Phenotype:

• Detectable clinical, physiological, or biochemical manifestation in an individual

Genotype:

• Genetic constitution of an individual.  Usually refers to a particular gene or a set of genes that have been altered (mutated)

Expression:

• Any clinical manifestation due to mutation in a single gene

Penetrance:

• % of individuals with mutation who will show clinical manifestations (relative term)

Affect of age:

• Huntington’s: 10% <20years, >90% >60years

Genetic heterogeneity:

• A clinical syndrome caused by > 1 gene is called non-allelic genetic heterogeneity

  • TSC caused by hamartin and tuberin gene mutations

Allelic heterogeneity:

• One gene (allele) causes >1 clinical syndrome is called allelic disorders (allelic heterogeneity)

  • Familial hemiplegic migraine-1, episodic ataxia type 2 and SCA 6 caused by mutations in CACNA1A (Ca channel) gene.

Lyonization:

• Refers to a normal biological phenomenon in females where one X chromosome is inactivated (genes silenced) in every cell. This is a random process (therefore, ~50% of the cells have either of the X chromosome working)

Autosomal dominant disorders: 

• Trait is encoded by a gene present on one of the 22 autosomes and is dominant in its relationship with its allele. Thus, it is fully expressed in heterozygotes - that is even if one copy of this gene is present. Thus only one parent must be affected for an offspring to be at risk for developing the phenotype.  The basic features of autosomal dominant inheritance are as follows: 

  • Trait is apparent in heterozygotes

  • A vertical pattern is observed in the pedigree, with multiple generations being affected.

  • Affected heterozygote has 50% chance of transmitting the gene to each offspring.

  • Trait is expressed in every generation.

  • The unaffected offspring of the symptomatic carrier does not transmit the trait.

  • Marfan's syndrome, achondroplasia, osteogenesis imperfecta, familial hypercholesterolemia, adult polycystic kidney disease, Wilm's tumor, spherocytosis, familial polyposis coli, Huntington's disease, neurofibromatosis, von-Willebrand's dz, Ehlers-Danlos syndrome

  • Examples of autosomal dominant neurological disorders:

    • NF-1 and NF-II

    • DM1 and DM2

    • TSC

    • JME

    • Huntingtion disease

    • Benign neonatal convulsions

    • Hereditary ataxias

    • Von hippel Lindau

    • Charcot-Marie-Tooth disease

    • Dementias including familial Alzheimer’s

Autosomal recessive disorders:

• Trait is encoded by genes located on one of the 22 autosomes. These genes are expressed only under homozygous conditions - that is only if paired with an identical allele. The basic features are as follows:

  • Tend to be more severe than autosomal dominant disorders.

  • A horizontal pattern is noted in the pedigree, with a single generation being affected.

  • Gene effect is apparent only in homozygotes.

  • Known to occur especially in the context of parental consanguinity.  The rarer the recessive phenotype, the more likely it is that the parents are consanguineous (related).

  • If both parents are carriers, the child has 50% chance of being a carrier, 25% chance of being affected, or 25% chance of being unaffected.

  • If one parent is a carrier and the other is normal, the child has 50% chance of being a carrier and 50% chance of being unaffected.

  • If both affected parents have the same recessive phenotype, all their offsprings will be affected. 

  • Example:  VRK1 is associated with a spectrum of autosomal recessive motor neuron disorders including distal hereditary motor neuropathy, amyotrophic lateral sclerosis, isolated spinal muscular atrophy, and pontocerebellar hypoplasia with infantile spinal muscular atrophy type 1a.  For an individual to develop one of these associated conditions, they must inherit not working, or mutated, copies of the VRK1 gene from each parent.  Only one not working copy of VRK1 was identified in patient.  Individuals with only one non-functioning gene are termed carriers.  Carriers are asymptomatic and not at risk to develop the condition.  Mutations in our genetic code are not caused by anything we've done, nor can they be prevented.  They are a result of a random error made by our cells and have likely been passed, unknown, through our families for many generations.   If two carriers have children together, there is a 25% chance with each pregnancy that the child would be affected with the condition, a 50% chance with each pregnancy that the child would be a carrier, and a 25% chance with each pregnancy that the child would be neither a carrier or affected.  These chances are independent of the outcome of any previous pregnancies.  So two carriers could have 4 affected children, 4 unaffected non-carrier children, 4 carrier children, or any mix of affected, unaffected non-carrier, and carrier.

