Introduction
Mendel wrote in 1865 that when crossing plants, “numerous experiments have demonstrated that the common characters are transmitted unchanged to the hybrids and their progeny.” Mendel described that “common characters,” or genes, are passed unchanged from the parent to the offspring, and therefore Mendelian patterns of inheritance are very predictable. Classically, these include single-gene disorders that follow autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Non-Mendelian patterns of inheritance are seen with disorders that occur due to hereditary unstable DNA repeats, parent-of-origin specific disorders, mitochondrial disorders, mosaicism, and a broad category of disorders with complex, multifactorial patterns of inheritance. It is important to remember, however, that even with Mendelian disorders, while the genes may be transmitted unchanged, the disease phenotype may not follow a predictable pattern because of variable expressivity and/or reduced penetrance .
What Are Hereditary Unstable DNA Repeat Disorders?
Variants that follow Mendelian patterns of inheritance are, in most cases, unchanged when passed from parent to offspring. Diseases that occur due to hereditary unstable DNA repeat expansions do not follow this rule. These conditions are a group of approximately 20 neurodevelopmental disorders that include fragile X syndrome, Huntington disease, Friedreich ataxia, and myotonic dystrophy (DM1 and DM2) ( Table 2.1 ). For some disorders, the unstable repeat sequence is within the transcribed region of the gene, and for others, the expansion is in the noncoding region. The inheritance pattern of these disorders is characterized by unstable transmission and so-called genetic anticipation , in which the length of the segment including the repeats increases in size with subsequent generations. Expansion of the repeats, which are in most (but not all) cases trinucleotide repeats, can disrupt gene function and result in a variety of largely neurologic conditions. Typically, the age of onset is earlier and/or the symptoms are more severe with increasing number of repeats.
| Disorder | Symptoms | Repeats (Gene) | Effect of Repeats |
|---|---|---|---|
| Fragile X syndrome | ID, ASD, dysmorphic facial features | CGG n ≥ 200 (FMR1) | Methylation and silencing of gene |
| Myotonic Dystrophy 1 Myotonic Dystrophy 2 | Muscle weakness and wasting | CTG n ≥ 50 (DMPK) CCTG n ≥ 75 (CNBP) | Repeats bind to RNA-binding proteins |
| Huntington Disease | Neurodegenerative disorder, chorea, death | CAG n ≥ 40 (HTT) | Repeats lead to mutant protein |
| Spinocerebellar ataxia Type 1 (SCA1) | Ataxia, dysarthria, bulbar dysfunction | CAG ≥ 39 in (ATXN1) | Repeats lead to abnormal protein |
What are Examples of Disorders Due to Hereditary Unstable Dna Repeats?
Fragile X Syndrome
Fragile X syndrome is the most common inherited form of intellectual disability, with a prevalence of approximately 16–25/100,000 in males and half of that for females. Clinical characteristics can be variable and include intellectual disability, which is typically moderate for males and more mild for females. Males with fragile X syndrome have characteristic facial features, connective tissue findings such as lax joints, and macroorchidism, although some have few or no physical findings. About 25% of individuals with fragile X syndrome also meet criteria for autism spectrum disorder (ASD).
Fragile X syndrome is a trinucleotide repeat disorder that results from expansion of a trinucleotide cytosine-guanine-guanine (CGG) segment of DNA of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome (Xq27.3). If the region expands to include greater than 200 CGG repeats, this leads to hypermethylation and inactivation of the gene product (fragile X mental retardation protein), which is expressed in many tissues but most abundantly in neurons.
