Neurogenetics and genetic and genomic testing …

Ravi Uniyal MD DM

Neuromuscular Disorders

Updated 12.09.2024
Released 09.27.2013
Expires For CME 12.09.2027

Neurogenetics and genetic and genomic testing

Author: Ravi Uniyal MD DM

See Contributor Disclosures

Editor: Aravindhan Veerapandiyan MD

Neurogenetics and genetic and genomic testing

In This Article

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Introduction

Overview

Neurogenetics encompasses heritable disorders in all the subspecialties of neurology and is an ever-growing field. New technologies such as next-generation sequencing (including whole exome or whole genome sequencing) are expanding testing options, discovering new mutations, and creating challenges in counseling, interpreting, and reporting results to the patient. Yet, next-generation sequencing does not detect many neurogenetic disorders. This article summarizes the types of genetic tests currently available and the resources for choosing appropriate and economical testing are discussed.

Key points

	• Deciding on the genetic tests to order can be simplified by narrowing the differential diagnosis and defining the patient’s phenotype.
	• Next-generation sequencing of the whole exome is useful for simultaneously testing for multiple candidate genes or for discovering new, rare disorders.
	• Whole exome sequencing is unsuitable for detecting polynucleotide repeat disorders or large insertion/deletions.
	• Genetic counseling, informed consent, and insurance preauthorization must be obtained before performing genetic testing.

Historical note and terminology

Genetic disorders affecting the nervous system typically present first to the general neurologist at any point in the patient’s lifespan. Neurogenetic disorders are a component of every neurologic subspecialty. The heritable nature of certain neurogenetic disorders was appreciated well before the discovery of DNA. Diagnosis by biochemical assays for metabolic and enzymatic defects or histologic changes on muscle biopsy well preceded the description of DNA. Indeed, the precedent for treatment of neurogenetic disorders with metabolic defects began before clinical genetic tests became available.

Table 1. Timeline of Therapies of Some Neurogenetic Disorders

Year therapy reported	Disease	Intervention
1930	Phenylketonuria	Dietary restriction, phenylalanine (01)
1965	Porphyria	Avoidance of precipitating medications (22)
1972	Wilson disease	Chelation therapy (53)
1982	Metachromatic leukodystrophy	Bone marrow transplant (Bayever and Ladisch 1985)
1994	Duchenne muscular dystrophy	Corticosteroids (31)
1998	Fabry disease	Enzyme replacement (47)
1999	Pompe disease	Enzyme replacement (02)
2015	Nonsense-mediated Duchenne muscular dystrophy	Ataluren (09; 26)
2016	Exon 51-skip amenable Duchenne muscular dystrophy	Eteplirsen (38)
2016	Spinal muscular atrophy	Nusinersen--antisense oligonucleotide altering splicing of SMN2 (19)
2019	Exon 53-skip amenable Duchenne muscular dystrophy	Golodirsen--antisense oligonucleotide promoting DMD exon 53 skipping (20)
2019	Spinal muscular atrophy	Onasemnogene abeparvoveccioi--viral‐mediated gene replacement (37)
2020	Spinal muscular atrophy	Risdiplam--splicing modifier of SMN2 (06)
2020	Exon 53-skip amenable Duchenne muscular dystrophy	Viltolarsen--antisense oligonucleotide promoting DMD exon 53 skipping (13)
2021	Exon 45-skip amenable Duchenne muscular dystrophy	Casimersen--antisense oligonucleotide promoting DMD exon 45 skipping (52)
2023	Friedreich ataxia	Transcription factor Nrf2 activation and pro-inflammatory transcription factor NF-κB inhibition (35)
2023	Duchenne muscular dystrophy	Delandistrogene moxeparvovec (ELEVIDYS®)--an adeno-associated virus vector-based gene therapy developed to deliver a gene encoding micro-dystrophin (138 kDa), a shortened version of the dystrophin protein typically expressed in normal muscle cells (427 kDa). (27; 11)

Clinical manifestations

Presentation and course

Approach to the symptomatic neurogenetics patient. The differential diagnosis for the patient may include both genetic and non-genetic possibilities (for example, ataxia, dementia, and Parkinson disease). The probability of a genetic cause within a differential diagnosis may vary and allow one to weigh or prioritize genetic testing in the evaluation. For example, 10% of amyotrophic lateral sclerosis is genetic.

Of course, taking a family history and constructing a pedigree may shift your ranking of a genetic cause in your differential diagnosis. Inquire about both sides of the family; a pedigree helps determine the inheritance pattern and identify who else may be at risk for being affected or being a carrier once the genetic disorder is identified. When taking a family history, your patient may not be aware of whether other family members are affected. For example, in families with Huntington disease, symptoms may be hidden or concealed from other family members, or family members may be divorced or scattered and had onset of symptoms after they were out of touch. Non-paternity may be concealed, but so may infertility, adoption, or sperm or egg donation. The family may be small and not have other affected members. A lack of family history would be expected in recessively inherited genetic disorders, particularly if there are few siblings. It is easy to calculate that the risk of sharing a recessive disorder for each sibling is 25%; however, the probability of having exactly one in four siblings affected follows a binomial distribution.