  • Often associated with deficient activity of enzymes and are thus termed inborn errors of metabolism.

  • Cystic fibrosis, sickle cell anemia, Thalassemia, Tay-Sachs disease, Niemann-Pick disease, Hurler syndrome, Hunter's syndrome, Phenylketonuria, Albinism, Gaucher's dz, Wilson's dz.

  • Examples of autosomal recessive neurological disorders:

    • PKU

    • SMA (infantile)

    • Tay-Sachs disease

    • Wilson disease

    • Metachromatic leukodystrophy

    • Ataxia-telangiectasia

    • Lafora body myoclonic epilepsy

    • Canavan disease

    • Ceroid lipofucinosis

    • Friedreich ataxia

    • Niemann-Pick disease

X-linked Recessive disorders:

• Coded by recessive genes located on X chromosome and not found on Y chromosome.

• Traits are expressed in males. Females rarely express the trait as they are usually heterozygous, and have a dominant allele for this trait on the other X chromosome. Expressed in females only if the person is homozygous or skewed inactivation of the normal X chromosome occurs (Lyonization).

• The basic features are as follows:

  • Gene effect is usually evident only in males and only rarely in females.

  • Gene is transmitted from an asymptomatic mother.

  • Sisters of an affected male are all asymptomatic. They could or may not be carriers. Unaffected brothers do not carry the gene and do not transmit the trait.

  • Each son of a carrier female has a 50% chance of being affected. Affected males do not transmit the gene to their sons, but all of their daughters are asymptomatic carriers.

  • Disease presents rarely in females, who are homozygous. These women have inherited one abnormal allele from the affected father and one from the asymptomatic carrier mother.

  • Thus, X-lined recessive disease shows almost exclusively in affected males in multiple generations with transmission through normal carrier females and never shows male-to-male transmission.

  • Hemophilia A and B, Duchenne type muscular dystrophy, Becker type muscular dystrophy, Agammaglobulinemia, Wiskot-Aldrich syndrome, X-linked immunodeficiency, Lymphoproliferative disorders, androgen insensitivity, Lesch-Nyhan syndrome.

  • Examples of X-linked neurological disorders:

    • ALD

    • Pelizaeus-Merzbacher disease

    • Emery-Dreifuss muscular dystrophy, X28 (Emerin)

    • Spinal bulbar muscular atrophy

    • OTC deficiency: Xp21(OTC enzyme, urea cycle)

    • Lowe’s disease Xq25 (oculo-cerebro-renal dis)

    • Menkes’ disease Xp11 (copper transport)

    • Lesch-Nyhan Xq26 (HGPRT deficiency)

    • Fragile-X Xq27 (FMR 1 gene)

    • Duchenne/Becker Xp21.2 (dystrophin)

    • CMTX Xq13 (connexin 32)

    • Adrenoleukodystrophy Xq28(peroxisomal disorder, ALDP membrane protein)

    • Hunter’s (MPS) Xq27 (Iduronate 2-sulfatase)

    • Subcortical band heterotopia Xq22 (Doublecortin)

    • Fabry’s disease Xq22 (Trihexoside storage)

    • Kennedy’s disease Xq21 (Androgen receptor)

    • X-linked hydrocephalus (aqueductal stenosis) / X -linked spastic paraplegia (SPG1) / (MR, aphasia, shuffling gait, adducted thumbs): Xq28 (L1CAM gene, adhesion molecule)

X-linked Dominant disorders:

• • • Xq28 (MECP2 mutation): Rett

    • Xp22 (MR, seizures, agenesis corpus callosum): Aicardi

    • Incontinentia pigmenti, Xq28 mutation in the nuclear factor-kappa-B essential modulator gene ( NEMO/IKKγ)

    • Fragile X syndrome

Maternal inheritance of the mitochondrial genome.