Normally, noncarrier individuals have fewer than 45 CGG repeats in this gene; the average is approximately 29 repeats. Individuals with 55–200 repeats are referred to as “premutation carriers” and are at risk of expansion to a full mutation (more than 200 repeats) in their offspring ( Fig. 2.1 ). Although premutation carriers have a 50% chance of passing on the abnormal allele, whether it expands to a full mutation and results in a child with fragile X syndrome depends on the size of the premutation. The chance of expansion of the gene, if it is passed on, ranges from about 3% with premutations that are 55–65 repeats, to nearly 100% if the premutation is larger than 100 repeats. Although premutation size alleles can be present in either parent, they only expand when passed on by the mother and are stable in size when passed on by the father. Individuals with 45–54 repeats are referred to as intermediate or “gray zone” carriers, as their gene may expand to the carrier or premutation size range but will not expand to a full mutation. Therefore, they are at risk to have grandchildren with fragile X syndrome, but not children. Expansion of less than 55 repeats to a full mutation has not been reported in a single generation. In families affected by fragile X syndrome, it is common to see more affected family members in subsequent generations due to genetic anticipation.
Unlike most autosomal recessive diseases, there are risks associated with being a premutation carrier in both men and women. Female premutation carriers are at risk for premature ovarian insufficiency (POI), defined as menopause earlier than 40 years old. Male, and sometimes female, premutation carriers are also at risk for fragile X–associated tremor/ataxia syndrome (FXTAS), a progressive, neurodegenerative disease that can lead to cerebellar symptoms and memory loss, as well as other neurologic deficits that increase with age. Individuals who have fragile X syndrome do not develop ataxia—it only affects premutation carriers.
Testing for fragile X syndrome can be performed on DNA from blood (to identify female carriers or affected individuals) or on amniotic fluid or chorionic villi (to identify affected fetuses) through a combination of polymerase chain reaction (PCR) and Southern blot analysis. Ideally, carrier screening for fragile X syndrome should be done in the preconception period, although it can also be performed during pregnancy. The American College of Obstetricians and Gynecologists (ACOG) recommends carrier screening for fragile X syndrome for women who are pregnant or considering pregnancy who have a family history of a fragile X–related disorder or of intellectual disability. ACOG also recommends testing for fragile X syndrome for women with unexplained premature ovarian failure or insufficiency, but at the present time, ACOG does not recommend universal screening for fragile X syndrome.
Myotonic Dystrophy
Myotonic dystrophy 1 (DM1) is a neuromuscular condition with symptoms that include muscle spasm (myotonia) and muscle weakness. It affects a variety of organ systems, leading to cardiac conduction defects, testicular atrophy, insulin resistance, cataracts, and in the congenital form, intellectual disability. The pathogenesis of DM1 is expansion (to 50 repeats or greater) of a cytosine-thymine-guanine (CTG) repeat in the 3′ untranslated region of the DMPK gene. DM1 has a severe, lethal congenital form that includes severe neonatal hypotonia and weakness, respiratory failure, death, and intellectual disability in those that survive the neonatal period.
Myotonic dystrophy 2 (DM2) shares many of the clinical features of DM1 but occurs due to a tetranucleotide (CCTG) repeat expansion in the gene CNBP. Clinically, the presentations of DM1 and DM2 are very similar, except that DM2 does not have a congenital form. With both forms of myotonic dystrophy, the chance of passing on the abnormal allele is 50%, so the genetics are similar to classical autosomal dominant inheritance. However, the expansion demonstrates anticipation and increased severity of symptoms with repeat size and through generations, as is seen with other trinucleotide repeat disorders. The congenital form of myotonic dystrophy results from anticipation and expansion to greater than 1000 repeats. There is also a mild, late onset adult form, a more classical adult form, as well as a childhood form.
Huntington Disease
Huntington disease is a neurodegenerative disorder that follows an autosomal dominant pattern of inheritance, leading to chorea, uncontrolled limb writhing movements, psychiatric abnormalities, dementia, and death usually by age 60 years. In this disorder, the expanding repeat sequence is a cytosine-adenine-glycine (CAG) repeat (to greater than or equal to 40 repeats) in the HTT gene. When this expansion occurs, it results in formation of an abnormal form of a protein called huntingtin that becomes toxic to neurons. As with other trinucleotide repeat disorders, Huntington disease demonstrates anticipation, with increasing number of repeats seen in subsequent generations and associated with younger age of onset. Inheritance through the father can lead to greater repeat expansion and earlier onset of symptoms.
