000). "Searching for the genetic determinants in a new millennium". Nature. 405 (6788): 847–856. doi:10.1038/35015718. PMID   10866211. S2CID   4392356.
  29. Altmüller J, Palmer LJ, Fischer G, Scherb H, Wjst M (2001). "Genomewide scans of complex human diseases: true linkage is hard to find". Am J Hum Genet. 69 (5): 936–950. doi:10.1086/324069. PMC   1274370 . PMID   11565063.
  30. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K (2002). "A comprehensive review of genetic association studies". Genet Med. 4 (2): 45–61. doi: 10.1097/00125817-200203000-00002 . PMID   11882781.
  31. Cooper RS, "Genetic factors in ethnic disparities in health", in Anderson NB, Bulatao RA, Cohen B, eds., Critical perspectives on racial and ethnic differences in health in later life, (Washington DC: National Academy Press, 2004), 267–309.
  32. Cardon LR, Palmer LJ (2003). "Population stratification and spurious allelic association". Lancet. 361 (9357): 598–604. doi:10.1016/s0140-6736(03)12520-2. PMID   12598158. S2CID   14255234.; Marchini J, Cardon LR, Phillips MS, Donnelly P (2004). "The effects of human population structure on large genetic association studies". Nat Genet. 36 (5): 512–517. doi: 10.1038/ng1337 . PMID   15052271.
  33. Thomas DC, Witte JS (2002). "Point: population stratification: a problem for case-control studies of candidate-gene associations?". Cancer Epidemiol Biomarkers Prev. 11 (6): 505–512. PMID   12050090.
  34. Wacholder S, Rothman N, Caporaso N (2002). "Counterpoint: bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer". Cancer Epidemiol Biomarkers Prev. 11 (6): 513–520. PMID   12050091.
  35. Morton NE, Collins A (1998). "Tests and estimates of allelic association in complex inheritance". Proc Natl Acad Sci USA. 95 (19): 11389–11393. Bibcode:1998PNAS...9511389M. doi: 10.1073/pnas.95.19.11389 . PMC   21652 . PMID   9736746.
  36. Hoggart CJ, Parra EJ, Shriver MD, Bonilla C, Kittles RA, Clayton DG, McKeigue PM (2003). "Control of confounding of genetic associations in stratified populations". Am J Hum Genet. 72 (6): 1492–1504. doi:10.1086/375613. PMC   1180309 . PMID   12817591.
  37. Freedman ML, Reich D, Penney KL, McDonald GJ, Mignault AA, Patterson N, Gabriel SB, Topol EJ, Smoller JW, Pato CN, Pato MT, Petryshen TL, Kolonel LN, Lander ES, Sklar P, Henderson B, Hirschhorn JN, Altshuler D (2004). "Assessing the impact of population stratification on genetic association studies". Nat Genet. 36 (4): 388–393. doi: 10.1038/ng1333 . PMID   15052270.
  38. Tian C, Gregersen PK, Seldin MF (October 2008). "Accounting for ancestry: population substructure and genome-wide association studies". Human Molecular Genetics. 17 (R2): R143–R150. doi:10.1093/hmg/ddn268. PMC   2782357 . PMID   18852203.
  39. Hoggart CJ, Shriver MD, Kittles RA, Clayton DG, McKeigue PM (2004). "Design and analysis of admixture mapping studies". Am J Hum Genet. 74 (5): 965–978. doi:10.1086/420855. PMC   1181989 . PMID   15088268.
  40. Patterson N, Hattangadi N, Lane B, Lohmueller KE, Hafler DA, Oksenberg JR, Hauser SL, Smith MW, O'Brien SJ, Altshuler D, Daly MJ, Reich D (2004). "Methods for high-density admixture mapping of disease genes". Am J Hum Genet. 74 (5): 979–1000. doi:10.1086/420871. PMC   1181990 . PMID   15088269.
  41. Smith MW, Patterson N, Lautenberger JA, Truelove AL, McDonald GJ, Waliszewska A, Kessing BD, et al. (2004). "A high-density admixture map for disease gene discovery in African Americans". Am J Hum Genet. 74 (5): 1001–1013. doi:10.1086/420856. PMC   1181963 . PMID   15088270.
  42. McKeigue PM (2005). "Prospects for admixture mapping of complex traits". Am J Hum Genet. 76 (1): 1–7. doi:10.1086/426949. PMC   1196412 . PMID   15540159.
  43. Chaturvedi N (2001). "Ethnicity as an epidemiological determinant—crudely racist or crucially important?". Int J Epidemiol. 30 (5): 925–927. doi: 10.1093/ije/30.5.925 . PMID   11689494.
  44. Collins FS, Green ED, Guttmacher AE, Guyer MS, US National Human Genome Research Institute (2003). "A vision for the future of genomics research". Nature. 422 (6934): 835–847. Bibcode:2003Natur.422..835C. doi: 10.1038/nature01626 . PMID   12695777. S2CID   205209730.

Further reading