610 likes | 1.35k Views
Traditional Inheritance. Mendelian inheritanceDiseasesSingle gene defects/disordersAutosomal inheritanceDominant e.g. Marfan's syndromeRecessive e.g. Thalassaemia majorX-linked recessive e.g. Haemophilia. Non-traditional Inheritance. Polygenic or multifactorial inheritanceE.g. Diabetes mellitusMitochondrial inheritanceE.g. Sensorineural hearing lossGenomic imprinting and uniparental disomyE.g. Prader-Willi SyndromeTrinucleotide repeat expansionE.g. Fragile X syndrome.
E N D
1. Non Traditional Inheritance
2. Traditional Inheritance Mendelian inheritance
Diseases
Single gene defects/disorders
Autosomal inheritance
Dominant e.g. Marfan’s syndrome
Recessive e.g. Thalassaemia major
X-linked recessive e.g. Haemophilia
3. Non-traditional Inheritance Polygenic or multifactorial inheritance
E.g. Diabetes mellitus
Mitochondrial inheritance
E.g. Sensorineural hearing loss
Genomic imprinting and uniparental disomy
E.g. Prader-Willi Syndrome
Trinucleotide repeat expansion
E.g. Fragile X syndrome
4. Mitochondrial Inheritance
5. Mitochondrial DNA Mitochondria contain extranuclear DNA material (mtDNA)
Inherited only from the mother, never from the father (paternal mtDNA lysed upon entrance of sperm into oocyte)
Normally all mtDNA within an individual are identical
mtDNA are prone to mutation
6. Mutation of mtDNA
7. Genomic Imprinting phenotypic expression depends on the parent of origin for certain genes and chromosome segments
8. Imprinting probably occurs in many different parts of the human genome but is thought to be particularly important in gene expression related to development, growth, cancer, evolution, and behavior.
9. What is genomic imprinting? Specific genes or DNA segments are reversibly modified during gametogenesis in a parent specific fashion.
Parent of origin I.e. whether the specific gene is paternally / maternally inherited can be distinguished.
10. Parent of origin The parent specific genes can be epigenetically marked
Epigenetically = gene structurally different but actual sequence of nucleotides is unchanged, e.g. methylation of the genes
For imprinted gene, the gene expression and therefore the distinct functions depend on parent of origin.
11. Phenotypic expression of the imprinted genetic region depends on the parent of origin.
Both paternal and maternal genetic regions are required for normal development.
Prader Willi syndrome
Angelman syndrome
Beckwith-Wiedemann syndrome
12. PWS / AS Absence / dysfunction of imprinted region can occur by:
Deletion
Uniparental disomy
mutation
13. Microdeletion Usually spontaneous
Grandmatrilineal inheritance in PWS
E.g. grandma with sporadic microdeletion, passes to her son as silent carrier. Her grandchildren will haave 50% chance of having PWS
Likewise, grandpatrilineal inheritance in AS
14. Uniparental Disomy Inheritance of 2 copies of a particular chromosome form one parent and none from the other.
The frequency of non-disjunctional events causing aneuploidy has been shown to increase dramatically with maternal age for most chromosomes
Kupke et al. 1989, Hassold et al. 1995, 1996, Antonarakis et al. 1992.
15. Trisomy rescue
Most trisomies are lethal, and the fetus survives only if a cell line loses one of the extra chromosomes post zygotally and becomes disomic.
Robinson et al. 1996, Robinson et al. 2000
Monosomy duplication
Monosomy followed by post-zygotic duplication of the single chromosome
showed isodisomy for markers throughout the entire long arm of chromosome
Gamete complementation
Non-dysjunction in both parents
i.e. 2 chromosomes from one parent and 0 from the other
Mechanisms
16. The origin of UPD is caused by pre-zygotic non-disjunction followed by post-zygotic correction of the monosomic/trisomic zygote, both of which are spontaneous events.
The recurrence of PWS or AS is probably non-significant in view of the rarity of UPD.
Nicholls et al. 1989b, Malcolm et al. 1991, Smeets et al. 1992, Smith et al. 1997, Robinson et al. 2000
17. Non deletional mutations Effect:
Lose ability for maternal to paternal or paternal to maternal switching.
Site:
Imprinting center
Imprinting region
Suggested to be due to a de novo imprint switch failure during parental gametogenesis and/or fertilization. Low recurrence risk.
18. Prader Willi Syndrome
19. Genetic Basis in PWS A sister disorder of Angelman syndrome
Both result of the absence or lack of expression of one parent’s contribution to the same region of the proximal long arm of chromosome 15q, 15q11-q13.
PWS –absence of paternally derived genes at 15q11-q13
AS–absence of maternally derived genes at 15q11-q13
20. Genetic basis in PWS Because of genetic imprinting, the maternally inherited genes are silent, I.e. not expressed / rendered inactive, likewise in AS.
