Neurogenetics is a broad and important topic for the neurology board, RITE, and shelf exams. Genetics of various disorders will be covered in other topic chapters in more depth. In this chapter, we will discuss the fundamentals of genetics, and touch upon the genetic inheritance patterns and disorders that are the most frequently tested. It is important to understand genetics concepts and inheritance patterns, as well as memorize some key chromosomes and genes, which we have included both in this chapter and in the chapter flashcards.
Author: Steven Gangloff, MD
Definitions
Genotype
- The markup of a set of two alleles for one gene. For example “B” and “b” where each letter represents a given allele for a gene. A capital letter indicates a dominant allele while a lowercase represents a recessive allele.
Phenotype
- The physical presentation of the genotype. For example, for eye color, one may write the dominant allele for brown eyes as “B” and the recessive allele for blue eyes as “b”. In this scenario, the genotype for a heterozygote would be written as “Bb,” while the phenotype would be “brown”.
Homozygous
- Both alleles are the same. Example: BB
Heterozygous
- Each allele is different. Example: Bb
Mendelian Patterns of Inheritance
- Humans have 23 pairs of chromosomes (46 total).
- Each gene has two copies, one on each chromosome.
- This second copy can be identical or different. These are called alleles.
- Genes are segments of DNA that are transcribed into RNA and then translated into protein.
- Whether a genotypic allele is expressed (i.e. seen “phenotypically”) depends on the protein that is transcribed by the gene.
- Each chromosomal copy is obtained from the male and female haploid cells (sperm and egg, respectively), which combine by a somewhat random shuffling process known as recombination.
- Because diploid organisms like humans have 2 copies of each allele, every haploid (sperm and egg) has a 1 in 2 chance of holding any given allele.
- When the sperm fertilizes the egg, a 46-chromosome diploid embryo is made. Usually, one of the two alleles will be seen phenotypically (they can also be expressed together, but we will discuss this later). This is the foundation of mendelian genetics.
Autosomal dominant
- An autosomal dominant allele will “overpower” a recessive allele for expression as the phenotype.
- In autosomal dominant diseases, therefore, only one mutated copy of an allele is required to express the mutated phenotype.
- These are usually “gain of function” mutations.
- The risk of inheritance in an offspring is 50% if one parent is affected.
- The inheritance pattern is described as “vertical” on the pedigree chart (no generations are skipped).
- Some of the most commonly tested autosomal dominant disorders include…
KCNQ2 gene. Read more→Â
TSC mutation. Autosomal dominant with variable penetrance. Read more→Â
NF1 and NF2 are autosomal dominant with complete penetrance but variable expression. NF1 is caused by neurofibromin gene mutation on chromosome 17. NF2 is caused by merlin gene mutation on chromosome 22. Read more→
HD gene. CAG trinucleotide repeat, ≥40 repeats. Autosomal dominant. This disorder is also listed under “anticipation” mutations. Read more→Â
DMPK gene, CTG repeat, >50 repeats. Autosomal dominant. This disorder is also listed under “anticipation” mutations. Read more→Â
CNBP gene, CCTG tetranucleotide repeat, >75 repeats. Autosomal dominant. This disorder is also listed under “anticipation” mutations. Read more→Â
TITF1 (a.k.a. NK2 homeobox-1, NKX2-1). This encodes thyroid transcription factor 1 (TTF-1).
Ryanodine calcium channel (RYR1). Read more→Â
SLC2A1 mutation results in inability to transport glucose into the brain, which results in low CSF glucose, while lactate is low-normal. Read more→
Trinucleotide expansion (CAG) of the ATN1 gene, causes late-onset ataxia, myoclonic epilepsy, and dementia, most commonly in Japanese. Read more →
Mutations of transthyretin (TTR), apolipoprotein A-1, or gelsolin proteins cause a length-dependent polyneuropathy and autonomic dysfunction.
Apolipoprotein A-1 can also cause multiorgan dysfunction due to amyloid deposition. Read more →
PABPN1 mutation. Onset in age 40’s with ptosis, progressing to dysphagia, then proximal muscle weakness.
Chromosome 17 deletion, including PAFAH1B1. Presents with lissencephaly, intellectual disability, developmental delay, seizures, spasticity, and hypotonia. Facies of prominent forehead, midface hypoplasia, micrognathia, and thick upper lip are seen.
VHL (a tumor suppressor) gene mutation causes numerous hemangiomas throughout the body, including the CNS. This disorder technically requires a mutation in both alleles for phenotypic presentation, but a single mutation is considered autosomal dominant because all patient’s will develop the second mutation in some cells via sporadic mutations throughout their life, and thus will all have phenotypic expression. Read more →
Ryanodine receptor mutation. Presents with muscle rigidity, hyperthermia, autonomic instability, and rhabdomyolysis after administration of anesthesia (usually succinylcholine). Read more →
Peripheral myelin protein (PMP22) duplication on chromosome 17p. Read more →
SCN4A voltage-gated sodium channel mutation, causes episodic weakness before age 10.