• Mitochondrial DNA is passed on exclusively in the maternal line: mitochondrial genetic diseases are transmitted only by mothers to their children (both male and female), but never by fathers.

• Mitochondria with mutated DNA can coexist in the same cell with other mitochondria whose DNA is normal. 

• In mitochondrial genetic diseases, the phenotype, i. e., the clinical finding depends on the proportion of normal to abnormal mitochondria in a given patient. This phenomenon is called heteroplasmy. The rate of heteroplasmy differs , often drastically, among maternal family members, and the proportion of abnormal mitochondria may vary from one organ to another organ in the same patient.  The cells develops the disease when the proportion of mutant mitochondrial DNA reaches a threshold.  Below this threshold the cell is normal phenotype.

• Point mutations in mtDNA tend to be inherited through females, whereas deletions of mtDNA tend to be sporadic events in isolated individuals.

• Mutation in the nuclear gene controlling the mtDNA expression.

• Examples of mitochondrial neurological disorders:

  • MEERF

  • MELAS

  • Leigh's encephalopathy

  • LHON

  • Kearns-Sayre syndrome

  • NARP

Disease severity increases in subsequent generations with expansion of TNR (biological phenomenon peculiar to neurological diseases)

• Fragile X syndrome: 

• Huntington’s disease

• Myotonic dystrophy 1: 19q, CTG, DMPK gene

• Myotonic dystrophy 2: 3q, CCTG, CNBP (a,k.a ZNF9) gene

• Spinal bulbar atrophy (Kennedy’s disease): Xq12, CAG, AR gene (androgen rcp)

• Various spino-cerebellar ataxias

• Friedreich’s ataxia: 9q, GAA, frataxin protein, FXN (frataxin) gene

• Denatatorubral-pallidoluysion atrophy (DRPLA): 12p, CAG, atrophin protein, ATN1 gene

Multifactorial Inheritance:

• Familial diseases not inherited according to the rules of Mendelian genetics.

• Diseases are a product of several genes that interact with each other and are also influenced by exogenous (epigenetic) factors. 

• Dwarfism, diabetes mellitus, hypertension, gout, mental retardation, anencephaly, cleft lip or palate.

Glossary.

Allele: the specific version of a gene. An individual typically inherits two alleles for each gene (unless those genes are located on the sex chromosomes in males), one from each biological parent.

Amino acids: the building blocks of protein.

Autosomal: related to the numbered chromosomes that are not sex chromosomes (X and Y).

Benign/likely benign: a type of variation in DNA that does not lead to known genetic conditions. DNA contains many variants and most are benign. Likely benign describes a genetic variant that is not expected to lead to a genetic condition, but the scientific evidence is not as strong as for the variants that are called benign.

Benign (pseudodeficiency allele): genetic variants that are not known to cause genetic conditions, but can alter the protein products or change the gene’s expression. Some of these variants may be associated with abnormal biochemical test results, but do not cause a genetic condition. Some biochemical studies can’t differentiate between pathogenic/likely pathogenic variants and pseudodeficiency alleles, so these must be distinguished with genetic testing.

Carrier: an individual with a single genetic variant (pathogenic or likely pathogenic) in a gene that causes a recessive condition. Two pathogenic or likely pathogenic genetic variants in a gene are needed to cause a recessive condition, but a carrier only has one of these. Being a carrier does not typically impact that individual’s health, but can impact reproductive risk and family planning.

Chromosome: a large piece of DNA that carries many genes. Humans typically have 23 pairs of chromosomes (22 pairs of autosomal or numbered chromosomes and 1 pair of sex chromosomes). Chromosomes are in pairs because one is inherited from each parent. Chromosome pairs 1-22 are the same, regardless of biological sex. The sex chromosomes are X and Y; a female has two X chromosomes and a male has one X chromosome and one Y chromosome.

DNA: deoxyribonucleic acid (DNA) is the material inside of each cell that contains all the genetic information the body needs to function.

Deletion or duplication: large sections of DNA that are missing (deletion) or extra (duplication). They can range in size from a small section within a gene to a larger section containing multiple genes. These are also called copy number variations (CNV).

De novo variant: a genetic variant that was not passed from a parent to a child, but arose new in an individual’s DNA.

