Genes and Human Health

Monogenic Disorders

What type of genetic disorder is characterized by a mutation in single genes with large effects and usually follows Mendelian inheritance?

Chromosomal disorders

What type of genetic disorder involves alterations in chromosomes?

Complex multigenic disorders

What type of genetic disorder results from interactions between multiple genetic variants and environmental factors?

Somatically acquired mutations

What type of mutations arise in somatic cells and are not transmitted to progeny?

Permanent change in DNA

What is the definition of a mutation?

Germ cells

In which type of cells must a mutation occur to be passed down to progeny?

Somatic cells

Mutations in which type of cells do not cause hereditary disease but are important in cancers and congenital malformations?

Missense mutation

What type of point mutation within coding sequences may replace an amino acid?

Conservative missense mutation

What term describes a missense mutation where the changed amino acid causes little change to protein function?

Non-conservative missense mutation

What term describes a missense mutation that results in a change to a biochemically different function?

Nonsense mutation

What type of point mutation changes a codon to a “stop” codon?

Reduction or lack of transcription

What can mutations within non-coding sequences (involving only introns) interfere with, leading to what outcome?

Thalassemia

What is an example of a disease caused by mutations within non-coding sequences that interfere with transcription factor binding?

Reading frame remains intact

What happens to the reading frame if deletions or insertions involve three base pairs or a multiple of three?

Frameshift mutation

What type of mutation occurs if deletions or insertions do not involve three base pairs or a multiple of three?

Premature stop codon

What usually forms as a result of a frameshift mutation?

Amplifications, deletions, rearrangements

What are examples of copy number changes, a type of structural alteration in coding genes?

Philadelphia Translocation t(9;22)

What specific structural alteration in coding genes is an example that leads to Chronic myeloid leukemia?

Trinucleotide-repeat mutations

What type of mutation is characterized by the amplification of a sequence of three nucleotides?

Guanine and Cytosine

Which two nucleotides are almost always shared by affected sequences in trinucleotide-repeat mutations?

Fragile X syndrome

What is a classic example of a trinucleotide-repeat mutation involving 250-4000 tandem repeats of CGG in the FMR1 gene?

Dynamic mutations

What term describes mutations where the degree of amplification increases during gametogenesis?

Triple repeat mutations, mutations in mitochondrial DNA, transmission influenced by genomic imprinting or gonadal mosaicism

What are the four patterns of single-gene disorders with nonclassic patterns of inheritance mentioned?

Hereditary disorders

What term refers to disorders derived from one’s parents, transmitted in the germ line, also known as familial?

Congenital

What term means “born with”?

Huntington disease

What is an example of a genetic disease that is not necessarily congenital?

Mendelian inheritance patterns

Single gene disorders usually manifest in families with what type of inheritance patterns?

Partial expression

How is expression described if an individual is heterozygous for a single gene disorder?

Full expression

How is expression described if an individual is homozygous for a single gene disorder?

Asymptomatic carriers

In what individuals can partial expression also be seen, indicating no haploinsufficiency?

Haploinsufficiency

What term refers to autosomal genes in which one functional allele is sufficient?

Co-dominance

What inheritance pattern describes when both alleles of a gene pair contribute to the phenotype, such as in ABO blood groups?

Pleiotropism

What term refers to a single mutant gene having many effects?

Sickle cell anemia

What is an example of a disorder exhibiting pleiotropism, where a point mutation replaces HbA with HbS?

Hemolysis and clogging of small vessels

What are the effects of the replacement of HbA with HbS in sickle cell anemia?

Sickle Cell TRAIT

What condition occurs in individuals heterozygous for sickle cell anemia, where sickling only occurs under certain circumstances?

Autosomal Dominant, Autosomal Recessive, X-linked

What are the three main transmission patterns for genetic disorders?

Heterozygous state

In Autosomal Dominant disorders, how is the genetic state of an affected individual described?

At least one parent is affected

For Autosomal Dominant disorders, what is typically true about the parents of an affected individual?

Both males and females

In Autosomal Dominant disorders, which sexes can be affected and transmit the condition?

New mutations

What explains why some proportion of patients with autosomal dominant disorders do not have affected parents?

Incomplete penetrance

What term describes when a mutant gene is inherited but the normal phenotype is expressed?

50% penetrance

If a trait has “50% penetrance,” what does that mean?

Variable expressivity

What term describes when a trait is seen in all individuals with the same mutated gene, but the severity differs?

Neurofibromatosis type 1

What is an example of a disorder with variable expressivity, presenting with brownish spots and skin tumors?

Delayed to adulthood

What is sometimes true about the onset of autosomal dominant disorders, such as Huntington disease?

Reduced production of a gene product or a dysfunctional/inactive protein

What occurs in loss-of-function autosomal dominant disease patterns?

Familial hypercholesterolemia, osteogenesis imperfecta

What are two examples of loss-of-function autosomal dominant diseases?

Increase in protein’s normal function or new activity

What occurs in gain-of-function autosomal dominant disease patterns?

Both sexes involved, generations not skipped

What are two characteristic features of an Autosomal Dominant pedigree?

Autosomal recessive disorders

Which category represents the largest group of Mendelian disorders?

Both alleles at a given gene locus are mutated

What must be true about the alleles at a given gene locus in autosomal recessive disorders?

Trait does not usually affect the parents of the affected individual

What is a characteristic of autosomal recessive disorders regarding the parents of the affected individual?

1 chance in 4

What is the probability that siblings of an affected individual will have an autosomal recessive trait?

