SINGLE-GENE DISORDERS WITH NONCLASSIC INHERITANCE

Introduction

Single-Gene Disorders with Nonclassic Inheritance refer to a group of genetic disorders that are caused by mutations in a single gene and exhibit inheritance patterns that deviate from the classical Mendelian inheritance. These disorders are characterized by atypical patterns of inheritance, which can include variable expressivity, incomplete penetrance, anticipation, genomic imprinting, and mitochondrial inheritance.

In classical Mendelian inheritance, a single gene mutation is responsible for the development of a specific disorder, and the pattern of inheritance follows predictable rules. However, in single-gene disorders with nonclassic inheritance, the expression of the disorder may vary among affected individuals or may not be expressed at all in some carriers of the mutation.

Variable expressivity is a characteristic of nonclassic inheritance where individuals with the same gene mutation may exhibit different symptoms or severity of the disorder. For example, in neurofibromatosis type 1 (NF1), individuals with the NF1 gene mutation can present with various clinical manifestations ranging from mild skin abnormalities to severe neurological complications.

Incomplete penetrance refers to situations where individuals carry a disease-causing gene mutation but do not develop any symptoms or signs of the disorder. This means that not all individuals who inherit the mutation will necessarily express the associated phenotype. An example of incomplete penetrance is seen in familial adenomatous polyposis (FAP), where some individuals carrying the APC gene mutation do not develop polyps in their colon.

Anticipation is a phenomenon observed in certain single-gene disorders where the severity or age of onset of the disorder increases in successive generations. This can be attributed to an expansion of trinucleotide repeat sequences within the affected gene. Huntington’s disease is an example of a disorder that exhibits anticipation, with earlier onset and more severe symptoms seen in subsequent generations.

Genomic imprinting is an epigenetic phenomenon that results in differential expression of genes depending on their parental origin. In some single-gene disorders, the expression of the disorder is influenced by whether the mutation is inherited from the mother or the father. Examples of disorders with genomic imprinting include Prader-Willi syndrome and Angelman syndrome.

Mitochondrial inheritance refers to the transmission of genetic material through the mitochondria, which are organelles responsible for energy production within cells. Mitochondrial DNA is inherited exclusively from the mother, and mutations in mitochondrial genes can lead to a variety of disorders that primarily affect organs with high energy demands, such as the brain, heart, and muscles. Examples of mitochondrial disorders include Leigh syndrome and MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome.

In conclusion, single-gene disorders with nonclassic inheritance are a diverse group of genetic disorders caused by mutations in a single gene but exhibit inheritance patterns that deviate from classical Mendelian inheritance. These disorders can manifest with variable expressivity, incomplete penetrance, anticipation, genomic imprinting, or mitochondrial inheritance.

 

Diseases caused by trinucleotide-repeat mutations

Diseases caused by trinucleotide-repeat mutations are a group of genetic disorders characterized by the expansion of a specific trinucleotide sequence within a gene. These mutations result in abnormal protein production or function, leading to a wide range of clinical manifestations. Trinucleotide-repeat mutations primarily affect the nervous system, although some disorders can also involve other organ systems.

One well-known disease caused by trinucleotide-repeat mutations is Huntington’s disease (HD). HD is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The CAG repeat encodes for an abnormally long polyglutamine tract in the huntingtin protein, leading to its misfolding and accumulation in neurons. HD typically manifests in mid-adulthood and is characterized by progressive motor, cognitive, and psychiatric symptoms.

Another example is Fragile X syndrome (FXS), which is the most common inherited cause of intellectual disability. FXS is caused by an expanded CGG repeat in the fragile X mental retardation 1 (FMR1) gene. The expanded CGG repeat leads to methylation of the FMR1 gene promoter, resulting in reduced expression of the fragile X mental retardation protein (FMRP). FMRP plays a crucial role in synaptic development and plasticity, and its deficiency leads to cognitive impairment, behavioral problems, and physical features such as a long face and large ears.

Myotonic dystrophy (DM) is another trinucleotide-repeat disorder that affects both skeletal and smooth muscles. DM type 1 (DM1) is caused by an expanded CTG repeat in the dystrophia myotonica protein kinase (DMPK) gene. The expanded CTG repeat leads to the formation of toxic RNA aggregates that sequester RNA-binding proteins, resulting in aberrant RNA processing and disrupted cellular functions. DM1 is characterized by muscle weakness, myotonia (prolonged muscle contraction), cardiac abnormalities, and various systemic manifestations.

Other diseases caused by trinucleotide-repeat mutations include spinocerebellar ataxias (SCAs), myotonic dystrophy type 2 (DM2), Friedreich’s ataxia, Kennedy’s disease, and spinobulbar muscular atrophy. Each of these disorders has its unique clinical features and genetic basis, but they all share the common mechanism of trinucleotide-repeat expansion leading to pathogenic effects.