Dominant inheritance: a genetic condition would only occur with a single pathogenic/likely pathogenic variant in a gene.

Exome: the part of our genetic material that consists of all the exons within our DNA and codes for proteins.

Exon: the portion of a gene that codes for amino acids and is typically the parts of the gene that are expressed in the final product (the protein).

Family variant testing (FVT): a service at Invitae through which blood relatives of individuals who pursued genetic testing may be eligible for genetic testing to clarify their personal or reproductive risk. For more information regarding eligibility, requirements, and details for this family member testing service, click here.

Gene: a section of DNA that instructs our body how to make a certain protein. Genes are made up of introns and exons and are arranged along chromosomes. Humans have approximately 20,000 genes and typically have two copies of each gene (unless those genes are located on the sex chromosomes in males).

Genetic counseling: an appointment with a healthcare provider specifically trained in medical genetics and counseling to help individuals understand the process of genetic testing, what their genetic test results mean, and the implications for themselves and their family members.

Genetic testing: the process of analyzing an individual’s DNA to look for variants in their genes that could be associated with genetic conditions.

Hemizygous: variant is present in a biological male’s single copy of the X chromosome.

Heterozygous: variant is present in only one of the two copies of a gene.

Homozygous: variant is present in both copies of the gene.

In-cis: when more than one genetic variant is located on the same copy of the gene.

In-trans: when more than one genetic variant is located on opposite copies of the gene.

Increased risk allele: the variant is not expected to directly cause a genetic condition on its own, but there is scientific evidence that it can lead to an increased risk/predisposition to develop the genetic condition in combination with other genetic variants or factors.

Intron: the portion of the gene that does not code for amino acids or expressed in proteins. Introns are located in between the exons.

Inheritance pattern: how a genetic condition is inherited through a family. This includes recessive, dominant, and X-linked.

Inherited variant: a genetic variant that was passed from a parent to a child.

MedGen UID: an identifier within the MedGen database. MedGen is an online database primarily used by healthcare professionals to obtain more information about a specific genetic condition. The MedGen UID is a number that correlates to information about a specific genetic condition.

Mosaic: when the cells studied from one individual have different genetic makeups. For example, a genetic variant may be present in some cells of the body and not present in others. There are different types of mosaicism and the level of mosaicism for a particular individual could influence the symptoms experienced with a genetic condition.

Multifactorial: a combination of factors (genetic and environmental) that lead to a predisposition to, or diagnosis of, a genetic condition.

Mutation: another term for a genetic variant. See definition of “variant” for additional information.

Next generation sequencing (NGS): a laboratory technique that allows for analysis of the exact sequence of letters within a gene and can analyze multiple genes at once.

Pathogenic/likely pathogenic: variants in DNA that are expected to lead to a known genetic condition. A likely pathogenic variant has a high likelihood of causing a known genetic condition and should be managed in the same manner as a pathogenic variant.

Pathogenic (low penetrance): variants in DNA that can cause a genetic condition, but some individuals who have this genetic variant don’t develop the condition or have milder symptoms. The reason why some people develop symptoms and others don’t is not fully known at the current time and not able to be predicted.

Pedigree: a chart showing the family tree of an individual that can be used to analyze inheritance of a genetic condition.

Penetrance: describes the likelihood that an individual with a pathogenic or likely pathogenic genetic variant(s) will actually develop symptoms of the condition. Full or complete penetrance means that every individual with the genetic variant is expected to develop symptoms. Incomplete or reduced penetrance indicates that not every individual with the genetic variant will develop symptoms. This is thought to be due to a combination of both known and unknown factors.

PIN network: Invitae specific service that allows individuals to connect with researchers, clinicians, pharmaceutical companies, and advocacy organizations. There is not a PIN for every genetic condition at this time, but a directory can be found here.

PMID: an abbreviation for PubMed ID. PubMed is an online database used primarily by healthcare professionals and scientists to access medical and scientific articles. A PMID is a number that correlates to a specific article for easier searching.