Grandmatrilineal inheritance
21. Genetic defects of PWS Absence of paternally derived genes
at 15q11-q13
~70% Paternal microdeletion
~25% Maternal uniparental disomy
2-5% Imprinting center defects
22. Maternal UPD was caused by a meiotic error in 90% of cases, of which 83% had arisen in the first meiotic segregation.
Robinson et al. 1998b, Robinson et al. 2000, Robinson 2000
The frequency of uniparental disomy is much higher in Prader-Willi syndrome than in Angelman syndrome, obviously because of the relatively rare occurrence of meiotic non-disjunction in male compared to female meiosis.
Martin et al. 1991, Antonarakis et al.1993b, Hassold et al. 1996).
23. Clinical features Many of the manifestations are related to functional hypothalamic deficiency
Clinical appearance changes as the child grows.
24. Infantile period Central hypotonia can be severe
Marked neonatal lethargy
weak cry, decreased arousal, poor reflexes
poor sucking and early FTT, which special feeding techniques e.g. special nipple / tube feeding may be needed to avoid severely impaired weight gain
25. Adults remain mildly hypotonic with decreased muscle bulk and tone.
Short stature almost always present by the end of 2nd decade.
26. Global developmental delay GM: average of sitting 12m, walking 24m
Delayed language development
Poor academic performance
27. Hypogonadism Hypogonadotrophic hypogonadism
Genital hypoplasia
Male: cryptorchidism, scrotal hypoplasia,
small penis
Female: hypoplasia of labia minora / clitoris
Pubertal insufficiency
Male: some with no voice change, male body habitus and substantial facial or body hair
Female: amenorrhoea, oligomenorrhoea, late menarche 30s
sexual activity is rare, infertility is the rule.
28. Hyperphagia and obesity Hyperphagia likely of hypothalamic origin, manifest as lack of satiety
Obesity commonly develops between 1-6 years, most often between 2-4.
food seeking behavior, eating of unappealing substances
A/w related obsessive behaviors
PWS is the most common recognized
genetic form of obesity. Obesity is a
major cause of morbidity.
e.g. garbage, pet food, frozen food
like stealing food or stealing money to buy food is common
Secondary to DM HT stroke sleep apnoeae.g. garbage, pet food, frozen food
like stealing food or stealing money to buy food is common
Secondary to DM HT stroke sleep apnoea
29. Cognitive impairment Usually Mild
IQ mostly 60-70,
30% between borderline to average
no evidence of IQ decline over time
Unusual skill with jigsaw puzzles
30. Maladaptive Behavior variable but frequent,
Common problems include
Overeats, skin picking, stubborn, obsessions temper tantrums, disobedience, impulsivity, mood labiality, excessive sleep, talk too much, anxious and worried, withdrawal.
Adapted from Dykens and Cassidy, 1999
31. Dysmorphic appearance narrow bifrontal diameter,
almond shaped palpebral fissures,
down-turned mouth with a thin upper lip
Small hands with tapering fingers
Hypopigmentation
Strabismus
Scoliosis, kyphosis
32. Genetic laboratory investigations Chromosomal analysis
Florescence in situ hybridization analysis with 15q11-q13 specific probes
Methylation analysis
PCR and markers
33. Angelman Syndrome (AS)
34. Genetic defect of AS Deletion of 15q11-q13 region of maternal origin (70%)
Chromosome 15 paternal uniparental disomy (UPD) (3%)
Imprinting center mutation (1%)
Intragenic mutation of maternal copy of UBE3A gene (6%)
35. Clinical features of AS Newborns have normal phenotype
Developmental delay first noticed at around 6 months
Other features manifest after 1 yr
Diagnosis may take several years
36. Neurological Epilepsy 90%
Delayed gross motor delvelopment
Gait & movement
Hyperkinetic movement
Characteristic gait
Cognitive level & speech
Mental retardation, attention deficit, hyperactivity
Understanding >>> expression
Minimal to complete absent use of words
37. Characteristic Gait of AS Lean forward
Uplifted arms
Flexed elbow
Downward turned hands
Legs kept wide based
Feet flat & turned outward
38. Behavioral Hyperactivity
Short attention deficit
Laughter & happiness
“Happy-puppet”
Reason unknown
Early or persistent social smiling
Sleep disturbance
Reduced need for sleep
39. Musculoskeletal Microcephaly
Brachicephaly
Occipital groove
Mandibular prognatism
Widely spaced teeth
40. Genotype vs. Phenotype Patients with UPD/small deletion when compared with those of large deletion have:
Later time of diagnosis
Less severe epilepsy, later onset
Less severe cognitive and speech impairment
Better weight gain and occipital frontal circumference
41. Genetics laboratory tests Chromosome analysis
Florescent in situ hybridization (FISH)
Methylation test
Paternal uniparental disomy (UPD) studies
Ubiquintin-protein ligase E3A mutations
Imprinting center (IC) mutations