Depending on the disorder, incomplete penetrance (carrying a gene but not exhibiting symptoms) can also occur. Sometimes, penetrance is age-dependent—perhaps gene carriers in the family tree died younger than the expected onset of symptoms.

New, or de novo, mutations can also occur. This is not only a once-in-remote-history occurrence but can be fairly common. For example, in dystrophinopathies, 33% of cases of Duchenne muscular dystrophy are de novo mutations (24). In fact, exome sequencing has shown us that each individual born has about 74 new mutations in their coding DNA that are not identifiable in either parent (51).

Noting the ethnic background can be useful. However, if the patient is not from the ethnic background to which a particular genetic disorder was initially associated, it does not necessarily exclude that disorder: mutations can arise independently in different populations. For example, 80% of Tay Sachs cases in the Ashkenazi population are associated with a four base pair insertion mutation, but different mutations are found in non-Ashkenazi groups (40).

It is important to ask sensitively about consanguinity, but your patient may not be aware of the family tree further back than one or two generations. Going back in the family tree is also going back in time; the disorder you are interested in may not have been widely recognized at that time, or the individual may not have sought treatment, or your patient in his or her youth may not have been aware of that elderly family member’s symptoms, or information about deceased relatives may not have been passed on. In conclusion, a noninformative pedigree does not exclude the possibility of a neurogenetic disorder.

If there is a prior positive genetic test for another family member whose clinical condition matches that of your patient, the need for a genetic test may be eliminated. If prior genetic testing was negative, it is important to know what was tested and be aware that additional genes within that phenotype may have been identified since the original testing, improvements in testing technique may have been developed, or pathogenicity of variants of unknown significance may have been demonstrated.

Even if no genetic testing has been done, family members willing to release their medical records–prior evaluations (biochemical, biopsy, imaging)–may provide important clues to narrow the differential or identify additional symptoms that may become apparent with age. For example, although your patient may have ataxia but not epilepsy, the presence of epilepsy in other ataxic family members significantly narrows the differential, saving substantial time and money by testing for fewer genes.

Despite the hope and promise of personalized medicine, insurance often does not cover genetic testing. It may be difficult for patients to find out from their insurance company the extent or lack of coverage for molecular testing. They may need help from your office with CPT or ICD9 codes. Your clinic team may need to help with the prior authorization process because some commercial genetic testing labs offer prior authorization assistance. Furthermore, the preauthorization process often requires a letter of medical necessity. Genetic testing labs sometimes have generic templates for letters of medical necessity, or, as a timesaver, you can develop your own for disorders you commonly see.

In a letter of medical necessity, emphasize how a genetic diagnosis would change clinical management in areas such as disease surveillance or testing; including references does help. Summarize clinical findings and other tests done to narrow the differential diagnosis or that have led to genetic testing as the next logical step. The adjudicator will want to know how it will affect cost to the company. Will it end the diagnostic odyssey? Will there be important surveillance tests (eg, cardiac monitoring or MRI scans) that will be started or stopped? For example, certain but not all limb-girdle muscular dystrophies have associated cardiomyopathy; this would affect the cost of echocardiograms for surveillance over time. The potential for surgical, obstetric, or anesthesia complications that could be avoided with knowledge obtained by genetic testing is an important point, and the letter should address genetic testing for family planning purposes that may be important to the patient and family.

Find out the self-pay cost for the test you are choosing–the patient needs to know his or her financial responsibility in case insurance coverage is declined. Costs of next-generation sequencing panels are going down over time, genetic testing and whole exome or genome sequencing can cost thousands of dollars, and real financial harm can be done if the cost to the patient is not considered. Alternatively, the patient may also choose to pay for the test out-of-pocket, bypass insurance authorization requests, and disallow insurance’s right to access the results. Some genetic testing labs have patient assistance programs or cap the out-of-pocket cost. Therefore, researching testing options is important. Consulting a genetic counselor familiar with the disorder can help you narrow down the search (www.nsgc.org).

Informed consent. All clinical genetic testing services require informed consent; some institutions and states may require additional consent forms. Take the time to review them before sitting down with the patient. It is important to allow time for discussion and questions. It is often at this point that you may discover the patient misunderstands the disease, its inheritance, or genetic testing and needs time for additional education and counseling. Ask your patient about his or her expectations regarding genetic testing. Discuss with your patient what you are testing for and why. Describe the genetic test you have chosen and why. Discuss your best estimate of the probability this test will provide a diagnostic result and what the results would mean. Additional topics that must be discussed include:

	• Variants of uncertain significance, which are mutations that have not been previously shown to cause the disease, may be detected.
	• Genomic testing may also detect disease-causing mutations unrelated to the patient’s symptoms, called incidental or secondary findings. Patients may need to choose whether to receive these results during the consent process.
	• You will be required to remind the patient that genetic testing could uncover unexpected family relationships, such as non-paternity, even if you are not collecting or testing parents or other family members. Inform your patient that genetic testing takes longer than most routine blood tests. Clinical labs generally post the turnaround time for their genetic tests.