In summary, diseases caused by trinucleotide-repeat mutations are a diverse group of genetic disorders that primarily affect the nervous system. These mutations result in abnormal protein production or function, leading to a wide range of clinical manifestations. Understanding the underlying mechanisms and developing targeted therapies for these disorders remains an active area of research.

 

Disorders caused by mutations in mitochondrial genes

Mitochondrial disorders are a group of genetic disorders that result from mutations in the genes found in the mitochondria, which are the energy-producing structures within cells. These disorders can affect various organs and systems in the body, leading to a wide range of symptoms and clinical presentations. In this comprehensive response, we will classify and briefly describe some of the most common disorders caused by mutations in mitochondrial genes.

1. Leber’s hereditary optic neuropathy (LHON): LHON is a maternally inherited mitochondrial disorder characterized by the degeneration of retinal ganglion cells, leading to vision loss. It primarily affects young adults, predominantly males. The most common mutations associated with LHON occur in mitochondrial DNA (mtDNA) genes encoding complex I subunits of the electron transport chain (ETC), including ND1, ND4, and ND6. The exact mechanisms by which these mutations lead to optic nerve degeneration are not fully understood but are thought to involve impaired oxidative phosphorylation and increased production of reactive oxygen species.

2. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS): MELAS is a multisystem disorder characterized by recurrent stroke-like episodes, seizures, muscle weakness, exercise intolerance, and lactic acidosis. It is caused by mutations in the MT-TL1 gene encoding transfer RNA for leucine. These mutations disrupt protein synthesis within mitochondria, leading to impaired energy production and tissue damage. The stroke-like episodes in MELAS can cause neurological deficits that resemble strokes but are not caused by vascular occlusion.

3. Leigh syndrome: Leigh syndrome is a severe neurodegenerative disorder that typically presents in infancy or early childhood. It is characterized by progressive loss of motor skills, developmental regression, seizures, respiratory problems, and lactic acidosis. Leigh syndrome can be caused by mutations in both nuclear DNA (nDNA) and mtDNA genes involved in mitochondrial function. Mutations in genes encoding subunits of the ETC, such as NDUFS1, SURF1, and COX10, are commonly associated with Leigh syndrome. These mutations disrupt the normal function of the ETC, leading to energy deficiency and subsequent neurodegeneration.

4. Mitochondrial myopathy: Mitochondrial myopathy refers to a group of muscle disorders caused by mitochondrial dysfunction. These disorders can present with muscle weakness, exercise intolerance, fatigue, and respiratory problems. Mutations in various mtDNA genes encoding ETC subunits or nuclear genes involved in mitochondrial biogenesis can lead to mitochondrial myopathies. For example, mutations in the MT-TL1 gene cause mitochondrial myopathy with ragged red fibers (MERRF), characterized by muscle weakness, ataxia, and ragged-red fibers on muscle biopsy.

5. Mitochondrial DNA depletion syndrome (MDDS): MDDS is a group of disorders characterized by a significant reduction in mtDNA content within cells. This reduction can occur due to mutations in nuclear genes involved in mtDNA replication or maintenance. MDDS can affect multiple organs and systems, leading to symptoms such as muscle weakness, liver dysfunction, neurological abnormalities, and developmental delays.

6. Kearns-Sayre syndrome (KSS): KSS is a rare mitochondrial disorder characterized by a triad of symptoms: progressive external ophthalmoplegia (weakness or paralysis of eye muscles), pigmentary retinopathy (abnormal pigmentation of the retina), and onset before the age of 20 years. KSS is typically caused by large-scale deletions or duplications of mtDNA rather than point mutations.

7. Mitochondrial cardiomyopathy: Mitochondrial cardiomyopathy refers to a group of heart muscle disorders caused by mitochondrial dysfunction. These disorders can lead to various cardiac abnormalities, including arrhythmias, heart failure, and hypertrophic or dilated cardiomyopathy. Mutations in mtDNA or nuclear genes involved in mitochondrial function can contribute to the development of mitochondrial cardiomyopathy.

8. Mitochondrial diabetes: Some forms of diabetes mellitus are associated with mutations in mitochondrial genes. These mutations can impair insulin secretion or action, leading to glucose dysregulation and diabetes. Mitochondrial diabetes often presents with features such as early-onset, non-autoimmune diabetes, hearing loss, and neurologic abnormalities.

It is important to note that this list only provides a brief overview of some common disorders caused by mutations in mitochondrial genes. There are many other mitochondrial disorders with distinct clinical presentations and genetic causes.