Potentially positive: a result that could be associated with a diagnosis of, or predisposition to, a genetic condition, but Invitae needs additional information before it can be confirmed. This additional information can include family member testing to determine segregation of variants (in-cis or in-trans) or that more scientific evidence about the pathogenicity of a specific variant is needed. This result type would apply to individuals with one of the following two scenarios:

1. More than 1 pathogenic/likely pathogenic variant in a gene associated with a recessive condition but the segregation of the variants are unknown 

2. At least one pathogenic/likely pathogenic variant and at least one variant of uncertain significance (VUS) in a gene associated with a recessive condition but the segregation of the variants is unknown.

Preliminary evidence gene: a gene that the scientific community has found to have some evidence to be associated with a genetic condition, but more information is needed to confirm or rule out this association.

Proband: the first person in a family to receive genetic testing, often prompted by this person’s health concerns. A proband’s genetic test result can have implications for their biological family members, especially if they have a genetic condition.

Protein: a molecule that is composed of amino acids and plays an important role in the structure, function, and regulation of our body.

Recessive inheritance: a genetic condition would occur only with pathogenic/likely pathogenic variants in both copies of the gene. A single pathogenic variant would confer carrier status (see definition of “carrier” for more information) and is unlikely to cause the genetic condition.

Segregation: analysis through family member testing to help determine how a variant or variants were inherited and could help clarify if the particular variant(s) is responsible for causing the genetic condition. This can lead to the variants being called in-cis (same copy of the gene) or in-trans (opposite copy of the gene).

Syndrome: a genetic condition that can cause health concerns in different body systems.

Transcript (reference sequence): the version of the genetic sequence for a particular gene that is evaluated through genetic testing. For example, NM_206933.2.

Variable expressivity: when individuals with the same genetic variant (within families or among different families) have different symptoms, age of onset, and progression associated with the same condition.

Variant: a genetic “spelling” change in the sequence of the DNA that may or may not affect the function of the gene(s) or product(s). Variants can be pathogenic, likely pathogenic, likely benign, benign, have unknown significance, or be considered an increased risk allele.

Variant classification: a process for analyzing the available evidence for a particular genetic variant(s) and applying a formal variant classification based on this information. A formal classification is meant to help answer the clinical significance of the variant. Variants can be pathogenic, likely pathogenic, likely benign, benign, have unknown significance, or be considered an increased risk allele. For more information regarding Invitae’s specific variant classification click here.

Variant of uncertain significance (VUS): a variation in DNA that has an uncertain or unknown impact on health. If someone has a VUS, they do not necessarily have an increased risk of developing a certain genetic condition. Over time, the scientific and medical community will identify new evidence about each particular VUS and the classification of the variant may be changed to benign/likely benign, or less commonly, to likely pathogenic/pathogenic.

VUS resolution: a service at Invitae to gather more evidence about a particular variant of uncertain significance by testing additional biological relatives to potentially help reclassify that variant. For more information regarding eligibility, requirements, and details for this family member testing service click here.

X-inactivation: a normal process in females (who typically have two X chromosomes) by which one X chromosome is randomly inactivated (turned off) during fetal development. This process occurs by chance and can sometimes impact health conditions with genes located on the X chromosome. This is also known as “lyonization.”

X-linked inheritance: means that the gene associated with the condition is located on the X chromosome. Females typically have two X chromosomes, while males typically have one X and one Y chromosome. As males typically have only one X chromosome, pathogenic or likely pathogenic variants in genes on the X chromosome usually affect males more often than females.

Zygosity: indicates the number of times a specific variant is present in the copy or copies of a gene. Zygosity can be described as heterozygous, homozygous, and hemizygous (see applicable definitions for more information on each term).

GENETIC COUNSELING

We reviewed that humans have 23 pairs of chromosomes within each of the cells of their body, for a total of 46. One copy of each chromosome comes from a person's mother, and one from their father. Each chromosome is made up of a single, long strand of DNA. It may be thought of as a recipe book. Specific segments of DNA, known as genes, provide codes for the body to make certain proteins. These may be thought of as individual recipes within the recipe books. There are around 20,000 genes in the human genome, and the proteins they code for have a wide variety of roles in our growth, development and functioning. The specific parts of a gene that act as instructions for making our proteins are called exons. Put together, the exons form our exome, which makes up approximately 2%-3% of our DNA. While the exome is such a small part of our DNA, we know that most genetic disorders are caused by mutations, or changes, to these areas. 