Return of results. A clinic visit for the return of results can be the time for discussion of the significance of results, education, emotional support, discussion of research opportunities, information on how to connect with foundations or support groups for the disorder, and planning of changes in clinical management. Even negative results deserve discussion, as the patient may feel disappointment and uncertainty. You may start another round of genetic testing if a sequential approach was previously planned.

Clinical examples of neurogenetic mechanisms.

Copy number variant: spinal muscular atrophy 2/3. Spinal muscular atrophy is a recessively inherited motor neuron disease caused by homozygous deletion of the gene SMN1 (see Spinal muscular atrophy article). SMN1 has a highly homologous gene nearby, SMN2, which arose during evolution from SMN1 by a duplication mutation; individuals may have between one and five copies of SMN2, exemplifying a copy number variant. SMN2 can partially compensate for missing SMN1 protein in spinal muscular atrophy patients, resulting in a milder form of spinal muscular atrophy with later onset or less severe symptoms. SMN2 can also be called a modifier gene in spinal muscular atrophy.

Deletion syndrome: facioscapulohumeral muscular dystrophy. Facioscapulohumeral muscular dystrophy is a dominantly inherited muscular dystrophy with variable penetrance and age of onset. It is associated with a deletion on chromosome 4 in a region of repetitive DNA called the C4Z4 domain. The deletion is thought to move a sequence (4gA) that stabilizes messenger RNA close to the DUX4 gene, allowing DUX4 gene expression at the wrong developmental stage (post-embryogenesis) and in the wrong tissue type (mature muscle) (see Facioscapulohumeral muscular dystrophy article).

Deletion syndrome (coding): hereditary neuropathy with pressure palsies. Hereditary neuropathy with pressure palsies is a dominantly inherited peripheral neuropathy with repeated episodes of neuropathy at vulnerable points of nerve compression–also called tomaculous neuropathy due to the abnormal myelination pattern seen in the peripheral nerve histology. In hereditary neuropathy with pressure palsies, one of the two copies of the PMP22 gene is missing, and a decreased amount of protein is made–this is called a gene dosage effect, or haploinsufficiency. Not all genetic disorders show a gene dosage effect: in typical autosomal recessive disorders, the carriers are asymptomatic because one copy of the gene and a decreased amount of the encoded protein are sufficient for normal function. Also, having half the number of copies of a gene does not automatically result in 50% of the expected amount of encoded protein. One or the other allele (gene copy) may be more highly translated, or there may be compensatory or redundant mechanisms to regulate the translation of the remaining allele; this is called expressivity of the gene.

Duplication syndrome (coding): Charcot-Marie-Tooth type 1a. Charcot-Marie-Tooth type 1a is a dominantly inherited peripheral neuropathy with slowed nerve conduction velocities due to abnormal peripheral nerve myelination. In Charcot-Marie-Tooth type 1a, there is duplication mutation of PMP22, resulting in excessive PMP22 protein production and classic “onion ring” sign of abnormal myelination on peripheral nerve histology.

Phenotypic variability: dysferlin. Dysferlinopathy is recessively inherited and can present either as a limb-girdle pattern muscular dystrophy (LGMD2B) or as a distal myopathy (Miyoshi myopathy). Dysferlinopathy’s phenotypic variability is not caused by different mutations within the same gene; in fact, within a family, one relative may have an LGMD2B phenotype, whereas another (with the same mutation) has the Miyoshi myopathy phenotype.

Genotype/phenotype correlations: dystrophinopathies. The dystrophinopathies include Duchenne muscular dystrophy (loss of ambulation before age 12) and Becker muscular dystrophy (loss of ambulation after age 12). Mutations that cause loss of protein expression result in Duchenne muscular dystrophy, whereas low levels of dystrophin expression result in Becker muscular dystrophy. Dystrophin is a large gene, and a variety of mutations can occur: deletions (60%), duplications (13%), and nonsense mutations (15%) (15). A deletion or duplication resulting in a frameshift or an early stop-gain (or nonsense) mutation will lead to an unstable mRNA or a nonfunctional protein. If an in-frame mutation occurs and key domains of the protein are preserved, a short but functional protein may be made, resulting in the milder Becker muscular dystrophy phenotype. Genotype/phenotype correlations are important to the clinician in treatment decisions (steroids) and prognosis discussions. Clinical trials targeting correction of specific mutations (nonsense mutations, exon skipping) are underway. An easy-to-use online tool to predict whether a dystrophin deletion is in-frame or not, and whether an exon skip will restore the reading frame, is available from Leiden University Medical Center at: https://www.dmd.nl/. There is an FDA-approved medication that promotes skipping of exon 51 to return an out-of-frame mutation to an in-frame mutation (see Table 1).

In the future, knowing the specific genetic mutation in this and other genetic disorders will determine whether a patient is eligible for specific mutation-targeted treatments.

Polynucleotide repeat disorder (coding): Huntington disease. Huntington disease is a polynucleotide repeat disorder. The three-base pair repeat (CAG in the DNA codes for glutamate) results in insertion of a string of glutamates into the protein, huntingtin. This is why Huntington disease is also called a trinucleotide repeat disorder or a polyglutamate disorder. The repeat number can increase across generations and is inversely correlated with the age of onset, a phenomenon called anticipation. Larger increases in the repeat number in Huntington disease occur more often when the mutation is inherited from the father. Repeat number is not a perfect predictor of age of onset; modifier genes or unknown environmental factors may influence age of onset.

