Mayo Clinic Led Study on Long QT Syndrome Sheds Light on Genetic Testing

Results of a Long QT Syndrome study in the current issue of Circulation play an important role in understanding genetic testing’s role in diagnosing disease, according to the senior author, Michael Ackerman, M.D., Ph.D., the Mayo Clinic pediatric cardiologist who directs Mayo’s Long QT Syndrome Clinic and is the director of the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory.
LQTS is a disorder of the electrical system of the heart and affects 1 in 2,500 people.
In the multi-center study that involved Dr. Arthur Wilde in the Netherlands and scientists from PGxHealth, genetic testing results of nearly 400 “slam dunk” LQTS patients and nearly 1,400 healthy volunteers showed that there is a background noise rate of rare variants present in about 4 percent of healthy Caucasian volunteers and that mutation type and mutation location are critical determinants to distinguish this background noise from true LQTS-causative mutations, Dr. Ackerman says.
“Our research shows that genetic testing is just one piece of the information a physician needs to look at,” he says. The results demonstrate that genetic testing does not give a “yes or no” answer for LQTS or other diseases, and it means that physicians need to meticulously interpret this particular diagnostic test with the same scrutiny and tenacity as any other diagnostic test, such as the electrocardiogram (ECG). “It’s proving what we’ve long know in genetic testing circles — that these are not binary tests but are probabilistic tests whereby some test results are going to provide ‘no-doubt-about-it’ diease mutations. Whereas other test results may report a mutation whose pathogenicity is uncertain.”
The Circulation paper is another critical piece in the maturation of LQTS genetic testing from discovery, translation, implementation and now post-implementation interpretation, Dr. Ackerman says. First clinically described in 1957, it took until 1995 until the first genes were discovered. In 2004, the first clinically available test for LQTS became available in North America.
In LQTS, approximately 5 percent to 10 percent of the time, its first symptom is sudden death, often related to physical exertion or auditory triggers such as an alarm clock. However, most cases can be diagnosed following warning signs (sudden, without warning, fainting spells or concerning family history) that suggest its potential presence and from objective data derived from an electrocardiogram (ECG), exercise or adrenalin stress testing, and genetic testing.
Mayo Clinic and Dr. Ackerman have a financial interest in LQTS technology. This technology has been licensed to a commercial entity and both Mayo Clinic and Dr. Ackerman receive royalties from that license.

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X-linked infantile spinal muscular atrophy – Genetics Home Reference

 

X-linked infantile spinal muscular atrophy is a condition that affects only boys and is characterized by severe muscle weakness and absent reflexes (areflexia). Affected children often have multiple joint deformities (contractures) from birth that cause joint stiffness (arthrogryposis) and impair movement. In severe cases, affected infants are born with broken bones. The muscle weakness worsens over time; affected children reach some early motor developmental milestones, such as sitting unassisted, but these skills are often lost (developmental regression).

Additional features of X-linked infantile spinal muscular atrophy include an unusually small chin (micrognathia), abnormal curvature of the spine (scoliosis or kyphosis), and undescended testes (cryptorchidism).

Weakness of the chest muscles used for breathing often leads to life-threatening breathing problems. Children with X-linked infantile spinal muscular atrophy usually do not survive past early childhood due to respiratory failure, although, in rare cases, affected individuals can survive into adolescence.

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Systemic mastocytosis – Genetics Home Reference

 

Systemic mastocytosis is a blood disorder that can affect many different body systems. Individuals with the condition can develop signs and symptoms at any age, but it usually appears after adolescence.

Signs and symptoms of systemic mastocytosis often include extreme tiredness (fatigue), skin redness and warmth (flushing), nausea, abdominal pain, bloating, diarrhea, the backflow of stomach acids into the esophagus (), nasal congestion, shortness of breath, low blood pressure (hypotension), lightheadedness, and headache. Some affected individuals have attention or memory problems, anxiety, or depression. Many individuals with systemic mastocytosis develop a skin condition called urticaria pigmentosa, which is characterized by raised patches of brownish skin that sting or itch with contact or changes in temperature. Nearly half of individuals with systemic mastocytosis will experience severe allergic reactions (anaphylaxis).

There are five subtypes of systemic mastocytosis, which are differentiated by their severity and the signs and symptoms. The mildest forms of systemic mastocytosis are the indolent and smoldering types. Individuals with these types tend to have only the general signs and symptoms of systemic mastocytosis described above. Individuals with smoldering mastocytosis may have more organs affected and more severe features than those with indolent mastocytosis. The indolent type is the most common type of systemic mastocytosis.

