This presentation is about some information about non mendelian disorder seen in human

1. GOOD MORNING

2. NON-MENDELIAN
DISORDER
PRESENTED BY DR ANIKET GHOSH
1ST YEAR PGT
PATHOLOGY DEPARTMENT
IQ CITY MEDICAL COLLEGE AND HOSPITAL

3. INTRODUCTION
 Transmission of some single gene disorder does not follow
classic MENDELIAN principles are called NON MENDELIAN
DISORDER.
 If the genotype of both parents are known then MENDEL’S
LAW used to determine the distribution of phenotypes
expected for the population of offspring.
 There are several situation where proportions of
phenotypes does not match the predictive value

4. MENDELIAN INHERITENCE

5. CLASSIFICATION
 This group of disorders can be classified into FOUR
categories
a. Disease caused by trinucleotide repeat mutation
b. Disease caused by mutation in mitochondrial genes
c. Disorder associated with genomic imprinting
d. Disorder associated with gonadal mosaicism

6. Disease caused by Trinucleotide Repeat
Mutations
 Expansion of trinucleotide repeat is an important genetic cause
of human disease particularly neurodegenerative disorder
 Mainly causative mutation involved stretch of trinucleotides
that usually share nucleotides G and C.
 In all cases DNA is unstable and expansion of repeats above a
certain threshold impairs gene function in various way.
 The proclivity to expand strongly depends on the sex of
transmitting parent.

7. EXAMPLE OF TRINUCLEOTIDE REPEAT
MUTATION

8. Three mechanisms by which unstable repeat cause disorder
1. Loss of function of the affected gene typically by transcription
silencing, repeats are generally in the noncoding part of the
gene.
Example- FRAGILE X SYNDROME
2. A Toxic gain of function by alterations of protein structure,
expansions are generally in coding regions of the genes.
Example-HUNTINGTON DISASE ,SPINOCEREBELLAR ATAXIA
3. A toxic gain of function mediated by RNA in the noncoding
part of the gene.
Example- FRAGILE X ASSOCIATED TREMOR/ATAXIA SYNDROME

10. FRAGILE X SYNDROME
 The discovery of FRAGILE X SYNDROME in 1991 was a
landmark in human genetics.
 Most common genetic cause of intellectual disability in
males and overall the second most common after down
syndrome.
 Mainly mutation occur during OOGENESIS.
 Trinucleotide expansion mutation in FMR1 gene.

11.  The cytogenetic alteration was discovered as
discontinuity of staining or as a constriction in the Long
arm of X chromosome when cultured in folate deficient
medium.
 Chromosome is “BROKEN” at this locale and named as a
fragile site.

12.  The molecular basis of intellectual disability and related
somatic changes due to loss of function of the fragile X mental
retardation protein the product of FMR1 gene.
 Normal FMR1 gene contains 55 trinucleotide repeats
 Trinucleotide repeat exceeds 230 cause transcriptional
suppression of FMR1 gene
 This results in absence of FMRP cause phenotypic change

13.  In the brain FMRP selectively binds with mRNA associated with
polysomes and regulates their intracellular transport to
dendrites.
 FMRP is a translator regulator and it controls protein synthesis
at synaptic junction through bound mRNA.
 But loss of FMRP in FXS results in increased translation of bound
mRNA
 Imbalance in the production of protein cause loss of synaptic
plasticity

14. CLINICAL FEATURE
 Predominantly MALE affected
 Marked intellectual disability
 Macro orchidism-most distinctive feature
 Long face with large mandible
 Large everted ear
 Hyperextensible joints
 Mitral valve prolapse

16. Pattern of transmission is different from x linked
recessive disorder
 Carrier male- 20% of male clinically normal .transmit
through all phenotypically normal daughter to affected
grandchildren, called normal transmitting male
 Affected female- 30-50% of carrier female affected
 Risk of phenotypic effects- depends on position of
individual in the pedigree. Grandchildren are more
effected than brothers
 Anticipation- Clinical feature worsen with each successive
generation

17.  In case of coding region mutation usually involve CAG
repeats coding for polyglutamine tracts in the
corresponding proteins.
 Polyglutamine expansion lead to toxic gain of function
whereby abnormal protein may interfere with the function
of normal protein or acquire a novel pathophysiologic
toxic activity
 The accumulation of aggregated mutant proteins in large
intranuclear inclusion is the morphological hallmark

