Genetics Principles

Question 1

Dominant negative mutations

Definition and examples

Answer 1

• Mutations that result in an altered gene product that acts antagonistically to the wild type allele
• Marfan syndrome, mutations in p53 and ATM genes

Question 2

Loss of heterozygosity

Definition and examples

Answer 2

• Loss of one parental copy of a single nucleotide polymorphisms (SNPs) from the chromosome (it needs a mutation in the other copy to develop the disease except in oncogenes)
• Retinoblastoma, Lynch syndrome, Li-Fraumeni syndrome, BRCA1 and BRCA2

Question 3

Codominance

Definition and examples

Answer 3

• Both alleles contribute to the phenotype of the heterozygote
• ABO blood group system and alpha1-antitrypsin deficiency

Question 4

Variable Expression

Definition, Factors that affect it and examples

Answer 4

• Variable phenotypic expression of the same genotype (penetrance should be 100%)
• Environmental influences, Allelic heterogeneity, Heteroplasmy (in mitochondrial pedigrees), Modifier loci
• Hereditary hemochromatosis and Neurofibromatosis 1

Question 5

Anticipation

Definition and examples

Answer 5

• Individuals in the most recent generations of a pedigree develop a disease at an earlier age or with greater severity than do those in earlier generations
• Huntington’s disease (CAG in 5’ coding), Myotonic dystrophy (CTG 3’ UTR), Dyskeratosis congenita (TTAGGG telomere repeat sequence), Friedreich ataxia (GAA intron 1), Fragile X syndrome (CGG 5’ UTR), Crohn’s disease and Behçet’s disease

Question 6

Heteroplasmy

Definition and examples

Answer 6

• Presence of both normal and mutated mtDNA, resulting in variable expression of mitochondrially inherited disease
• Leber optic atrophy, MELAS and MERRF

Question 7

Uniparental disomy

Definition and examples

Answer 7

• Offspring receives 2 copies of a chromosome from one parent and no copies from the other. Heterodisomy indicates meiosis I error. Isodisomy indicates meiosis II error or postzygotic chromosomal duplication of one pair of chromosomes and loss of the other of original pair
• Prader-Willi syndrome, Angelman syndrome, Beckwith-Wiedemann syndrome, Silver-Russel syndrome and cystic fibrosis

Question 8

Imprinting

Definition and examples

Answer 8

• Two alleles at the same locus (one is paternal and the other is maternal) one of them is inactivated normally
• Prader-Willi syndrome, Angelman syndrome, Beckwith-Wiedemann syndrome, Silver-Russel syndrome, and pseudohypoparathyroidism.

Question 9

Mosaicism

Definition and examples

Answer 9

• Existence of two cell lines with different genetic constitution that have been derived from a single zygote
• McCune-Albright syndrome, Kearns-Sayre syndrome, Pearson syndrome, progressive external ophthalmoplegia and Androgen insensitivity syndrome (AIS)

Question 10

Pleiotropy

Definition and examples

Answer 10

• A single disease-causing mutation affects multiple organ systems
• Phenylketonuria (PKU), Marfan syndrome, albinism and sickle cell anemia

Question 11

Locus Heterogeneity

Definition and examples

Answer 11

• The same disease phenotype can be caused by mutations in different loci
• Osteogenesis imperfecta type 2, retinitis pigmentosa, hypertrophic cardiomyopathy and familial hypercholesterolemia

Question 12

Allelic heterogeneity

Definition and examples

Answer 12

• Different mutations in the same locus produce the same phenotype
• Beta-thalassemia, Cystic fibrosis, Duchenne dystrophy, Alkaptonuria, Albinism, Achondroplasia and PKU

Question 13

Delayed age of onset

Examples

Answer 13

Acute intermittent porphyria (peri or postpubertal), Huntington’s disease, hereditary hemochromatosis and familial breast cancer

Question 14

Incomplete Penetrance

Definition and examples

Answer 14

• Some individuals who have the disease genotype do not display the disease phenotype
• Hereditary hemochromatosis (15%), Retinoblastoma (90%), HNPCC (Lynch syndrome), BRCA1 and BRCA2

Question 15

Acrocentric Chromosomes 
(Definition and importance)

Answer 15

• Chromosomes that have the centromere far toward one end (the p arm contains little genetic information). They are chromosomes 13, 14, 15, 21, and 22.
• They are the only chromosomes that are involved in Robertsonian translocations.

Question 16

Aneuploidy

Definition and examples

Answer 16

• A deviation from the euploid number, which represents either a gain (Trisomy) or a loss (Monosomy) of a specific chromosome. It can involve autosomal as well as sex chromosomes.
• Autosomal aneuploidy (Trisomy 21 [Down syndrome], trisomy 18 [Edward syndrome], trisomy 13 [Patau syndrome])
• Sex chromosome aneuploidy (Klinefelter syndrome [47,XXY], Turner syndrome [45,XO], and others)

Question 17

Reciprocal translocation

Definition and examples

Answer 17

• Its the exchange of genetic material between non-homologous chromosomes. Alternate segregation results in a normal liveborn and a translocation carrier. Adjacent segregation results in unbalanced genetic material leading to partial trisomies and partial monosomies (most likely loss of pregnancy)
• CML t(9;22) (c-abl), AML t(15;17) (retinoid receptor-alpha), Follicular lymphomas t(14;18) (bcl-2 that inhibits apoptosis), Burkitt lymphoma t(8;14) (c-myc), Mantle cell lymphoma t(11;14) (cyclin D)

Question 18

Robertsonian translocation

Definition and examples

Answer 18

• Occurs in acrocentric chromosomes and involve the loss of short arms of two of the chromosomes and subsequent fusion of the long arms. Alternate segregation results in a normal livebirth or a translocaton carrier. Adjacent segregation results in unbalanced genetic material leading to trisomies or monosomies (most likely loss of pregnancy)
• 5% of Down syndrome (46,XX,-14,+t(14;21). Recurrence rate is 10-15% if mom is translocation carrier; 1-2% if dad is translocation carrier

Question 19

Deletions

Definition and examples

Answer 19

• Occurs when a chromosome lose some or all of its genetic information (it could be terminal or interstitial)
• Turner syndrome (whole chromosome deletion, or ring chromosome), Cri-du-chat syndrome, DiGeorge syndrome, Wilms tumor, and Williams syndrome (microdeletions), Prader-Willi and Angelman syndrome (single gene deletions), Cystic fibrosis (codon deletions), Duchenne muscular dystrophy (nucleotide deletions)