Polynucleotide repeat disorder (non-coding): myotonic dystrophy type 1. Myotonic dystrophy type 1 is a polynucleotide repeat disorder in which the CTG repeat expansion is in the non-coding region of the dystrophia myotonica protein kinase (DMPK) RNA. Like Huntington disease, myotonic dystrophy type 1 also shows anticipation, though larger expansions are inherited from the maternal side. The trinucleotide repeat expansion in the RNA is thought to sequester important splicing proteins, resulting in abnormal splicing of RNAs not only of dystrophia myotonica protein kinase but also of a multitude of other proteins. This effect is termed “toxic RNA” and is also an example of a gain-of-function mutation. Because RNA splicing is a globally important cellular function, myotonic dystrophy type 1 is termed “spliceopathy.” A variety of polynucleotide repeat disorders can express polypeptides coded by those RNA repeats in a process called repeat-associated non-ATG translation, which may be another “toxic RNA” gain-of-function mechanism (12).

Mitochondrial disorder (maternal inheritance): mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). MELAS is a disorder caused by mutations in either one of several tRNA genes or complex 1 subunits encoded in mitochondrial DNA. Unlike autosomal genes in which only one copy is inherited from each parent, a population of mitochondria is inherited from only the mother. The severity of MELAS can be affected by the proportion of mitochondria carrying the mutation, which is called heteroplasmy. This proportion can vary between family members and even between tissues within an individual. This can contribute to the phenotypic variability in MELAS.

Mitochondrial disorder (autosomal inheritance): progressive external ophthalmoplegia. Progressive external ophthalmoplegia is a mitochondrial disorder of weakness of primarily extraocular muscles and ptosis that can be either dominantly or recessively inherited. It is caused by mutations in several autosomal genes encoding for mitochondrial proteins, which result in multiple deletions in the mitochondrial DNA and mitochondrial DNA dysfunction.

Phenotypic variability, genetic heterogeneity, and phenocopy: familial amyotrophic lateral sclerosis. Approximately 10% of amyotrophic lateral sclerosis patients have a positive family history of amyotrophic lateral sclerosis. Multiple genes have been associated with amyotrophic lateral sclerosis, including C9ORF72, SOD1, TDPBP, and FUS, that cannot be distinguished from each other by age at onset, rate of progression, clinical presentation, or EMG findings. Multiple genes causing the same phenotype is called genetic heterogeneity. One may test for a panel of these genes or begin with testing for the gene responsible for the highest proportion of familial amyotrophic lateral sclerosis (C9ORF72). Sporadic amyotrophic lateral sclerosis is clinically indistinguishable, or a phenocopy, of familial amyotrophic lateral sclerosis.

C9ORF72 amyotrophic lateral sclerosis deserves additional comment in that it is not only clinically indistinguishable from other familial amyotrophic lateral sclerosis genes but also shows phenotypic variability; it can present as frontotemporal dementia, ataxia, or parkinsonism. It is a polynucleotide repeat disorder with variable/incomplete penetrance–all of which is a consideration when providing genetic counseling to patients and families with or at risk for C9ORF72 mutations.

Prognosis and complications

Some prognostic information may be available if genetic testing supplies a definitive diagnosis or if genotype/phenotype correlations are available. However, for some neurogenetic disorders, a genetic confirmation of diagnosis does not provide additional prognostic information.

Diagnostic workup

When faced with the array of genetic tests clinically available, it is useful to know which methods detect what kinds of mutations and what kinds of mutations are reported in your neurogenetic disorder. One test method may not capture all the possible disease mutations of interest. One classic example is dystrophinopathy–an initial test for deletions will pick up 60% of cases, but sequencing would be required to detect point mutations. Many labs offer tests as paired or reflex tests–if the initial test is negative, the second is automatically performed. Another choice to be made when faced with genetic heterogeneity is whether to test for the most prevalent mutation as a single test or for all available genes included in a panel.

Sanger sequencing. Sanger sequencing is performed by designing primers that frame the target sequence being amplified, followed by polymerase chain reaction and then sequencing. Sequencing may be done on “hot spots” (regions where most known mutations are located) or may include the entire coding, splicing, or promoter areas of a gene, depending on the mutations in the disease gene.

Single-nucleotide polymorphism oligonucleotide microarray analysis. Single-nucleotide polymorphism (SNP) oligonucleotide microarray analysis is designed to detect large-scale duplications or deletions. In this technique, selected SNPs spaced throughout the genome are spotted at high density on a microarray chip. The patient’s DNA sample is fluorescently labeled and mixed with a control DNA sample labeled with a different fluorescent color. The labeled patient and control samples are mixed and allowed to compete for binding the SNPs on the microarray chip. If the patient sample is missing an SNP (or multiple SNPs) due to a deletion, the control sample outcompetes the patient sample in binding that SNP, which is seen as a color change at that SNP spot. SNPs can be quite closely spaced, about 400 kb apart (32).