18. FRAGILE X ASSOCIATED TREMOR/ATAXIA SYNDROME
AND FRAGILE X ASSOCIATED PRIMARY OVARIAN
FAILURE
 Phenotypically different from FXS –occurs through toxic gain of
function
 Instead of methylation and silencing FMR1 gene continues to
be transcribed.
 20% female carrying prematuration have premature ovarian
failure. FSH elevated and antimullerian hormone levels
decreased
 Approximately 50% of prematuration carrying male exhibit a
progressive neurodegenerative syndrome in sixth decade –
Fragile x associated tremor/ataxia

19. MUTATION IN MITROCHONDRIAL GENES
 A unique feature of mtDNA is maternal inheritance
 Ova contain numerous mitochondria within their abundant
cytoplasm where spermatozoa contain few
 Mother transmit mtDNA to all their off springs male and
female .But only daughters transmits the DNA further to
their progeny.
 Example- LEBER HEREDITARY OPTIC NEUROPATHY

20.  Human mitochondrial DNA contains 37 genes among which
13 genes codes for respiratory enzymes and helps in
oxidative phosphorylation.So deletion of them affecting
the organs which depends on oxidative phosphorylation.
 HETEROPLASMY- Individual harbour both wild type and
mutant mtDNA
 THRESHOLD EFFECT- A minimum number of mutant
mtDNAs must be present in a cell or tissue before
oxidation dysfunction gives rise to disease

22. LEBER HEREDITARY OPTIC NEUROPATHY
 Neurodegenerative disease that manifest as progressive
loss of central vision.
 Visual impairment first noted at age of 15-35yrs leading to
blindness
 Cardiac conduction defect and minor neurologic
manifestation also seen.

23. GENOMIC IMPRINTING
 Important functional difference exists between the
paternal allele and the maternal allele these difference
results from epigenetic process called IMPRINTING
 Imprinting selectively inactivate either maternal or
paternal allele
 Maternal imprinting - transcriptional silencing of maternal
allele
 Paternal imprinting -the paternal allele is inactivated
 Imprinting occurs in the ovum and sperm before
fertilization then is stably transmitted to all somatic cells
through mitosis
 EXAMPLE- PRADER WILLI SYNDROME
ANGELMAN SYNDROME

24. COMPARISON OF PRADERWILLI
SYNDROME AND ANGELMAN SYNDROME
PRADER WILLI SYNDROME
 Deletion of band q12 in long arm of
chromosome 15
 Maternal silencing
 Deletion of paternally derived
chromosome
 Intellectual disability ,short
stature,hypotonia ,profound
hyperphagia, obesity ,small hand
feet and hypogonadism
ANGELMAN SYNDROME
 Deletion of same region of the
chromosome 15
 Paternal silencing
 Deletion of maternally derived
chromosome
 Intellectual disability,
microcephaly, ataxic gait, seizure
,inappropriate laugh(HAPPY
PUPPET)

26. ANGELMAN SYNDROME PRADER WILLI
SYNDROME

27. GENETIC BASIS
 Deletion
 Uniparental disomy
 Defective imprinting
MOLECULAR BASIS
 Angelman syndrome-Absence of
UBE3A
 PRADERWILLI SYNDROME- Loss of
SNORP function

28. GONADAL MOSAICISM
 In every autosomal dominant disorder some patients do not
have affected parents. So their siblings are neither
affected nor increased the risk for development of disease
due to new mutation.
 But in some AUTOSOMAL DOMINANT DISEASE have more
than one affected child and violates mendelian
inheritance.
 Postzygotically mutation during early development

29.  A phenotypically normal parent who has gonadal
mosaicism can transmit the disease-causing mutation to
the offspring through their mutated gamets .
 So more than one child of such parent would be affected.
 Example-Osteogenesis imperfecta

30. CONCLUSION
 Those disorders do not follow mendelian law called Nonmendelian disorder
 In Fragile x syndrome clinical feature worsen with each successive generation
and disease mainly transmitted from grandfather to grand son
 Mitochondrial gene mutation mainly follow maternal inheritance
 Genomic imprinting mainly occur due to deletion ,uniparental disomy and
defective imprinting .
 In gonadal mosaicism mainly autosomal dominant diseases does not follow
mendelian law and affecting more than one child

31. THANK YOU