Unexpected Events In Inheritance

Question 1

Summarize mitochondrial inheritance

Answer 1

Mitochondria are inherited from the mother- all of her offspring are affected, father doesn’t transmit

Question 2

Describe variable expression in mitochondrial disorders

Answer 2

The severity of mitochondrial disorders can vary in individuals with the disorder

This is due to the phenomenon of heteroplasmy

The severity of the disorder depends on the number of mitochondria that have mutant gene

Question 3

Summarize heteroplasmy in mitochondria disorders

Answer 3

• Mitichondrial DNA segregates passively when a cell divides
• Unequal distribution of mutant and non-mutant mitochondrial DNA, results in the phenomenon of heteroplasmy in mitochondrial disorders
• explains the variable expression of the disease in the offspring

Question 4

Summarize mitichondrial disorders

Answer 4

-Mitichondrial mutations generally affect multiple organ systems

• Leber hereditary optic neuropathy
  
  • manifests as progressive blindness arrplund 20-30 years
• MELAS: mitichondria, encephalopathy, lactic acidosis, and stroke like episodes
• Myoclonic epilepsy with ragged red fibers (MERRF)
• When a female is affected with a severe Mitichondrial disorder, one of the options is artificial reproduction technology
• The mom’s nuclear DNA is fused to the donor’s ovum (enucleated) and fertilized with the dad’s sperm cells

Question 5

What are the Disorders with non-Mendelian/ unexpected inheritance patterns?

Answer 5

Digenic disorders
-Retinis Pigmentosa

Imprinting

• Prader Willi syndrome
• Angelman syndrome

The above 2 are parent of origin effect

Triplet repeat disorders with anticipation (Mendelian-but mutation is unstable)
-Huntington 
-myotonic dystrophy
The above 2 are autosomal dominant 
-fragile x syndrome (X-linked)

Question 6

What are digenetic disorders?

Answer 6

Mutations in two genes (A,B) are additive and necessary to produce the disorder -individuals with mutations in both genes demonstrate the phenotype

One form of retinis Pigmentosa

• A disease of progressive visual impairment
• A result of a mutation in two independent genetic loci(ROM1 and peripherin)
• Heterozygous for gene A and gene B have retinis Pigmentosa.

Question 7

Explain the functioning imprinting (parent of origin effects)

Answer 7

Some genes are active only when transmitted by mother or father

-Imprinting involves methylation of specific loci (epigenetic change) and silencing of the gene

Normal imprinting pattern on chromosome 15:

• SNRPN gene is silenced by methylation on maternal ch15, but UBE3A is active
• UBE3A is active on the maternal chromosome 15
• On parental ch15, SNRPN is active and UBE3A is inactive (silenced by methylation).
• SNRPN is active on the paternal chromosome 15

Question 8

Explain Prader Willi syndrome

Answer 8

Prader Willi syndrome may be caused by:

• Microdeletion of paternal chromosome 15 (70% of patients)
• Maternal uniparental disomy of chromosome 15

Prader Willi syndrome due to micro deletion of Paternal 15q11-13(absence of SNRPN)

• Microdeletion of this region in paternal chromosome—> Prader Willi syndrome (about 70% of cases)
• Microdeletion can be detected by FISH using specific probes against the region or by array CGH (CMA)
• Children are usually obese, have mental and developmental delay and underdeveloped genitalia
• Hypotonia in infancy, failure to to thrive

Question 9

Explain Prader Willi syndrome as a result of Microdeletion.

Answer 9

In children with Microdeletion if the region on paternal chromosome 15, there is production of UBE3A protein from maternal gene , but SNRPN that is normally produced from the paternal chromosome 15 is absent, resulting in the phenotypic manifestations

Question 10

Summarize how uniparental disomy can lead to Prader Willis syndrome

Answer 10

Uniparental disomy is a condition when the child has two copies if the maternal chromosome 15 (absence of paternal chromosome 15)

• The region 15q11-13 is normally inactive in the maternal chromosome due to imprinting (methylation)
• Such children have two active copies of UBE3A and NO active copies of SNRPN gene
• Can be detected by methylation analysis - there are two methylated copies of ch15

Question 11

Describe methylation analysis

Answer 11

• Methylation sensitive restriction enzyme analysis uses the differential methylation patterns of chromosome 15 (maternal and paternal)
• The restriction enzyme doesn’t cleave methylated maternal DNA; paternal chromosome 15 at this region is cleaved by the enzyme
• May be exploited by Southern blot, PCR and DNA sequencing

Question 12

When is methylation pattern analysis ?

