dr. muhammad rafique assist. prof. paediatrics college of medicine k k u abha k s a
TRANSCRIPT
![Page 1: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/1.jpg)
Dr . Muhammad RafiqueAssist. Prof. Paediatrics
College of MedicineK K U Abha K S A
![Page 2: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/2.jpg)
![Page 3: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/3.jpg)
Human Genetics
Introduction: Genetic diseases common cause of diseases, death and prolonged handicap. • 1% newborns monogenic diseases like CF,SCD etc.• 0.5% chromosomal disorders like Down Syndrome.• 1-3% multifactorial disorders like CHD , spina bifida.• 40% deaths due to genetic disorders& birth defects.
![Page 4: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/4.jpg)
Modes of Genetic
Inheritance
![Page 5: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/5.jpg)
Mode of inheritance
Mendelian PolygenicmultifactoriaLl
Non traditional
AD
AR
XD
XR
Y-linked
Imprinting disorders
Triple repeat expansion
Mitochondrial
Chromosomal
Numerical
Structural
![Page 6: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/6.jpg)
MENDELIAN INERITENCE
• Classically 4 forms of genetic inheritance. .Autosomal dominant (A D ) .Autosomal recessive (A R ) .X-linked recessive. .X-linked dominant-Foundation of single gene inheritance.-Single gene sufficient to impact phenotype.
![Page 7: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/7.jpg)
AUTOSOMAL DOMINENT
• Either parent can transmit to 50% offspring.• Same family show variable expressivity.• Male /female equally affected.• Vertical transmission-(parents to offspring).• Involve all generations (no skip generation).• No carrier state.
![Page 8: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/8.jpg)
AUTOSOMAL DOMINANT DISORDERS
• Achondroplasia• Cong.spherocytosis• Marfan syndrome• Tuberous sclerosis• Ostseogenesis imperfecta
• Von-willebrand disease
• Polycystic kidneys
![Page 9: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/9.jpg)
![Page 10: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/10.jpg)
![Page 11: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/11.jpg)
![Page 12: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/12.jpg)
![Page 13: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/13.jpg)
MUTATIONSpontaneous change in genetic material
1-Gain function mutation; over/inappropriate expression of a gene product . Mostly produce AD disorder e. g. achondroplasia. 2-Loss of function mutation; observed in A R disorders.50% enzyme
activity in hetro- normal function e.g.(SCD)
![Page 14: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/14.jpg)
![Page 15: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/15.jpg)
![Page 16: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/16.jpg)
AUTOSOMAL RECESSIVE
• Both parents are clinically normal but carrier.• Both M&F but homozygous are affected.• 25% offspring pt.,25% normal,50% carrier risk.• If a pt. marries a normal person,all kids carrier.• Mostly conditions are enzyme defects& IEM .• Less variability among affected persons.• Consanguinity increases its risk.
![Page 17: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/17.jpg)
AUTOSOMAL RECESSIVE DISORDER
• SCD• Thalassemia• Cystic fibrosis• Wilson’s disease• Glycogen storage
disease• Gauscher disease
• Werdnig-Hoffman disease
• Cong. adrenal hyperplasia
• Galactosemia• Penylketonuria• Friedrick’s ataxia
![Page 18: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/18.jpg)
![Page 19: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/19.jpg)
![Page 20: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/20.jpg)
![Page 21: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/21.jpg)
![Page 22: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/22.jpg)
![Page 23: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/23.jpg)
X-LINKED RECESSIVE INHERITENCE
• Males are affected.• Females – carrier , normal/only mild s/sympt.• Male’s daughters,100% carrier,(XY).• All sons normal(no male to male transmission)• Carrier female’s sons 50 % norml,50 % pts(XX).• Carrier mother’s 50% daughters normal (XX).
![Page 24: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/24.jpg)
X-LINKED RECESSIVE DISORDERS
• Duchene muscular dystrophy.• Haemophelia A & B.• Nephrogenic diabetes insipidus.• G6-PD deficiency.• Colour blindness.
![Page 25: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/25.jpg)
![Page 26: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/26.jpg)
![Page 27: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/27.jpg)
![Page 28: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/28.jpg)
X-LINKED DOMINANT INHERIT.