Huntington disease is 100% penetrant, and essentially all affected individuals develop symptoms, usually at the same age or somewhat earlier than their affected parent. In most cases, individuals do not become symptomatic until age 40 years or older, generally after they have had children. Many patients wish to have unaffected children but prefer not to learn their own status given that treatment is not available. In such situations, a form of nondisclosure preimplantation genetic testing can be performed, in which only unaffected embryos are implanted, but the parents are not informed as to whether any of the embryos are affected. It is also possible in some cases to perform prenatal diagnosis through linkage analysis without revealing the status of the parent.
What are Imprinting Disorders and Uniparental Disomy?
Genomic imprinting and uniparental disomy (UPD) refer to the genetic parent-of-origin and are relevant to a specific group of genes that have different function depending on whether they were inherited from the mother or the father. Mendelian patterns of inheritance typically dictate that we receive one copy of each of our genes from each of our parents and, usually, that they are both equally active or functional. However, there are times when only the maternal or paternal copy is active (because of genomic imprinting). A number of different genetic conditions result from situations in which the normal active gene is not present, because of either a deletion of the active gene or the presence of two copies of the inactive form of the gene.
Genomic imprinting is a process whereby methylation (the addition of methyl groups to DNA during oogenesis or spermatogenesis) deactivates one copy of a gene. It is not entirely understood why some genes function differently when they are paternally or maternally inherited. However, for a number of genes, only the maternal or paternal copy is active because of genomic imprinting. Many imprinted genes affect fetal and/or postnatal growth. For example, macrosomia is seen in Beckwith-Wiedemann syndrome and fetal growth restriction seen in Russell-Silver syndrome. Approximately 80% of imprinted genes are found in clusters on specific regions of chromosomes, and about 75 imprinted genes have been identified in humans.
| Disorder | Symptoms | Region | Parent-of-Origin Defect |
|---|---|---|---|
| Prader-Will syndrome | Mild ID, obesity, hypogonadism | 15q11-13 | Paternal |
| Angelman syndrome | Severe ID, seizures, developmental delay | 15q11-13 | Maternal |
| Beckwith-Wiedemann syndrome | Macrosomia, macroglossia, omphalocele, predisposition to embryonic tumors | 11p15 | Maternal |
| Russell-Silver syndrome | Intrauterine growth restriction, poor postnatal growth, triangular faces, developmental delay, learning disabilities | 11p15.5 | Paternal |
Uniparental disomy occurs when both copies of the same chromosome are inherited from one parent. UPD can happen due to trisomic rescue, when a zygote with trisomy loses the extra chromosome. Although the embryo is no longer trisomic, if the two remaining chromosomes were inherited from the same parent, UPD will result. In many cases, UPD has no effect because most genes do not undergo genomic imprinting (i.e., both copies are active and there is no consequence if both copies come from the same parent). However, in cases of an imprinted gene, UPD may lead to loss of function of a gene. For example, if imprinting normally deactivates the maternal copy of the gene and the embryo is left with two copies of the maternal gene, there will be no active copies, and therefore, no functional gene. UPD can also result in unmasking of an autosomal recessive disorder if, for example, the mother carries a recessive condition (such as cystic fibrosis) and the fetus has UPD for the chromosome carrying that gene. Even if the father is not a carrier, if both copies of the gene are inherited from the mother and she is a carrier, the fetus may be affected.
A classic example of UPD that obstetrician-gynecologists encounter is complete hydatidiform mole, which affects about 1 in 1500 pregnancies. Hydatidiform moles have 46 chromosomes, all of paternal origin. Partial moles, in contrast, demonstrate triploidy and have 69 chromosomes (typically 23 of maternal and 46 of paternal origin).
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