9/15

Question 1

Reasons for Nonpenetrance

Answer 1

Failure to manifest with genotype present

1. Expressed primarily by individuals of one sex: hereditary breast/ovarian cancer
2. Influenced by modifier genes and polymorphism: SNP in mutant promoter for Huntingtons delay symptoms by 10 years while SNP in wild Type make happen 4 years earlier
3. Environmental trigger needed to activate gene susceptibility: adult onset diabetes or lung cancer

Question 2

Variations in dominant phenotype

Answer 2

Rarely see same symptoms and severity within or among families

Nonpenetrance, variable expressivity, de novo mutations, Germaine mosaicism, genetic heterogeneity, parent of origin effects

Question 3

Variable expressivity

Answer 3

Affected individuals in the same family show different features

Other genes, SNPs, and CNVs modify expression

Neurofibromatosis type 1 is the classic example

Anticipation with triplet nucleotide repeat disorders, earlier age of onset or worse symptoms in succeeding generations due to increasing number of repeats

Myotonic dystrophy is another example

Question 4

De novo mutations

Answer 4

Predisposition to de novo mutations:
large genes with repeated motifs, regions of methylated CpG bases (normal deamination of C), some nucleotides appear more predisposed

Clinical Presentation:
Classic autosomal dominant disease but without existence elsewhere in family, early lethality or reduced reproductive potential

Achondroplasia and Thanatophoric dysplasia both have mutations in the FGFR3 gene

Question 5

Germline mosaicism

Answer 5

New appearance of a typical autosomal dominant disease in a family

Unable to distinguish between de novo mutations and this in parent unless a second child is affected

Question 6

Variations in recessive phenotype

Answer 6

Common allele in pop.

Founder pop.

Level of gene expression

Consanguinity

Question 7

Normal epigenetic roles

Answer 7

Transcriptional control of developmental genes and tissue-specific genes

Inactivation of X chromosome in females

Imprinting: inactivation of some growth genes according to parent of origin

Mediation between the genome and environment: aging, environmental chemicals, and learning

Question 8

DNA Methylation

Answer 8

Becomes 5-methylcytosine

Any cytosine can be methylated but CpG are primary target, use MECP2 as the main methyl-CpG binding proteins

Located near promoter or exon 1 of 5’ end

Hypermethylation correlates with transcriptional repression

Question 9

Histone Modification

Answer 9

Acetylation: increases transcription, could change electric charge to separate DNA from histones or create binding site for basal transcription machinery

Histone acetyltransferase (HAT) adds -CH2CH3 to Lys, Histone deacetylase decreases transcription

Methylation: constitutive heterochromatin, could allow binding of transcriptional repressor protein

Ubiquitylation, phosphorylation, sumoylation

Question 10

MECP2 and associated disorders

Answer 10

MECP2 is the main methyl-CpG binding protein

Present all over but abundant in brain

1. Rett Syndrome: LOF mutation, progressive neurodeveloment disorder in girls (guys die in infancy), autistic, hand wringing
2. MECP2-related Severe Neonatal Encephalopathy: guys with LOF mutation that causes Rett syndrome in girls, die by respiratory failure at 2, microcephaly, hypotonia to rigidity, seizures, apnea
3. PPM-X Syndrome (Psychosis (bipolar), Parkinsonism, mild-to-severe intellectual disability X-linked): guys affected have worse intellectual disability than girls, LOF mutation that disrupts the DNA binding site
4. MECP2 Duplication Syndrome: Duplication of MECP2 gene on q arm of X, X-linked disorder and females don’t show symptoms cuz X inactivation, GOF with production of excess MEPC2

Intellectual disability, initial hypotonia, feeding difficulties, lack of speech, seizures, delayed other development, recurrent respiratory infections

Question 11

Genomic Imprinting

Answer 11

Only one allele expressed in a gene pair, determined by parent of origin

Imprinted gene is the inactivated gene, frequently involves CpG methylation, occurs in clusters

Normally imprinted: growth of embryo, placental function, neurobehavioral processes

Disrupted imprinting: carcinogenesis, diseases with abnormal physical growth and neurobehavioral development

Question 12

Uniparental Disomy

Answer 12

Inheritance of both homologues of a chromosome or region of one from the same parent and no copies from the other parent

Whole chromosome UPD results when trisomy of fertilized ovum is rescued by loss of 3rd chromosome

Only parent-of-origin genes affected: two active genes can cause overexpression, two inactive genes from inheriting two parentally imprinted gene is the same as a gene deletion

Question 13

Disruption of parent-of-origin effects

Answer 13

Uniparental disomy

Deletions/duplications of segments of a chromosome

Changes in epigenetic pattern

Small mutation in imprinting control centers located in imprinted gene region

Altered ncRNA function

Question 14

Angelman Syndrome

Answer 14

Retarded, microcephaly, macrostomia, hypotonia, ataxic gait, inappropriate laughter, seizures

Deletion 15q imprinting region from mom

Question 15

Prader Willi Syndrome

Answer 15

Neonatal hypotonia, feeding difficulty, genital hypoplasia, hyperplasia, developmental delay, obesity, distinctive facies, short, small hands and feet, hypopigmentation

Deletion of 15q imprinting region from father