Whole exome sequencing (WES) functions by reading through, or sequencing, the genetic code contained in our exome to look for any changes or misspellings. Whole exome sequencing is currently one of the most comprehensive genetic tests available to look for the cause of genetic conditions. This testing is implicated for Todd because he has already had a very large diagnostic workup that has not identified a particular disorder or genetic change responsible for his/her health concerns.

In addition to the exome sequencing we have requested mitochondrial genome sequencing to be completed at the same time. Our mitochondria provide energy for our cells and contain their own small amount of DNA. This DNA is only inherited from the mother.

Data analysis: All individuals have rare changes, or variants, in their genetic code. While examining the exome, the lab is expecting to find thousands of changes in an individual’s DNA, but most of these will represent normal variation, or what makes us different from one another. The vast majority of these changes do not actually change the way the protein is being made and do not lead to clinical features. When the sequencing is completed the laboratory, directed by their medical geneticists, will review the mutations found to determine the importance of the findings. They will filter through these changes by using various databases, medical literature, and by comparing a patient's sample to their parents/family members. 

Family member samples: Exome testing is ideally performed on 3 or more individuals in a family. Using these additional family members significantly improves the chance of identifying a disease causing gene and decreases the chance of resulting a VUS. Additionally, comparing Todd's results to his parents' results could reveal the inheritance pattern and would give information for chances of other family members to have a child with the same condition. 

Variants identified by genetic testing may have been inherited from a parent or may be new within the tested individual. Genetic testing results should be discussed with a genetic counselor, as they may have implications not only for the tested individual, but also for their biological relatives. Today, we reviewed a couple of common inheritance patterns (though others are also possible):

Autosomal dominant conditions: symptoms can occur when only one copy of the gene has a disease-causing variant. In those cases, affected individuals have a 50% chance of passing the variant, and the syndrome, to each child conceived. 

Autosomal recessive conditions: individuals with a disease-causing variant in one copy of the gene (heterozygous) are generally asymptomatic, while individuals with a disease-causing variant in both copies of the gene (homozygous) are typically affected with the disorder. Such conditions present a 25% risk of having affected offspring when both parents are found to be heterozygous “carriers.” Children of affected individuals are obligate carriers, but could be affected if their other parent is also affected or a carrier. 

Test results may be classified as:

Positive/pathogenic: the specific variant is known to cause disease 

Negative: no changes were identified by the analysis that are thought to be responsible for the patient's features

Variant of unclear significance (VUS): In some cases, data about the variant may be limited or conflicting. Some variants may have never been reported before, making interpretation difficult. When it cannot be determined whether a variant may be associated with disease, the variant is classified as a VUS. This result does not change medical management. However, it is recommended that individuals retain such results because they may be reclassified over time, as more data become available. 

Gene of uncertain significance: A change may be identified in a candidate gene, where it is suspected that the gene is responsible for disease, but not confirmed.

Incidental findings are known disease-causing mutations that are in genes unrelated to xxx current health issues but could have a medical management impact for both the patient and their family. These are reported rarely at the lab's discretion.

Additionally, the American College of Medical Genetics recommends reporting on incidental findings in 78 genes that are associated with genetic conditions determined to be well-recognized and known to have a strong link of causation. These genes were chosen because preventative measures and treatments do exist for the associated conditions. The genes include some associated with cancer predisposition risk, adult-onset cardiology conditions, and connective tissue disease, among other conditions. There may be other genes associated with these conditions that are not reported as they are not included on the ACMG 78 list. A negative result for incidental findings does not rule out all heritable causes for these conditions. The testing lab will only report on these particular findings in family members if they are first identified in the patient. It is an individual's choice as to whether or not they want to learn this information. 