Multiplex ligation-dependent probe amplification. Multiplex ligation-dependent probe amplification is designed to detect deletions smaller than those detected by SNP oligonucleotide microarray analysis but larger than those by next-generation sequencing in a specific gene. In this technique, neighboring PCR primers are designed to require a ligation reaction before the PCR reaction can occur. The ligation enzyme only functions when the primers bind their target sequence. The presence of deletions or duplications can be detected by comparing the ratio of ligation reactions in the patient sample to a control sample.

Next-generation sequencing. Next-generation sequencing refers to massive parallel sequencing of fragmented DNA or RNA. This can be applied to a panel of genes or the exome (the coding portion of nuclear DNA). The DNA or RNA is fragmented into pieces approximately 50 to 100 base pairs. All of these fragments are amplified at the same time. One technique (Illumina) captures individual fragments on beads, which are then amplified using color-coded bases: the flashes of colored light are captured by a high-resolution camera, and the sequential images are analyzed to yield the sequence of the fragment. If the whole nuclear or mitochondrial genome is being sequenced, the capture step is excluded. Alternatively, the unique energy signature released during DNA amplification is detected and used to determine the fragment’s sequence.

Next-generation sequencing analysis. The sequence of the variants (called “reads”) is then assembled by using the human genome sequence as a reference. Assembling the reads requires enough matching sequence to anchor the read to the right spot in the genome sequence. For this reason, insertions, deletions, polynucleotide repeats, and rearrangements do not map well to the reference sequence. Small indels (insertion/deletions) (about 10 to 30 bases) can be captured, depending on the technique used to assemble the genome. Sequence changes or variants are also called single-nucleotide polymorphisms or single-nucleotide variants.

Next-generation sequencing is very accurate, but 98% accuracy across the genome is compatible with nearly 63 million errors. For this reason, read quality measures are important in determining whether variant calls are real. Finding the variant from fragments of different lengths and strand direction, and with sufficient read depth, helps validate a detected SNP as genuine. Read coverage, or the percentage of the genome or exome represented at a certain depth, is also important in understanding how much of the genome is not represented in the patient’s sequence. Patient samples can be “bar-coded” and pooled with other samples during sequencing, lowering cost but also resulting in shallower coverage or lower read depth of the genome, exome, or transcriptome.

Every person has hundreds of variants, many of which are common allelic variants; some are rare, and others are unique to the individual. The challenge is discovering if one of them could be responsible for the phenotype. The patient’s variant calls are compared to databases that archive common and rare variants and how often they occur in the general population (allelic frequency), and a list of variant calls is developed. Efforts are being made to better represent the diversity in allelic frequency in the human population (examples: 1000 Genome Project and gnomAD). On the assumption that causal alleles are rare due to evolutionary pressure, allelic frequency can be used to filter variant calls. Databases archiving variants associated with human diseases (example: ClinVar) are useful in filtering the patient’s variant calls.

It is also valuable to have DNA from other family members. A trio analysis using parents’ DNA is valuable, allowing easy identification of recessive and de novo variants. Comparison to other affected and unaffected family members can be very important in disease gene identification. A variant may be shared simply because it is common to the family, like any other trait, such as blue eyes, or it may be shared only by other affected family members, making it more likely to be disease-associated.

Rapid exome sequencing. Rapid exome sequencing is an accelerated variant of clinical exome sequencing that condenses the entire process from sample receipt to report delivery to mere hours or days rather than the typical weeks or months. Rapid exome sequencing is warranted when an urgent molecular diagnosis can influence critical clinical decisions (39). It has been proven to reduce costs and optimize resource allocation (16; 49). The value of rapid genome sequencing was initially demonstrated in anecdotes and has since been substantiated through randomized case-control studies, particularly in neonatal and pediatric intensive care settings (46; 33; 16). Integrating automated processes for some of the key elements of whole-genome sequencing, alongside bioinformatics-driven gene-variant analysis and clinical interpretation, has enabled the achievement of a rapid differential molecular diagnosis for genetic disorders within approximately 50 hours (46).

In a recent development, Gorzynski and colleagues achieved a remarkable reduction in turnaround time to approximately 7.5 hours (21). Their approach involved the utilization of nanopore genome sequencing, which offers both accuracy and swiftness in providing genetic diagnoses. Their method integrates a streamlined setup for commercial nanopore sequencing, cloud-based distributed bioinformatics, and a tailored approach for prioritizing genetic variants.

Diagnostic findings. Databases archiving variants associated with human diseases (example: ClinVar) are useful in filtering the patient’s variants in order to determine if your patient has a reported disease-associated mutation. It should also report whether the mutation is homozygous (two copies), heterozygous (one copy), hemizygous (for a male [XY], having one copy of an X-linked gene), or compound heterozygous. Compound heterozygosity means having one mutation in one copy of the gene and a different mutation in the second copy of a gene.