Consanguineous marriage

If a mutant gene occurs with a low frequency in autosomal recessive disorders, what is most likely true about the parents of the affected individual?

Uniform expression, common complete penetrance, early onset

What are three features of autosomal recessive diseases regarding their expression, penetrance, and onset?

Mutated genes encode enzymes

In autosomal recessive diseases, what do the mutated genes typically encode?

Almost all inborn errors of metabolism

What broad category of diseases are included under autosomal recessive disorders?

Both sexes involved, generations skipped

What are two characteristic features of an Autosomal Recessive pedigree?

X-linked

What type of sex-linked disorders are almost all sex-linked disorders?

Recessive

What is the typical inheritance pattern for X-linked disorders?

Males

Which sex is primarily affected by X-linked recessive disorders?

Females

Which sex are typically carriers of X-linked recessive disorders?

No Y-linked inheritance

Is there Y-linked inheritance?

Does not transmit to sons; daughters are carriers

How does an affected male transmit an X-linked disorder?

Daughters have 50% chance of becoming carriers; sons have 50% chance of being affected

What are the transmission probabilities for a heterozygous woman carrying an X-linked disorder?

Does not express phenotypic change

What is generally true about a heterozygous female regarding phenotypic expression of an X-linked disorder?

Random inactivation of normal genes in the X-chromosome

Why may females sometimes have partial expression of an X-linked disorder?

Glucose-6-phosphate dehydrogenase deficiency (G6PD)

What X-linked disorder predisposes patients to episodic red cell hemolysis after infection or certain drug exposure?

Rett syndrome

What X-linked disorder can affect females and results from haploinsufficiency of the MECP2 gene?

Vitamin D-resistant rickets, Alport syndrome

What are two examples of X-linked dominant disorders?

Males only, sons of affected males are OK

What is a characteristic feature of an X-linked recessive pedigree regarding affected individuals and transmission?

Alterations in structural proteins, defects in membrane receptors and transport systems, enzyme defects, disorders of epigenetic machinery

What are the four categories of mechanisms involved in single gene disorders?

Accumulation of "upstream" substrate, end product deficiencies, overproduction of intermediate

What are three consequences of enzyme defects due to mutations?

Neurologic dysfunction + Intellectual disability

What are the usual syndromes associated with disorders of epigenetic machinery?

Marfan Syndrome

What is a disorder of connective tissue principally involving the skeleton, eyes, and cardiovascular system?

Autosomal dominant

What is the mode of inheritance for Marfan Syndrome?

FIBRILLIN-1

Marfan Syndrome is caused by an inherited defect in what extracellular glycoprotein?

Loss of structural support in microfibril ECM, excessive activation of TGF-β signaling

What are the two main pathogenic mechanisms of Marfan Syndrome?

Scaffold for tropoelastin to create elastin fibers

What is the function of microfibrils, of which Fibrillin-1 is a major component, in the extracellular matrix?

Haploinsufficiency

What accounts for 10-15% of Marfan Syndrome cases, leading to a reduction of fibrillin-1 content below a critical threshold?

Controls bioavailability of TGF-β by sequestering it with microfibrils

What is the normal function of Fibrillin-1 regarding TGF-β?

Bone overgrowth and myxoid changes in mitral valves

What specific morphological features of Marfan Syndrome are explained by the excessive release and activation of TGF-β?

Unusually tall, extremely long extremities, lax joints, dolichocephalic, spinal deformities, chest deformities

What are some skeletal abnormalities seen in Marfan Syndrome?

Ectopia lentis

What ocular finding, described as bilateral subluxation or dislocation of the lens, is characteristic of Marfan Syndrome?

Mitral valve prolapse, dilation of the ascending aorta

What are two significant cardiovascular lesions associated with Marfan Syndrome?

Aortic dissection

What is a life-threatening complication of aortic dilation in Marfan Syndrome?

Revised Ghent Criteria

What clinical tool is used for the diagnosis of Marfan Syndrome, considering the variation in clinical expression?

Different mutations that affect the fibrillin locus

What causes the variation in clinical expression seen in Marfan Syndrome?

Ehlers-Danlos Syndrome

What group of disorders results from mutations in genes encoding collagen, enzymes that modify collagen, or other ECM proteins?

Autosomal Dominant or Autosomal Recessive

What are the possible modes of inheritance for Ehlers-Danlos Syndrome?

Hyper-extensible skin and hypermobile joints

What are the classic features of Ehlers-Danlos Syndrome?

Vascular EDS, Kyphoscoliosis EDS, Classic EDS

Name three subtypes of Ehlers-Danlos Syndrome that have serious internal complications.

Familial Hypercholesterolemia

What disorder is primarily caused by a mutation in the gene encoding the LDL receptor?

Inadequate removal of plasma LDL in the liver

What is the primary effect of the LDL receptor gene mutation in Familial Hypercholesterolemia?

Elevated levels of cholesterol, premature atherosclerosis, myocardial infarction

What are the consequences of inadequate LDL removal in Familial Hypercholesterolemia?

50% of normal high-affinity LDL receptors

How many normal high-affinity LDL receptors do heterozygotes for Familial Hypercholesterolemia possess?

2-3x levels

How much are plasma cholesterol levels elevated in heterozygotes with Familial Hypercholesterolemia?

No normal high-affinity LDL receptors

How many normal high-affinity LDL receptors do homozygotes for Familial Hypercholesterolemia possess?

5-6x levels

How much are plasma cholesterol levels elevated in homozygotes with Familial Hypercholesterolemia?