42. Trinucleotide repeat expansion "An increased number of contiguous trinucleotide repeats in the DNA sequence from one generation to the next.” Fig. 1?Genetic locations of repeat expansions. The relative locations of known repeat expansions are portrayed on a prototypical gene. Expansions have been discovered in all regions of a gene. They are found in the upstream flanking region, as in episodic myoclonic epilepsy. They may occur in exons or in introns. Those that are present within exons may occur within the upstream untranslated region, as is found in fragile X syndrome; they may occur within the protein coding region, as is the case with Huntington disease; or they may occur within the downstream untranslated region, as is seen with myotonic dystrophy. There is one example of an intronic repeat expansion: Friedreich ataxia. The size of the triangles reflects the size of the triplet repeat expansion. EPM1 = episodic myoclonic epilepsy type 1; OPMD = oculopharyngeal muscular dystrophy; SCA = spinocerebellar ataxia; SBMA = spinal and bulbar muscular atrophy; DRPLA = dentatorubral-pallidoluysian atrophy.Fig. 1?Genetic locations of repeat expansions. The relative locations of known repeat expansions are portrayed on a prototypical gene. Expansions have been discovered in all regions of a gene. They are found in the upstream flanking region, as in episodic myoclonic epilepsy. They may occur in exons or in introns. Those that are present within exons may occur within the upstream untranslated region, as is found in fragile X syndrome; they may occur within the protein coding region, as is the case with Huntington disease; or they may occur within the downstream untranslated region, as is seen with myotonic dystrophy. There is one example of an intronic repeat expansion: Friedreich ataxia. The size of the triangles reflects the size of the triplet repeat expansion. EPM1 = episodic myoclonic epilepsy type 1; OPMD = oculopharyngeal muscular dystrophy; SCA = spinocerebellar ataxia; SBMA = spinal and bulbar muscular atrophy; DRPLA = dentatorubral-pallidoluysian atrophy.
43. Anticipation
44. Consequence of postzygotic changes in repeat length
Consequence of incomplete penetrance
Reversion of a repeat to a length below the disease threshold
Expansion of a repeat from below to above disease thresholdConsequence of postzygotic changes in repeat length
Consequence of incomplete penetrance
Reversion of a repeat to a length below the disease threshold
Expansion of a repeat from below to above disease threshold
45. Currently known expansion mutation disorders fall into 3 general groups.
46. 8 diseases caused by expanded CAG repeats encoding the amino acid glutamine. Clincial manifestation of thse diseases: may include abnormalities of voluntary and involuntary movement; dementia, affective, spychotic, or obsessive compulsive symptoms; apathy; irritability; and other less specific personility changes.Clincial manifestation of thse diseases: may include abnormalities of voluntary and involuntary movement; dementia, affective, spychotic, or obsessive compulsive symptoms; apathy; irritability; and other less specific personility changes.
47. Disease caused by relatively short repeat expansions. Synpolydactyly -abnormal skeletal patterning
Cleodocranial dysplasia - disorder of skeletal development.Synpolydactyly -abnormal skeletal patterning
Cleodocranial dysplasia - disorder of skeletal development.
49. Fragile X Syndrome
50. Genetics Verkerk in 1991 found the FMR-1 gene located at Xq27.3
Fragile X mental retardation gene 1
Normal population:
FMR-1 varies from 5-50 repeats
Premutation unaffected carriers:
FMR-1 enlarges to up to 200 repeats.
Affected patients:
FMR-1 repeats more than a thousand times. Distal long arm of chromosome X at Xq27.3Distal long arm of chromosome X at Xq27.3
52. Physical manifestation Macroorchidism
Large ears
Prominent jaw
Long face
53. Neurodevelopmental abnormalities Cognitive dysfunction
Executive
Visual-spatial
Visual motor abilities Behavioral symptoms
Autism
Attention-deficit/hyperactivity disorder
Social anxiety
55. References Margolis RL. Ross CA. Genetics of Childhood Disorders: IX. Triplet Repeat Disorders. J Am Acad Child Adolesc Psychiatry,38:12, 1598-1600 December 1999
Eliez S. Reiss AL. Genetics of Childhood Disorders: XI. Fragile X Syndrome. J Am Acad Child Adolesc Psychiatry, 39:2, 264-266 February 2000
Chiurazzi P et al. Understanding the biological underpinnings of fragile X syndrome. Curr Opin Pediatr 15:559-566 2003
Lombroso PJ. Genetrics of Childhood Disorders: XLVIII. Learning and Memory, Part 1: Fragile X Syndrome Update. J Am Acad Child Adolesc Psychiatry, 42:3 372-375 March 2003
McFarland R et al. The neurology of mitochondrial DNA disease. Lancet Neurology 1:343-51 2002
RenzoGuerrini et al. Angelman syndrome. Pediatr Drugs 5(10):647-667 2003
Wagstaff J et al. Genetics beyond Mendel. Postgraduate Medicine 108(3):131 September 2000