The severe types include aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia. These types are associated with a reduced life span, which varies among the types and affected individuals. In addition to the general signs and symptoms of systemic mastocytosis, these types typically involve impaired function of an organ, such as the , . The organ dysfunction can result in an abnormal buildup of fluid in the abdominal cavity (ascites). Aggressive systemic mastocytosis is associated with a loss of bone tissue (osteoporosis and osteopenia) and multiple bone fractures. Systemic mastocytosis with an associated hematologic neoplasm and mast cell leukemia both involve blood cell disorders or blood cell cancer (). Mast cell leukemia is the rarest and most severe type of systemic mastocytosis.

Individuals with the milder forms of the condition generally have a normal or near normal life expectancy, while those with the more severe forms typically survive months or a few years after diagnosis.

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Rosacea – Genetics Home Reference

 

The causes of rosacea are complex and not well understood. Both genetic and environmental factors appear to influence the disorder, although many of these factors have not been identified.

Studies suggest that rosacea is associated with abnormalities of blood vessels (the vascular system) and the immune system. In people with this condition, blood vessels expand (dilate) too easily, which can cause redness and flushing of the skin. Rosacea is also associated with abnormal inflammation. Inflammation is a normal immune system response to injury and foreign invaders, such as bacteria. Abnormal inflammation impairs the skin’s ability to act as a protective barrier for the body. Researchers believe that a combination of blood vessel abnormalities, abnormal inflammation, and a disruption of the skin barrier underlie the signs and symptoms of rosacea.

Among the genes thought to play roles in rosacea are several genes in a family called the . The HLA complex helps the immune system distinguish the body’s own proteins from proteins made by foreign invaders. Each HLA gene has many different variations, allowing each person’s immune system to react to a wide range of foreign proteins. Certain variations in HLA genes likely contribute to the abnormal inflammation that is characteristic of rosacea.

Another group of genes that appear to be involved in the development of rosacea are glutathione S-transferases (GSTs). The proteins produced from these genes help protect cells from oxidative stress. Oxidative stress occurs when unstable molecules called reactive oxygen species (ROS) accumulate to levels that can damage or kill cells. Variants in several GST genes have been associated with an increased risk of developing rosacea. Researchers suspect that these variants reduce the ability of GSTs to protect skin cells from oxidative stress, leading to cell damage and inflammation.

Environmental (nongenetic) factors can also increase the risk of developing rosacea and trigger its symptoms. Among the best-studied risk factors for rosacea is exposure to ultraviolet (UV) radiation from the sun. UV radiation causes oxidative stress that can damage skin cells. Studies suggest that having an overgrowth of certain microorganisms that live on facial skin, particularly mites called Demodex folliculorum, may also contribute to the development of rosacea. These mites stimulate an abnormal immune response and disrupt the normal skin barrier. Other factors that can trigger the signs and symptoms of rosacea or make them worse include heat exposure, spicy food, cigarette smoking, and alcohol, all of which cause blood vessels in the skin to dilate.

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49,XXXXY syndrome – Genetics Home Reference

 

49,XXXXY syndrome is a chromosomal condition in boys and men that causes intellectual disability, developmental delays, physical differences, and an inability to father biological children (infertility). Its signs and symptoms vary among affected individuals.

Boys and men with 49,XXXXY syndrome have mild or moderate intellectual disability with learning difficulties. Speech and language development is particularly affected. Most affected boys and men can understand what other people say more easily than they themselves can speak. People with 49,XXXXY syndrome tend to be shy and friendly, but problems with speech and communication can contribute to behavioral issues, including irritability, difficulty tolerating frustration, defiant behavior, and outbursts or temper tantrums.

49,XXXXY syndrome is also associated with weak muscle tone (hypotonia) and problems with coordination that delay the development of motor skills, such as sitting, standing, and walking. Affected infants and young boys are often shorter than their peers, but some catch up in height later in childhood or adolescence.

Other physical differences associated with 49,XXXXY syndrome include abnormal fusion of certain bones in the forearm (radioulnar synostosis), an unusually large range of joint movement (), elbow abnormalities, curved pinky fingers (fifth finger ), and flat feet (). Affected individuals have distinctive facial features that can include widely spaced eyes (), outside corners of the eyes that point upward (), skin folds covering the inner corner of the eyes (epicanthal folds), and a flat bridge of the nose. Dental abnormalities are also common in this disorder.