Indeterminate findings. If no reported disease-associated variant is found, analysis tools can be used to predict whether variants of uncertain significance are deleterious. Variants in coding regions can be categorized based on their effect on the encoded protein sequence. Synonymous mutations do not change the amino acid sequence (for example, both UCC and UCA encode serine), whereas non-synonymous mutations do (UCC to UGC changes a serine to a cysteine). A stop-gain changes an amino acid coding sequence to a stop sequence (UAA, UAG, UGA); a stop-loss changes a stop codon to an amino acid coding sequence. Another name for a stop-gain mutation is a nonsense mutation. Splice site mutations alter important intronic sequences needed to excise introns to make mature mRNA. Promoter mutations affect the non-coding sequence important in responding to and organizing transcription, which are just prior to where the protein-coding sequence begins.

Multiple analysis tools have been developed to determine whether a variant of uncertain significance may be deleterious to the protein function and, thus, to the patient. Most utilize evolutionary conservation of the sequence at a variant’s location and across species: SIFT and polyphen2 are examples. A highly conserved sequence is less likely to tolerate change. Other tools also incorporate protein function and structure information, including SwissProt and MutationTaster. The predictive scores generated by these analysis tools may not be in agreement. Inclusion of scores predicting whether a variant is deleterious is increasingly being included in clinical genetic testing reports. It is important to weigh this information with data regarding what is known about the pathophysiology of the disease and whether the variant follows the disease in the family’s pedigree.

Secondary findings. Analysis of your patient’s variants may discover disease-associated genes, though perhaps not associated with the disease you are looking for. These have also been termed incidental findings, though the impact and significance to the patient are hardly incidental. They may also be termed secondary findings. A discussion of secondary findings, what they are, and what types of secondary findings would be returned if found should be included in the genetic counseling before genomic testing. The American College of Medical Genetics has published recommendations of a list of reportable incidental findings. These disease genes include cancer, cardiac, and anesthesia risk genes that would alter treatment or surveillance. The American College of Medical Genetics recommends that these results be returned for both children and adults, with the understanding that the discovery of incidental finding genes in a child could have health implications for a parent (23; 30). It is useful to identify a colleague in oncology, cardiology, or anesthesiology to refer to if an incidental finding requires additional counseling or surveillance.

Negative findings. It is important to counsel patients that despite the word “whole” in whole exome sequencing and whole genome sequencing, testing does not yield a result in all cases. In some series, a 30% yield has been reported. Whole exome sequencing is not designed to detect polynucleotide repeat diseases, large insertions, deletions, chromosomal abnormalities, or epigenetic disorders. In such cases, a result will not be found.

Management

The application of genomic sequencing information in guiding clinical care is the growing field of personalized medicine. Surveillance for cardiomyopathy in dystrophinopathy carriers and screening for breast cancer in ataxia telangiectasia carriers are two examples of changes in preventive medicine based on genotype.

Pharmacogenomics, the choice or dosage of medications based on genomic information, is also an existing and growing field. Examples of current usage include testing for genes of hypercoagulability in central venous and sinus thrombosis (17), testing the genotype of enzymes involved in the metabolism of azathioprine for myasthenia gravis patients (42), and the avoidance of aminoglycosides in patients with 12S rRNA mitochondrial mutations (25).

Direct-to-consumer genetic testing has increased in popularity to inform individuals about their heritage and can even include the proportion of Neanderthal DNA. The informed consent process is online, and results and interpretation are returned directly to the consumer. The FDA has approved direct-to-consumer genetic testing for certain neurogenetic disease risk markers, including Alzheimer disease (APOE), Parkinson disease, early-onset primary dystonia, and Gaucher disease, among others (18). There is also whole exome/genome testing marketed directly to consumers, with online informed consent and direct-to-consumer return of results, requiring a physician’s signature (physician-mediated genetic testing).

Your patients may bring you direct-to-consumer genetic or genomic testing results for your interpretation to put in context of their own medical concerns and diagnoses. They may have misassumptions about what the tests can and cannot detect, such as a “negative” test, meaning they are not at risk for a feared disease, and carrier status reporting. They may have concerns about the privacy of their genetic data. Lab reports may overemphasize pharmacogenomic and lifestyle modifications based on low-impact GWAS variants (43). It is helpful to have the assistance of a genetic counselor when available, and do not hesitate to contact the testing lab for additional information if the scope, accuracy, and interpretation of results reported are unclear.

Special considerations

Pregnancy

Genetic counseling, pregnancy, and reproductive options in neurogenetic diseases. Many individuals with neurogenetic disease or a family history of neurogenetic disease present to their physician with questions about reproductive options and prenatal testing. Counseling will depend on who in the family is affected, the neurogenetic condition of concern, and the specific interests of the patient (34).

Reproductive options. Options include natural pregnancy with no testing, prenatal testing by amniocentesis (usually performed at 16 to 20 weeks’ gestation) or chorionic villus sampling (CVS, usually performed at 10 to13 weeks’ gestation), preimplantation genetic diagnosis (PGD) through in vitro fertilization, adoption, sperm or egg donation, or choosing not to have children.