CACNA1S encodes L-type voltage-gates calcium channels. Mutation causes episodes of weakness lasting hours to days.
SCN4A sodium channel mutation causes episodic weakness triggered by cold. Read more →
CLCN1 chloride channel mutation. Read more →
GTP cyclohydrolase I (GCH1), chromosome 14. Read more→
Type I is caused by a mutation in the voltage-gated potassium channel (KCNA1), and episodes last minutes. Type II is caused by a mutation in the voltage-gated calcium channel (CACNA1a), and episodes last hours to days. Read more→
Presenilin (PSEN) 1 (chromosome 14) and Presenilin (PSEN) 2 (chromosome 1)
Autosomal Recessive
- Both copies of the allele must be mutated in order to express the mutated phenotype.
- These are usually “loss of function” mutations.
- The risk of inheritance in an offspring is 25% if both parents are asymptomatic carriers.
- Population genetics equations can be used to calculate risk if only one parent is a carrier and one is unknown, but this is beyond the scope of neurologic examinations.
- The inheritance pattern is described as “horizontal” on the pedigree chart (some generations are skipped).
- Most diseases are autosomal recessive, and for this reason, it is easiest for exams to memorize which diseases are inherited by other means, and suppose that all the rest are likely autosomal recessive.
X-linked
- The mutated allele is on the X chromosome.
- In X, X females, only one X is expressed, while the other is randomly silenced as a Barr body on a cell-by-cell level. Often, the result is that most women are “asymptomatic carriers” or have only mild symptoms for X-linked disorders.
- This Barr body phenomenon is often what causes mosaicism.
- X, Y males have a higher chance of expressing a mutated phenotype because only one X chromosome is present.
- However, in some X-linked disorders, you will see that living affected men are actually less commonly seen since some unopposed X chromosome mutations can be fatal in early development.Â
- X-linked disorders can be dominant or recessive as well.
X-linked dominant:
- The most commonly tested X-linked dominant neurologic disorders are:
Other Patterns of Inheritance
Mitochondrial DNA Inheritance
- Mitochondria, interestingly, carry its own DNA, which does not follow the rules of standard mendelian inheritance.
- Mitochondrial DNA is passed on only by the mother;Â it is maternally inherited.
- The most commonly-tested mitochondrial-inherited neurologic disorders are:
MT-TK is the most common cause (80% of cases). Read more →
MT-TL1 is a common mutation, but multiple genes have been associated with MELAS. Read more →
MT-ATP6 gene mutations. Symptoms, which are listed in the name, develop in childhood or adulthood, and worsen over time.
Symptoms present in infancy with psychomotor regression, vomiting, diarrhea, dysphagia, failure to thrive, dystonia, ataxia, ophthalmoparesis, and neuropathy. Death usually occurs within two to three years of life, usually due to respiratory failure. Imaging will show T2 hyperintensities of the basal ganglia, periaqueductal grey, and cerebral peduncles. Numerous genes have been linked, but it is most important to simply know this is a mitochondrial disorder.
Develops in the teens or twenties, blurring and clouding of central vision are usually the first symptoms. Usually progresses from one eye to the other. Various MT-ND mutations have been linked.
A POLG (polymerase gamma) mitochondrial gene mutation results in epilepsy onset in early childhood (1-5 years) or adolescence. Read more→
A neuromuscular disorder with triad of (1) pigmentary retinopathy (2) progressive external ophthalmoplegia (3) cardiac conduction abnormalities. Although resulting from mitochondrial DNA mutation, it is most often caused by a somatic sporadic mitochondrial mutation that occurs after conception and is not usually inherited. In rare cases, though, mitochondrial inheritance can occur. Read more→
Anticipation
- Regions of DNA with long repeats of information are especially prone to errors in transcription due to the monotonous repeats. Because of this, an error often results in a portion being skipped and subsequently transcribed longer.
- Because of this, these areas of repeats often grow larger over consecutive generations, in a process called repeat expansion.
- Over time, repeats will reach a threshold, after which phenotypic disease expression occurs.
- Anticipation is the phenotypic expression of disease after successive generations that have undergone repeat expansion.
- Most of these disorders have a correlation between the number of repeats and the severity of disease or the age of onset (younger with more repeats).
- The most commonly tested neurologic disorders of anticipation include:
HD gene. CAG trinucleotide repeat, ≥40 repeats. Autosomal dominant. Read more→Â
FMR1 gene. CGG repeat, 75-200 repeats. X-linked dominant. Read more→Â
FMR1 gene. CGG repeat, >200 repeats. X-linked dominant. Read more→Â
FXN gene, GAA trinucleotide repeat, ≥66. Autosomal recessive. Read more→Â
DMPK gene, CTG repeat, >50 repeats. Autosomal dominant. Read more→Â
CNBP gene, CCTG tetranucleotide repeat, >75 repeats. Autosomal dominant. Read more→Â
Androgen receptor (AR) gene, CAG repeats, >35. X-linked recessive. Read more→Â
Trinucleotide expansion (CAG) of the ATN1 gene causes late-onset ataxia and epilepsy. Read more→
Imprinting
- Some alleles are variably silenced by a process called methylation. Some alleles are always methylated in the paternal gamete, while some are always methylated in the maternal gamete. This is a process known as “imprinting.”