Technical Limitations of WES: This testing will not look at all of the genes in Todd, just those that code for proteins. Also, this testing is not able to look at all of the parts of every gene that is tested. The family is aware that there is a chance that despite this comprehensive testing we may not find an answer for Todd's history or we may find results that are not medically actionable. A negative test can occur because a genetic cause is located outside of the exome, is outside the scope of our current knowledge, or because of limitations with the technology. WES is able to detect some, but not all, missing or extra pieces of DNA (deletions/duplications). WES is also unable to detect repeat expansion disorders, like fragile X syndrome , Huntington's disease, and myotonic dystrophy.

Sometimes, someone's symptoms are multifactorial in nature. That is, although a single genetic cause can sometimes help explain such features, in other cases they may result from a combination of multiple genetic and/or environmental factors interacting during development and beyond. Such multifactorial contributions cannot be easily identified by current genetic testing. Autoimmune conditions are often multifactorial.

For your reference, the Genetic Information Non-discrimination Act (GINA) of 2008 prohibits most employment or health insurance discrimination on the basis of genetic information. However, it has certain limitations, such as for federal and military personnel (although these individuals may be covered under other policies with similar protections). GINA does not prevent health insurance companies from making coverage decisions based on the diagnosis of a health-related condition, even if genetic information contributed to that diagnosis. GINA does not provide protections when applying other types of insurance, such as life, long-term care, or disability. More information can be found at <www.ginahelp.org>. 

VUS

The myopathy panel did identify a variant of uncertain significance in xxx.

When a variant is identified through genetic testing, the lab investigates the possibility of whether the variant is a normal variation or possibly linked to an increased chance for a condition.  In his case, there is insufficient evidence to classify variant as benign or harmful.  Thus it has been reported as a variant of uncertain significance (VUS), meaning it could be normal variation or cause an increased chance for health concerns.  It just is not known yet which is true for this particular variant.  Typically, variants remain unclassified until a sufficient number of individuals are found to have the same variant and its effect on humans can be more clearly understood.  The testing lab will continue to collect data about all variants that are identified through their testing, and when they have accumulated enough evidence to support reclassification, they will contact the ordering provider with updates.  About 90% of the time uncertain variants are reclassified as benign, or normal variation, so they are typically managed as such without additional medical management or family member testing recommendations based on the finding of a variant of uncertain significance.

Importantly, the lab report indicates the specific change found in xxx has been seen in healthy population databases, has not been reported in individuals with the associated condition(s), and computer algorithms suggest the variant is unlikely to impact function.  As such this finding is leaning toward benign status and therefore considered limited suspicion for this variant causing health concerns even with it reported as a VUS.  As such, familial VUS testing is not recommended by the clinical team.

As discussed at the visit, genetic testing is not perfect and unfortunately cannot rule out either of these conditions.  As such, further evaluation by her other providers may assist in determining other differential diagnoses, some of which may be genetic.  If this is the case, we would be happy to help coordinate additional genetic evaluation in the future.

Recommendations/Plan:

No further genetic testing is recommended; however, we would be happy to see xxx for a revisit if there are any significant changes to medical or family histories. 

xx should continue to follow with appropriate specialists. 

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

A variation in DNA that has an uncertain or unknown impact on health. If someone has a VUS, they do not necessarily have an increased risk of developing a certain genetic condition. Over time, the scientific and medical community will identify new evidence about each particular VUS and the classification of the variant may be changed to benign/likely benign, or less commonly, to likely pathogenic/pathogenic.

How to read this?

VUS, c.305C>T (p.Ala102Val).  How to read this?  

• p. mean protein.  The sequence p.ALA102Val means the protein Alanine which is a neutral and non-polar is replaced by Valine, which is neutral and non-polar, at codon 102 of the CAV3 protein. 

• The c.424G>A (p.V142I) alteration (also known as p.V122I) is located in coding exon 4 of the TTR gene. This alteration results from a G to A substitution at nucleotide position 424, causing the valine (V) at amino acid position 142 to be replaced by an isoleucine (I). p. mean protein. 

FKRP c.632C>T (p.Ser211Leu) heterozygous Likely Pathogenic 

• p. means protein.  The sequency p.Ser211Leu means the amino-acid Serine is replaced by Leucine, at codon 211.  This alteration results from C to T substitution at neucleotide 632, causing the amino acid Seine at codon 211 to be replaced by amino acid Leucine. 

•