49,XXXXY syndrome disrupts male sexual development. The penis is often short and underdeveloped, and the testes may be undescended, which means they are abnormally located inside the pelvis or abdomen. The testes are small and do not produce enough testosterone, which is the hormone that directs male sexual development. The shortage of testosterone often leads to incomplete puberty. Starting in adolescence, affected boys and men may have sparse body hair, and some experience breast enlargement (gynecomastia). Their testes do not produce sperm, so all men with 49,XXXXY syndrome are infertile.

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48,XXXY syndrome – Genetics Home Reference

 

48,XXXY syndrome is a chromosomal condition in boys and men that causes intellectual disability, developmental delays, physical differences, and an inability to father biological children (infertility). Its signs and symptoms vary among affected individuals.

Most boys and men with 48,XXXY syndrome have mild intellectual disability with learning difficulties. Speech and language development is particularly affected. Most affected boys and men can understand what other people say more easily than they themselves can speak. The problems with speech and communication can contribute to behavioral issues, including irritability and outbursts or temper tantrums. Boys and men with 48,XXXY syndrome tend to have anxiety, a short attention span, and impaired social skills.

48,XXXY syndrome is also associated with weak muscle tone (hypotonia) and problems with coordination that delay the development of motor skills, such as sitting, standing, and walking. Affected boys and men tend to be taller than their peers, with an average adult height of over 6 feet.

Other physical differences associated with 48,XXXY syndrome include abnormal fusion of certain bones in the forearm (radioulnar synostosis), an unusually large range of joint movement (), elbow abnormalities, curved pinky fingers (fifth finger ), and flat feet (). Affected individuals may have distinctive facial features, including widely spaced eyes (), outside corners of the eyes that point upward (), and skin folds covering the inner corner of the eyes (epicanthal folds). However, some boys and men with 48,XXXY syndrome do not have these differences in their facial features.

48,XXXY syndrome disrupts male sexual development. The penis is shorter than usual, and the testes may be undescended, which means they are abnormally located inside the pelvis or abdomen. The testes are small and do not produce enough testosterone, which is the hormone that directs male sexual development. The shortage of testosterone often leads to incomplete puberty. Starting in adolescence, affected boys and men may have sparse body hair, and some experience breast enlargement (gynecomastia). Their testes typically do not produce sperm, so most men with this condition are infertile.

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Obsessive-compulsive disorder – Genetics Home Reference

 

Obsessive-compulsive disorder (OCD) is a mental health condition characterized by features called obsessions and compulsions. Obsessions are intrusive thoughts, mental images, or urges to perform specific actions. While the particular obsessions vary widely, they often include fear of illness or contamination; a desire for symmetry or getting things “just right;” or intrusive thoughts involving religion, sex, or aggression. Compulsions consist of the repetitive performance of certain actions, such as checking or verifying, washing, counting, arranging, acting out specific routines, or seeking assurance. These behaviors are performed to relieve anxiety, rather than to seek pleasure as in other compulsive behaviors like gambling, eating, or sex.

While almost everyone experiences obsessive feelings and compulsive behaviors occasionally or in particular contexts, in OCD they take up more than an hour a day and cause problems with work, school, or social life. People with OCD generally experience anxiety and other distress around their need to accommodate their obsessions or compulsions.

About half the time, OCD becomes evident in childhood or adolescence, and most other cases appear in early adulthood. It is unusual for OCD to start after age 40. It tends to appear earlier in males, but by adulthood it is slightly more common in females. Affected individuals can experience periods when their symptoms increase or decrease in severity, but the condition usually does not go away completely.

Some people with OCD have additional mental health disorders such as generalized anxiety, depression, phobias, panic disorders, or schizophrenia. OCD can also occur in people with other neurological conditions such as Tourette syndrome and similar disorders, traumatic brain injury, stroke, or dementia.

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Wilms tumor – Genetics Home Reference

 

Changes in any of several genes are involved in the formation of Wilms tumor. Wilms tumor is often associated with mutations in the WT1 gene, CTNNB1 gene, or AMER1 gene. These genes provide instructions for making proteins that regulate gene activity and promote the growth and division (proliferation) of cells. WT1, CTNNB1, and AMER1 gene mutations all lead to the unchecked proliferation of cells, allowing tumor development.