- If a mutation occurs in one allele, and imprinting naturally occurs in the other (the wild type) allele, there will be no normal expression of that protein, and thus it can result in a genetic disorder.
- The most commonly-tested disorders of imprinting are:
Presents with hypotonia, developmental delay, intellectual impairment, infertility, and chronic overeating (hyperphagia).
Occurs due to the deletion, mutation, or inappropriate methylation of the paternal copy of the q11-q13 segment on chromosome 15; Only the maternal chromosome 15 related genes are functional.
Angelman can be thought of as the reverse of Prader Willi. The maternal copy of chromosome 15q11-q13 is impaired and only paternal chromosome 15 related genes are functional.
Angelman syndrome presents with delayed development, intellectual disability, ataxia, epilepsy, and a happy disposition with frequent smiling, hyperactivity, laughter, and hand-flapping.
Translocation
- Translocation is when genetic information is transferred between chromosomes.
- If this process is interrupted, the result may be an aberrantly fused chromosome and malfunctioning genes.
- Most translocation disorders are cancers, but the following are the most commonly-tested neurologic translocation disorders:
A non-balanced translocation causing a 1p/19q co-deletion is associated with oligodendroglioma.Â
Robertsonian translocation is the cause of around 5% of Down syndrome cases.
Chromosome 1;11 translocations have been linked to forms of familial schizophrenia.
GWAS
- Many diseases are not caused by a single genetic mutation, but rather a combination of multiple genetic variants. Genome-wide Association Studies (GWAS) are complex genetic studies that analyze the entire genome to associate risk genes.
- The most commonly tested “risk” or “susceptibility” genes are for:
Apolipoprotein E-4 (APOE-4) is a risk allele (more likely to develop AD), while APOE-2 is a protective allele (less likely to develop AD).
MAPT gene.
Various alleles of human leukocyte antigen (HLA), IL2R, and IL7R.
MEIS1 &Â BTBD9.
Other Genetic Concepts
Codominance
- Both genes are expressed, and the resulting phenotype is a combination of the two genes. Blood type is an example.
- There are not commonly-tested codominant neurologic disorders.
Penetrance
- Inheritance is not always black and white. Some genes have variable penetrance, meaning that two individuals may have the same mutation yet one may have the phenotypic disorder while the other does not.
Expressivity
- Some genes can have a variation in the expression of abnormal phenotype, meaning individuals have different severity of the disorder in question.Â
- A great example of a disorder with marked variability in expressivity is neurofibromatosis type 1 (NF1):
- NF1 has 100% penetrance, meaning everyone with the gene has the disease. However, expressivity is variable. Some individuals only have mild cutaneous malformations, while others have severe neurological impairment.
Types of Mutations
Point
- A mutation of a single base pair.
Silent
- A mutation of a single base pair results in no change in the amino acid.
- This is possible due to redundancy in code for trinucleotide combinations and their amino acid pairs.
- This usually occurs when the third base pair in the trinucleotide is mutated.
Missense
- A mutation results in a single amino acid change.
Nonsense
- A mutation causes a premature stop codon, thus ending transcription and translation of the protein too early.
Frameshift
- An insertion or deletion occurs where the number of base pairs is not a factor of three. For example, an insertion of 7 base pairs.
- This results in all downstream trinucleotides to be shifted, causing numerous amino acid mutations down the line.
References
- Vgontzas, Angeliki, and William Renthal. “Introduction to Neurogenetics.” The American Journal of Medicine 132.2 (2019): 142-152.
Chamberlain, S. J., & Lalande, M. (2010). Angelman syndrome, a genomic imprinting disorder of the brain. Journal of Neuroscience, 30(30), 9958-9963.
Yang, J., Cai, J., Zhang, Y., Wang, X., Li, W., Xu, J., … & Chen, Y. (2010). Induced pluripotent stem cells can be used to model the genomic imprinting disorder Prader-Willi syndrome. Journal of Biological Chemistry, 285(51), 40303-40311.
Heyes, S., Pratt, W. S., Rees, E., Dahimene, S., Ferron, L., Owen, M. J., & Dolphin, A. C. (2015). Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders. Progress in neurobiology, 134, 36-54.
Klein, C., Kumar, K. R., & Sue, C. M. (2014). Neurogenetics. Oxford University Press.
- Tan, M. S., Jiang, T., Tan, L., & Yu, J. T. (2014). Genome-wide association studies in neurology. Annals of translational medicine, 2(12), 124. https://doi.org/10.3978/j.issn.2305-5839.2014.11.12
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