medical genetics medical genetics 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. for a non-technical introduction to the topic, see introduction to genetics. part of a series ongenetics key components chromosome dna rna genome heredity mutation nucleotide variation outline index history and topics introduction history evolution (molecular) population genetics mendelian inheritance quantitative genetics molecular genetics research geneticist dna sequencing genetic engineering genomics ( template) medical genetics branches of genetics personalized medicine personalized medicine category 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. 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 birth defects developmental disability, autism, epilepsy short stature and skeletal dysplasia 3. adult genetics cardiomyopathy and cardiac dysrhythmias inherited kidney disease dementia and neurodegeneration connective tissue disease 4. cancer genetics breast/ovarian cancer bowel cancer endocrine tumors examples of genetic syndromes that are commonly seen in the genetics clinic include chromosomal rearrangements (eg 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, doctors who practice clinical genetics are accredited by the american board of medical genetics and genomics (abmgg). 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. 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. 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. 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. the nazi misuse of eugenics sounded its death knell. 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: referral to an out-patient genetics clinic (pediatric, adult, or combined) or an in-hospital consultation, most often for diagnostic evaluation. specialty genetics clinics focusing on management of inborn errors of metabolism, skeletal dysplasia, or lysosomal storage diseases. referral for counseling in a prenatal genetics clinic to discuss risks to the pregnancy (advanced maternal age, teratogen exposure, family history of a genetic disease), test results (abnormal maternal serum screen, abnormal ultrasound), and/or options for prenatal diagnosis (typically non-invasive prenatal screening, diagnostic amniocentesis or chorionic villus sampling). multidisciplinary specialty clinics that include a clinical geneticist or genetic counselor (cancer genetics, cardiovascular genetics, craniofacial or cleft lip/palate, hearing loss clinics, muscular dystrophy/neurodegenerative disorder clinics). 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 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. 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