It is necessary to know the affected parent’s underlying genetic mutation for both prenatal and preimplantation genetic diagnosis testing. Patients and families may not realize it is not possible at this time to test egg or sperm prior to fertilization. A pregnant woman may not realize that prenatal screening, routine or expanded carrier testing, or noninvasive prenatal testing (NIPT) may not test for the specific neurologic disease for which they are at risk. Do not underestimate the time that it will take to perform genetic testing. If the gene associated with her or her partner’s or the family’s disease is not known, it might not be possible to discover it in a time frame for decisions regarding pregnancy termination. Those interested in pursuing genetic testing predictively for themselves or for reproductive purposes should be referred to a genetic counselor familiar with the given condition http://www.nsgc.org.

Inheritance pattern. If counseling an affected individual, the physician should assess the family history to determine the mode of inheritance. Someone with an autosomal recessive condition will have children who are carriers but are unlikely to be affected unless the spouse is a carrier. In this situation, genetic testing of the spouse may be the best option. If a male has an X-linked disorder (for example, Becker muscular dystrophy), his daughters, but no sons, will be carriers.

People with autosomal dominant disorders present the greatest risk of passing their condition to their children. All reproductive options should be discussed. If they wish to achieve a natural pregnancy but determine if their child is at risk, they can be referred for either preimplantation genetic diagnosis or prenatal testing. These individuals should have genetic testing to confirm their own gene mutation before proceeding to prenatal testing or preimplantation genetic diagnosis. Unlike preimplantation genetic diagnosis, prenatal testing presents the possibility of determining a positive gene status of the fetus and deciding not to terminate the pregnancy. This situation presents an ethical dilemma because all existing guidelines on genetic testing for adult-onset disease recommend that children not be tested except in unusual situations (04; 14; 41; 44). Thus, if a pregnancy is found to be positive, yet the parents decide to keep the fetus, the result would be the same as testing the child after birth. This dilemma needs to be discussed in advance with the potential parents.

Pregnancy risk. Additionally, the physician should discuss how a pregnancy could affect the patient’s condition. For example, certain seizure medications increase the risk of fetal malformation in pregnancy. Women with Ehlers-Danlos type IV have a high risk of complications and even death (10). Some women with neuromuscular disorders report a progression of their symptoms during pregnancy (05).

Parenting with a neurologic disease. Further concerns are the ability of an individual with a neurogenetic condition, especially a neurodegenerative one, to parent effectively and the ability of the unaffected parent to take care of both the child and the spouse, family and social support networks, and financial planning. This concern should be raised and discussed.

Penetrance. Counseling should include the risk of a child inheriting a gene or manifesting the disorder. Some neurogenetic diseases, such as primary dystonia caused by a mutation in DYT1, display incomplete penetrance. Patients should understand that even though genetic testing can reveal a mutation, it might not predict when or if the child will develop symptoms or how severe they will be; the child could be more or less severely affected than the affected parent.

Anticipation. Additionally, some diseases, such as Huntington disease and myotonic dystrophy type 1, display anticipation; whereby, the age of onset decreases through the generations. Patients should be prepared for the possibility of juvenile-onset or even infantile-onset symptoms in certain polynucleotide disorders that show anticipation.

At-risk family members. Counseling for unaffected individuals with a family history of neurogenetic disease can be more complicated. Although these individuals may want to prevent the possibility that their child will inherit the disease, they may not want to know their own genetic status. If at all possible, refer these individuals to a genetic counselor. Presymptomatic testing for neurogenetic diseases for which there is no screening or prevention follows the Huntington disease protocol, which was designed to reduce potential adverse psychological effects of testing (28; 29). The protocol entails several counseling sessions, a neurologic or psychiatric evaluation, and the presence of a support person at pre- and post-counseling sessions. Although some people object to the time and cost involved in this protocol, most recognize the importance, and the great majority of people at risk for these diseases opt not to test after counseling. Counseling sessions include discussions on the genetics of the condition, implications for other family members, exploration of the motivation for testing, the potential impact of receiving a positive result, coping mechanisms, plans for the future, and insurance implications. Anyone interested in predictive testing should be encouraged to obtain life, disability, and long-term care insurance before proceeding with testing as these forms of insurance are not covered under the Genetic Information Non-discriminatory Act (GINA), and regulations vary state-by-state and may be the subject of future legislative change.

Non-disclosure preimplantation genetic diagnosis. Those individuals wanting to prevent transmission of a gene but not wanting to know their own status should be referred to a fertility doctor familiar with non-disclosing preimplantation genetic diagnosis. This procedure, first tested in 1996 (48), allows embryos to be tested and implanted without the parent being told if they carry the gene or not. The procedure, however, does not always achieve pregnancy, either because the IVF fails or because all embryos are gene carriers.

Conclusion. For people concerned about passing neurogenetic diseases to their children, genetic counseling for predictive testing or reproductive options can provide needed genetic and technological information and thoughtful guidance by which they can make informed decisions.

Anesthesia

Certain neurogenetic disorders are associated with anesthetic, surgical, and procedural complications. These risks should be included in patient education and, where possible, noted prominently in the patient’s chart. Patients at risk should be instructed to carry a medical alert card or bracelet.