 

Disorders associated with genomic imprinting

Disorders associated with genomic imprinting are a group of genetic disorders that occur due to abnormalities in the process of genomic imprinting. Genomic imprinting is an epigenetic phenomenon where certain genes are expressed in a parent-of-origin-specific manner. This means that the expression of these genes depends on whether they are inherited from the mother or the father.

During the process of genomic imprinting, specific regions of DNA are marked with chemical tags, such as methyl groups, which can either activate or silence gene expression. These marks are established during gametogenesis (formation of eggs and sperm) and are maintained throughout development. Any disruption in this process can lead to disorders associated with genomic imprinting.

There are several known disorders associated with genomic imprinting, including:

1. Prader-Willi syndrome (PWS): PWS is a complex genetic disorder characterized by a range of physical, cognitive, and behavioral symptoms. It occurs due to the loss of function of genes on the paternal chromosome 15q11-q13 region. This loss of function can result from a variety of genetic abnormalities, such as deletion of the region, uniparental disomy (both copies inherited from one parent), or imprinting defects. Individuals with PWS typically exhibit hypotonia (low muscle tone) in infancy, followed by excessive eating leading to obesity, intellectual disability, short stature, and behavioral problems.

2. Angelman syndrome (AS): AS is another complex genetic disorder caused by the loss of function of genes on the maternal chromosome 15q11-q13 region. Similar to PWS, AS can result from various genetic abnormalities, including deletion, uniparental disomy, or imprinting defects. Individuals with AS typically have severe developmental delay, intellectual disability, speech impairment, seizures, and a characteristic happy demeanor with frequent laughter.

3. Beckwith-Wiedemann syndrome (BWS): BWS is a rare overgrowth disorder characterized by excessive prenatal and postnatal growth, abdominal wall defects, macroglossia (enlarged tongue), and an increased risk of developing certain tumors. BWS is associated with abnormalities in the imprinted genes on chromosome 11p15.5 region, which can include loss of imprinting or paternal duplications.

These disorders associated with genomic imprinting are considered rare, but their impact on affected individuals and their families can be significant. The symptoms and severity of these disorders can vary widely, even among individuals with the same genetic abnormality.

In conclusion, disorders associated with genomic imprinting are a group of genetic disorders that occur due to abnormalities in the process of genomic imprinting. Prader-Willi syndrome, Angelman syndrome, and Beckwith-Wiedemann syndrome are some examples of these disorders. Understanding the underlying genetic mechanisms and clinical manifestations of these disorders is crucial for accurate diagnosis and appropriate management.

 

Disorders associated with gonadal mosaicism

Gonadal mosaicism refers to a genetic condition in which an individual has two or more populations of cells with different genetic compositions in their gonads (ovaries or testes). This phenomenon can lead to the development of disorders associated with gonadal mosaicism. Here, we will classify and briefly describe some of these disorders.

1. Gonadal dysgenesis: Gonadal dysgenesis is a disorder characterized by abnormal development of the gonads, resulting in either partial or complete failure of gonadal function. This condition can manifest as Turner syndrome in females, where one X chromosome is missing or structurally abnormal. In some cases, individuals with Turner syndrome may have mosaic karyotypes, meaning that some cells have a normal chromosomal complement while others are affected by the missing or abnormal X chromosome. Mosaic Turner syndrome can lead to a range of symptoms, including short stature, infertility, heart defects, and hormone imbalances.

2. Androgen insensitivity syndrome (AIS): AIS is a disorder that affects individuals with XY chromosomes but results in incomplete masculinization of the external genitalia. In AIS, the body’s tissues are partially or completely insensitive to androgens (male sex hormones), leading to the development of female external genitalia despite having male chromosomes. Some individuals with AIS may have mosaic forms of the condition, where some cells are responsive to androgens while others are not. The severity of AIS can vary widely, ranging from complete androgen insensitivity (CAIS) to partial androgen insensitivity (PAIS). CAIS individuals typically have female external genitalia and are infertile, while PAIS individuals may have ambiguous genitalia and varying degrees of fertility.

3. Ovotesticular disorder of sex development (OT-DSD): OT-DSD is a rare condition characterized by the presence of both ovarian and testicular tissue in an individual’s gonads. This disorder occurs due to abnormal gonadal development during embryogenesis, resulting in the presence of both male and female reproductive tissues. Individuals with OT-DSD may have mosaic forms of the condition, where some cells in the gonads are ovarian while others are testicular. The external genitalia can vary widely, ranging from ambiguous to predominantly male or female. Hormonal and surgical interventions may be necessary to address fertility and gender identity concerns in individuals with OT-DSD.

These are just a few examples of disorders associated with gonadal mosaicism. It is important to note that the specific manifestations and severity of these conditions can vary depending on the extent and distribution of mosaic cells in the gonads.