Week 6 Molecular Genetics - 721

Allelic Heterogeneity

Different mutations can cause the same phenotype.

• E.g. : CF. There are over 400 different mutations in the CFTR gene. These can all cause the CF phenotype.

  • This is also an example of locus homogeneity. All mutations occur in the same gene.

Locus Heterogeneity

Mutations in different genes cause the same disease.

• E.g. : Xeroderma Pigmentosa. There are 9 different genes that can be affected and lead to the same XP phenotype. 

Phenotypic Heterogeneity

• Different mutations in the same gene result in different disorders

  • E.g. : Different B-globin mutations lead to different anemias (e.g. sickle cell vs. B thalassemia), or FGFR3 mutations can lead to achon, thanatotrophic dysplasia, craniosynostosis.

Pleiotropy

• Variety of systems affected by single gene change.

  • E.g. : Sickle cell leading to anemia, bone crises, chronic heart/kidney/lung damage

Variable expressivity

• Patients with the same disease present with different onset and progression of the disease

  • E.g. : differing severity of vaso occlusive crises in patients, caused by differing hemoglobin alleles

Epistasis

• One allele blocks the phenotypic expression of another.

  • E.g. : Patients with persistent fetal hemoglobin and SCD have much milder SCD.

Penetrance

• Probability a given gene will result in any phenotypic expression

Incomplete penetrance

• A mutation which does not have 100% penetrance for a given phenotype.

  • Breast cancer in BRCA1 mutation ~85% of people by age 70

Age dependent penetrance

• HD phenotype appears later in life

Complete penetrance

• FGFR3 gene leading to achon dwarfism

Gain of function mutation - dominant inheritance

• FGFR3 involvement in achon leads to always-on fibroblast growth factors. 

Haploinsufficiency

• A single normal copy of a gene is insufficient for normal function

  • e.g. familial hypercholesterolemia, LDLR heterogeneity 

Loss of heterozygosity

• two-hit model. An individual inherits a mutation in a gene copy, then undergoes a second spontaneous mutation leading to a loss of heterozygosity.

  • E.g HNPCC. A broken copy of the tumor causing gene, then another spontaneous mutation leads to HNPCC phenotype.

Dominant negative effect

• Mutated protein interferes with wildtype protein

  • E.g. : Osteogenesis imperfecta. COL1A/2 mutation produces non-functional collagen that also disabled properly coded collagens

Muscular Dystrophy - X-inactivation

• Hemizygous males are typically more severely affected.

• Mosaicism is evident in females, x-inactivation leads to different phenotype compared to males.

Muscular Dystrophy - In frame mutation

• Results in less severe Becker Muscular dystrophy. Early stop codon is not made. Only one amino acid is subbed

Muscular Dystrophy - Out of frame mutation

• Results in severe Duchenne Muscular dystrophy phenotype. Early stop codon is introduced

Germline mosaicism - DMD

• Occurs when a germ cell develops a mutation and propagates to all clones. Possible ½ of all germ cells (sperm or egg) have the mutation.

  • Very difficult to detect.

  • Observed only in X-linked and autosomal dominant disorders.

X-inactivation Skewing - DMD

• In women with a mutation in Xist, X inactivation may be unfavorably skewed such that more than 50% of the somatic cells in the body have DMD phenotype.

• The opposite may also occur where <50% of the cells in the body have the DMD phenotype, leading to a decreased disease prevalence.

NF1 - Age related penetrance

• Penetrance is complete by age 8

• Development of tumors is age dependent. Optic gliomas may occur in young children. Neurofibromas occur post-adolescence

NF1 - Variable Expression

• Variations in NF1 function given pathogenic variant. Some individuals have milder disease, others may be more severely affected.

NF1 - Allelic heterogeneity

50/50 split between de novo and familial NF1 cases. Types of mutations can vary widely.

NF1 - Pleiotropy

NF1 is multisystemic and includes ophthalmology, neurology, dermatology.

NF1 - Somatic Mosaicism

• If the mutation occurs in zygote post first division, a mutation will be present in some but not all tissues.

• Clinically, this means the recurrence risk is population risk, but individual may still be affected

Type II Collagenopathy - Phenotype-Genotype correlation

• Null mutations of COL2A1 result in diminished TII collagen production.

• Missense mutations of COL2A1 result in a glycine substitution which affects the tertiary structure of collagen.

  • This has a deleterious effect on correctly constructed collagens. Hence, AD.

Type II Collagenopathy - Phenotypic Hetergoeneity

• De Novo mutations explain lethal cases, germline mosaicism can also play a role in TII Collagenopathy recurrence.

  • Low severity - Stickler Syndrome - (premature osteoarthritis, flatten facial profile, midline cleft palate, ocular myopia and retinal detachment)

  • Medium severity - Kniest syndrome - dwarfing disorder with severe retinal degeneration, cleft palate and scoliosis

  • High Severity - achondrogenesis tII, skeletal dysplasia with almost complete lack of bony ossification

Type II Collagenopathy - Somatic Mosaicism

• Occurs post-fertilization leading to a mix of normal and mutated cells in the body.

  • So, some symptoms can be sequestered.

  • In a case study, a father has myopia and mild vision problems. Son has more severe Stickler-characteristic retinal detachment. Dad had mutation sequestered, so still present in germline.