• Can manifest in heterozygous female.• In female twice common (XX).• Manifestations more variable in females.• 50% risk for both f/m offspring of hetro. F.• All daughters of pt. father are affected(XY).• Example-Vit. D resistant ricket - Pseudo-hypo-parathyroidism -X-linked hypophosphatemic rickets
![Page 29: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/29.jpg)
![Page 30: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/30.jpg)
![Page 31: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/31.jpg)
![Page 32: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/32.jpg)
Y-LINKED INHERITANCE
• There are only few Y- linked traits.• Male to male transmission only.• Most Y–linked genes are related to sex
determination & reproduction and are associated with infertility.
• Rare familial transmission of Y-linked disorders.
![Page 33: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/33.jpg)
Polygenic/multifactorial Inheritence
• Combination of geneti+environmental factors.• General population incidence 1-1.5/1000.• Recurrence risk (2nd time)for kid/sibling 3-5%.• Re-recurrence risk(3rd time) about 8-10%.• Risk/severity increas with more pts. relatives .• CDH is F>M while pyloric stenosis is M>F.• Recurrence risk cleft lip+palat> only cleft lip.
![Page 34: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/34.jpg)
![Page 35: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/35.jpg)
MULTIFACTORIL DISORDERS
• Cleft lip+/-palat.• pyloric stenosis.• Hirschsprung’s disease.• Neural tube defects(spina bifida).• CHD (VSD, ASD, PDA etc.).• CDH, club foot.• Diabetes mellitus.• Asthma
![Page 36: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/36.jpg)
![Page 37: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/37.jpg)
![Page 38: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/38.jpg)
![Page 39: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/39.jpg)
![Page 40: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/40.jpg)
Mitochondrial DNA
![Page 41: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/41.jpg)
Mitochondrial Inheritance
A woman with a mitochondrial genetic disorder will have affected offspring of either sex.
An affected father will have no affected offspring.
![Page 42: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/42.jpg)
Mitochondrial Inheritance
DiseasedNormal
![Page 43: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/43.jpg)
CURRRENT UNDERSTANDING OF GENETICS OF COMMON DISORDERS
• Impact of genetics in paediatrics diseases is being realized.
• Prevention and intervention may soon be possible in ,at risk children.
• Examples; .Type 1 diabetes mellitus. .Early onset childhood obesity .Asthma
![Page 44: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/44.jpg)
Type 1 Diabetes Mellitus
• Polygenic multi-factorial paediatric illness.• In affected families many loci appears to be
linked to increase risk.• A few gene variants confer risk for disease.• Some environmental factors like viral illness.• Heritability estimates about 66-72%.• Twins concordance 30-50%.
![Page 45: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/45.jpg)
T1DM-----cont----
• Relative risk in general population --0.4%.• Pt.s siblings has 15 times more risk (6%).• Many studies indicate locus of gene on 6p21 .• 30% pts. have association with HLA-DQ2/DQ8.•
![Page 46: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/46.jpg)
CHILDHOOD OBESITY
• It is a multi-factorial disease.• Many contributing factors still unknown like .Modern environment of plentiful calories. .Low physical activity. .With combination of gene result—obesity.• Many studies suggest rare gene, acting as
recessive .
![Page 47: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/47.jpg)
CHILHOOD OBESITY
![Page 48: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/48.jpg)
CHILDHOOD OBESITY –CONT.--
• Example is MC4R (melanocortin 4 receptor), found in 3% obese children.
• Families and twin studies estimate 50% heritability.
• 100 genetic associations with obesity reported in positional and functional candidates.
![Page 49: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/49.jpg)
CHILDHOOD ASTHMA
• Asthma and atopy are heritable.• Asthmatic parents have 60% increase risk of
atopy in their kids .• 3-6years children have double risk if both
parents are asthmatic.• Twin studies found heritability about 80%.• Higher concordance in monozygotic twins.
![Page 50: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/50.jpg)
CHILDHOOD ASTHMA– CONT.--
• Children of asthmatic mother have more risk to develop asthma than asthmatic father.
• Some environmental factors involved are : endotoxin, cockroach, dust-mite antigens, and diesel particles.• Implicated genes are found on 5q,6p,13q and
20p13.
![Page 51: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/51.jpg)
Autosomal Dominant Inheritance
![Page 52: Dr. Muhammad Rafique Assist. Prof. Paediatrics College of Medicine K K U Abha K S A](https://reader035.vdocuments.us/reader035/viewer/2022062312/55163a42550346c6758b513b/html5/thumbnails/52.jpg)
Autosomal Recessive Inheritance