Malignant hyperthermia during anesthesia can occur in ryanodine receptor mutations in central core myopathies (36). A malignant hyperthermia-like state and risk of cardiopulmonary complications are associated with dystrophinopathies (08; 50). Myotonic dystrophy patients may have complications such as failure to wean from ventilation, arrhythmia, and generalized myotonia in response to certain anesthetic agents (45).

In connective tissue disorders, the surgery itself may be complicated by poor wound healing, or arterial dissection can occur during angiography. In ataxia telangiectasia, repeated x-ray exposure can increase the risk of lymphoma (03).

Table 2. Examples of Mutation Types for Patient Discussion

Normal sequence:
Missense mutation:
Nonsense mutation:
Deletion (in frame):
Deletion (out of frame):

THE BIG RED DOG RAN AND SAT
THE BAG RED DOG RAN AND SAT
THE BIG RED DOG RAN END
THE RED DOG RAN AND SAT
THE BIG RED DGR ANA NDS AT

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Ravi Uniyal MD DM

Dr. Uniyal of King George's Medical University has no relevant financial relationship to disclose.
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Editor

Aravindhan Veerapandiyan MD

Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.
See Profile

Former Authors

Sarah Teed
Jacinda B Sampson MD PhD
Jill Goldman MS MPhil CGC

ICD & OMIM codes

ICD-10: Amyotrophic lateral sclerosis: G12.2

Early-onset cerebellar ataxia: G11.1

Fabry disease: 75.21

Family history of carrier of genetic disease: Z84.81

Family history of other specified conditions: Z84.89

Hereditary progressive muscular dystrophy: G71.0

Hereditary peripheral neuropathy: G60.0

Huntington disease: G11

MELAS: E88.41

Metachromatic leukodystrophy: E75.25

Myotonic dystrophy type 1: G71.11

Person with feared complaint in whom no diagnosis was made: Z71.1

Phenylketonuria: E70.0

Pompe disease: E74.02

Porphyria: E80.0, E80.21, E80.29

Progressive external ophthalmoplegia: H49.43

Spinal muscular atrophy: G12
ICD 11: Amyotrophic lateral sclerosis: 8B60.0

Hereditary ataxia: 8A03.1

Fabry disease: 5C56.01

Congenital muscular dystrophy: 8C70.6

Hereditary motor and sensory neuropathy: 8C20

Huntington disease: 8A01.10

Mitochondrial myopathies: 8C73

Metachromatic leukodystrophy: 5C56.02

Myotonic dystrophy: 8C71.0

Phenylketonuria: 5C50.0

Porphyria: 5C58.1

Progressive external ophthalmoplegia: 9C82.0

Spinal muscular atrophy: 8B61

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Neurogenetics and genetic and genomic testing

Also Relevant

Amyotrophic lateral sclerosis
Autosomal dominant hereditary ataxias
Becker muscular dystrophy
Charcot-Marie-Tooth disease type 1A
Duchenne muscular dystrophy
- Emery-Dreifuss muscular dystrophy
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- Huntington disease
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- MELAS
- Mitochondrial disorders
- Myotonic dystrophy
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- Pregnancy: neuromuscular complications
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Neurogenetics and genetic and genomic testing …

Neurogenetics and genetic and genomic testing

Introduction

Overview

Key points

Historical note and terminology

Table 1. Timeline of Therapies of Some Neurogenetic Disorders

Clinical manifestations

Presentation and course

Clinical examples of neurogenetic mechanisms.

Prognosis and complications

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Table 2. Examples of Mutation Types for Patient Discussion

References

Contributors

Author

Editor

Former Authors

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Acute traumatic spinal cord injury

Tumors of the skull base

Toxic and nutritional deficiency optic neuropathies

Third nerve palsy

Nystagmus

Asymptomatic hyperCKemia

Limb-girdle muscular dystrophies

Brain death/death by neurologic criteria

	• Online Mendelian Inheritance in Man (OMIM) database includes alternate disease names, the gene name, description of the clinical features, mutations discovered, genotype/phenotype correlations, and description of any animal models. It is searchable by symptom, gene, or disease name.
	•GeneReviews are up-to-date, expert-authored, peer-reviewed clinically relevant summaries of genetic disorders, including diagnosis, management, counseling, genetic testing, and resources such as disease foundations.
	• Gene Tests Registry is a National Center for Biotechnology Information (NCBI) database that is searchable for genes, labs, diseases, phenotypes, GeneReviews, and genetic tests.

Neurogenetics and genetic and genomic testing

Introduction

Overview

Key points

Historical note and terminology

Table 1. Timeline of Therapies of Some Neurogenetic Disorders

Clinical manifestations

Presentation and course

Clinical examples of neurogenetic mechanisms.

Prognosis and complications

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Table 2. Examples of Mutation Types for Patient Discussion

References

Contributors

Author

Editor

Former Authors

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Acute traumatic spinal cord injury

Tumors of the skull base

Toxic and nutritional deficiency optic neuropathies

Third nerve palsy

Nystagmus

Asymptomatic hyperCKemia

Limb-girdle muscular dystrophies

Brain death/death by neurologic criteria

This is an article preview.
Start a Free Account
to access the full version.