Answer 12

Most useful when the children are very young and have not developed classical phenotypes if the disorders

Question 13

How can the cause of Prader Willi syndrome be differentiated?

Answer 13

Polymorphic marker analysis

Due to the Microdeletion of chromosome 15 or due to uniparental disomy of maternal ch15

Question 14

What is Angelman syndrome ?

Answer 14

Angelman syndrome can be caused by :

• deletion of maternal 15q11-13 (absence of active UBE3A gene)
• Uniparental disomy of paternal chromosome 15 (two copies of active SNRPN and absence of UBE3A gene)
• “happy puppet syndrome”
• Happy disposition, laugh inappropriately
• Severe intellectual disability, seizures
• Puppet like posture of limbs

Question 15

How can uniparental disomy/deletion lead to angel,an syndrome ?

Answer 15

Maternal deletion of ch15 region- SNRPN gene active and NO active copy of UBE3A

Paternal uniparental disomy of ch15- two copies of SNRPN gene and NO active copy of UBE3A

Question 16

What are the four classes of triplet repeat disirders?

Answer 16

The triplet repeat may be present
-At the promoter region of the gene, resulting in reduced expression of the gene (CGG repeat in the fragile x syndrome )

• In an intron, resulting in formation of heterochromatin (Friedrich ataxia)
• In the coding region of the gene, resulting in a polyglutamine expansion in the protein (Huntington disease: CAG codes for glutamine )
• At the 3’ end (3’ UTR) of the gene (myotonic dystrophy)

Question 17

Explain what is anticipation

Answer 17

Individuals in the recent generations of a pedigree develop disease at an earlier age and generally with greater severity

Huntington disease

• Triplet repeat expansion: CAG repeat in the exon
• There is a polyglutamine tract in the Huntington protein

Greater the number of repeats, earlier is the age of onset of symptoms and more severe is the disirder

Repeats are unstable, and repeat size influences disease severity and age of onset -this is anticipation

Question 18

Explain anticipation in triplet repeat expansion disorders

Answer 18

The larger the repeat, the grater is the chance for it to be unstable and it tends to expand from one generation to the next

Anticipation is observed in the triplet repeat expansion disorders:

• In Huntington disease (autosomal dominant disorder), is generally more severe if transmitted from the father
• Myotonic dystrophy(autosomal dominant disirder)- expansion takes place in the mother
• Fragile X syndrome (X-linked disorder)- repeat expansion in the mother

Question 19

What is the net result of anticipation of myotonic dystrophy ?

Answer 19

Increasing severity from one generation to the next

Question 20

What are fragile X syndrome ?

Answer 20

Triplet repeat expansion (CGG repeat) on the X chromosome

• The triplet repeat is present at 5’ end (promoter region) of the FMR1 gene- resulting in increased methylation of this region and silencing of the FMR1 gene (epigenetics)
• females are less severely affected than males (only 50% of females with the full mutation may manifest with learning difficulties)
• Shiws anticipation in successive generations (repeat expansion takes place during oogenesis; disease tends to be more severe when a female transmits the mutation )
• Higher the number of repeats, greater is the severity of the disorder and earlier is the onset

Question 21

What are the characteristic features of fragile x syndrome ?

Answer 21

Intellectual disability

Learning difficulties

Prominent ears

Elongated face

Macro orchidism (enlarged testis)

Question 22

What are the diagnostic tests for fragile x syndrome ?

Answer 22

Southern blot analysis if the triple repeat gives an indication of the number if triplet repeat sequences

The X chromosomes show breakage (fragile X) in a folate deficient medium- cytogenetic test. The fragile site is demonstrated only in individuals who carry the full mutation

Analysis of the mother’s X chromosome usually demonstrates a prematuration