Changes on the short (p) arm of chromosome 11 are also associated with developing Wilms tumor. Two genes in this area, IGF2 and H19, are either turned on or off depending on whether the copy of the gene was inherited from the mother or the father. This parent-specific difference in gene activation is a phenomenon called genomic imprinting. In some cases of Wilms tumor, abnormalities in the process of genomic imprinting on chromosome 11 lead to a loss of H19 gene activity and increased activity of the IGF2 gene in kidney cells. The resulting loss of H19 gene activity, which normally restrains cell growth, and increase in IGF2 gene activity, which promotes cell growth, together lead to uncontrolled cell growth and tumor development in people with Wilms tumor.

In most cases of Wilms tumors involving one kidney and nearly all cases involving both kidneys, the tumors are thought to arise from immature kidney tissue that never developed properly. These immature tissues are known as nephrogenic rests. It is likely that genetic changes are involved in the presence of nephrogenic rests and that additional genetic changes trigger nephrogenic rests to develop into a tumor.

Genetic conditions that share a genetic cause with Wilms tumor can also have this cancer as a feature. These conditions include WAGR syndrome, Denys-Drash syndrome, and Frasier syndrome, which are caused by mutations in the WT1 gene. Wilms tumor has also been seen in individuals with Beckwith-Wiedemann syndrome, which can be caused by changes in the genomic imprinting of the IGF2 and H19 genes. Wilms tumor can be a feature of other genetic conditions caused by mutations in other genes.

Many children with Wilms tumor do not have identified mutations in any of the known genes. In these cases, the cause of the condition is unknown. It is likely that other, unknown genes are also associated with the development of Wilms tumor.

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MAND – Genetics Home Reference

 

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  • Mullegama SV, Elsea SH. Clinical and Molecular Aspects of MBD5-Associated Neurodevelopmental Disorder (MAND). Eur J Hum Genet. 2016 Aug;24(9):1235-43. doi: 10.1038/ejhg.2016.35. Epub 2016 May 25. Review. Erratum in: Eur J Hum Genet. 2016 Aug;24(9):1376.
  • Mullegama SV, Pugliesi L, Burns B, Shah Z, Tahir R, Gu Y, Nelson DL, Elsea SH. MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith-Magenis and fragile X syndromes. Eur J Hum Genet. 2015 Jun;23(6):781-9. doi: 10.1038/ejhg.2014.200. Epub 2014 Oct 1.
  • Mullegama SV, Rosenfeld JA, Orellana C, van Bon BW, Halbach S, Repnikova EA, Brick L, Li C, Dupuis L, Rosello M, Aradhya S, Stavropoulos DJ, Manickam K, Mitchell E, Hodge JC, Talkowski ME, Gusella JF, Keller K, Zonana J, Schwartz S, Pyatt RE, Waggoner DJ, Shaffer LG, Lin AE, de Vries BB, Mendoza-Londono R, Elsea SH. Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder. Eur J Hum Genet. 2014 Jan;22(1):57-63. doi: 10.1038/ejhg.2013.67. Epub 2013 May 1.
  • Tadros S, Wang R, Waters JJ, Waterman C, Collins AL, Collinson MN, Ahn JW, Josifova D, Chetan R, Kumar A. Inherited 2q23.1 microdeletions involving the MBD5 locus. Mol Genet Genomic Med. 2017 Aug 8;5(5):608-613. doi: 10.1002/mgg3.316. eCollection 2017 Sep.
  • Talkowski ME, Mullegama SV, Rosenfeld JA, van Bon BW, Shen Y, Repnikova EA, Gastier-Foster J, Thrush DL, Kathiresan S, Ruderfer DM, Chiang C, Hanscom C, Ernst C, Lindgren AM, Morton CC, An Y, Astbury C, Brueton LA, Lichtenbelt KD, Ades LC, Fichera M, Romano C, Innis JW, Williams CA, Bartholomew D, Van Allen MI, Parikh A, Zhang L, Wu BL, Pyatt RE, Schwartz S, Shaffer LG, de Vries BB, Gusella JF, Elsea SH. Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder. Am J Hum Genet. 2011 Oct 7;89(4):551-63. doi: 10.1016/j.ajhg.2011.09.011.
  • Walz K, Young JI. The methyl binding domain containing protein MBD5 is a transcriptional regulator responsible for 2q23.1 deletion syndrome. Rare Dis. 2014 Nov 3;2(1):e967151. doi: 10.4161/2167549X.2014.967151. eCollection 2014.

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