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    Genetics Short

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    Sabir Hossain

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    © All Rights Reserved
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    C) the offspring risk is 50% (Ans) d) Variable penetrance and expressivity present €) offspring risk is true for each pregnancy 4 Raa 0 19] 1). Males and females are affected in roughly equal numbers b) there are affected individuals in each seneration another ehild if born can have the disease? (Jan 5. Features of X linked recessive inheritance [Ja - 2021) 19) Ral Dovid 2k ge nots 8) X linked diseases are mostly recessive a) 25% (Ans) and restricted to males who carry the b) 10% ‘mutant allele c) 50% b) Occasionally female cartiers may exhibit d) 100% signs of an X linked disease e) 75% (c) The gene can be transmitted from female carriers to theie sons 2 TT d) Affected males cannot transmit the 2 condition to their sons (Jan 2021] €) Risk of female carrier having affected Ref: Robbins pathology 10, child is 25% Ban Fb group: Road To PG ¢) genomic imprinting (Ans) 6. vineeuanaeaealien @ xp having webby neck and amenortiea should ou have the following ehromosomal pater - + Disease diagnosed by chromosomal anal? 15} Duly 2021] a) ATXXY a) Down syndrome [Ans] b) 45,0 (Ans) b) Glycogen storage disease ©) 47.XXx ‘c) Haemochromatosis d) 45xv 4) Cystic fibrosis ))46x0 e) Hypercholesteroiae 4 {Ja-20) 7. Genetic disease involving protein and a) oceurs in heterozygous state ‘manifestation is adult life rather than childhood 1b) presentation at later stage of life Ju-14] C) uniform deformity than AD Disease a) Mitochondrial disease (ans) b) AD (Ans) d) complete penetrance is not common €) parents of affected individual is always affected c) AR d) X-linked recessive €) X-linked dominant Fb group: Road To PG 8. Which is a classically inherited in autosomal AG RRAAETAHIONu-13) a) Cystic fibrosis b) Alpha 1 antitrypsin defiency c)_Alzeimer's disease (Ans) ) Hereditary hemochromatosis ) Wilson's disease a) Actinic keratosis 1b) Xeroderma pigmentosa (Ans) ¢) Large pi d) Acanthosis nigricans €) Epidermoly nented naevus bullosa 10. 8-20 years old female presented with short ‘stature and amenorrhoea. Which is the most appropriate karyotype of this patient [J3-12] a) 45,XO (Ans) b) 47.Xx¥ c) 47,.XYY d) 47,.Xxx e) 46,0 COTES CATH TITAS & GT SPY GTIOH | 1. Features of Mendelian disorder (AD/AR/XRIXD)> 1 2. Example of Mendelian disorder (AD/AR/XRIXD)> 1 3. Choromosomal abnormality > 1 4. Others > 2 Gene is the basic unit of inheritance for a given characteristics. Gene is the shortest segment of chromosome within which genetic information is stored. Large numbers of genes are attached end ‘on end in extremely long double-stranded, helical molecules of DNA 1. A promoter region-binds RNA polymerase for the initiation of transcription 2. A transcription initiation site 3. A translation initiation site- Designate the first A in the protein 4. A transcription termination codon 5.3’ untransjated region - Stabilize mRNA -Allows it to exit nucleus ~Permits to be translated A pair of genes controls the appearance of a given characteristic and is situated at a specific site or locus on a pair of chromosomes- one gene at the ‘same relative locus on each chromosome. Each gene of a pairs calledialiele and they may not be identical. (HGMOZVGOUs- |t the two alleles are identical the individual is called homozygous. HISIEF@2YWOUS- 1 the two alleles are diferent the individual is heterozygous. DBffifafit! A gene may be dominant, i.e. it leads to manifestations, or RECESSIVE, i. the trait is not manifested but is capable of being transmitted to offsprings. Genotype is the genetic constitution of an individual. The manifestation of the genotype is called phenotype. Mutation is defined as a permanent change in the DNA and may be classified into three categories: 4. Genome mutation. There is loss or gain of whole chromosome eg. monosomy or trisomy, 2. Chromosome mutation. Mutation involving number or structure of chromosome, 3. Gene mutation. Gene mutation may result in Partial or complete deletion of a gene or more commonly a single nucleotide base’ (a) A single nucleotide base may be substituted by a different base resulting in a point mutation, (b) In frameshift mutation, one or more bases are inserted into, or deleted from the DNA. Causes of Mutation: Mutants arise by: 1. Spontaneous Mutation. Mutation occurs spontaneously during the process of DNA synthesis. 2. Mutagens. Certain environmental factors increase the rate of spontaneous mutations, or induce mutation. a) PRYSIGalIMURAGERS. Ultraviolet (UV) rays and ionizing radiations. UV light damages DNA by linking neighbouring thymine bases to form dimers. b)iChemical mUtagens are most anticancer drugs such as methotrexate. ©) WifGSES such as rubella virus ‘Oncogene activated by translocation > CML Burkit's lymphoma ‘Mantle cell lymphoma Folicular lymphoma T-cell acute lymphoblastic leukaemia Ewing sarcoma Melanoma Vy 1. Single gene disorders. a) Single gene disorder with classic inheritance : Mendelian disorder (AD,AR.XR,XD) b) Single gene disorder with Non- Classic inheritance: [SBA-Jan 2021] i. Disease caused by trinucleotide repeat mutation Disorder caused by mutation in mitochondrial genes iii, Disorder associated with genomic imprinting jv. Disorder associated with gonadal mosaicism 2. Multifactorial disorders/Polygenic disorders. These disorders are influenced by Gethigeniticlanid ‘SfivironimentallfaGtOFS. The genetic component involves the additive results of multiple genes of small effect 3. Cytogenetic disorders or Chromosomal abnormalities. Types of Chromosomal mutation/abnormalities > Aneuploidy > Monosomy, > Polyploidy Trisomy Tetrasomy , Tetraploids + Transiocation >Burkit's * Deletion lymphoma, + Inversions Philadelphia * Ring chromosome | chromosome + _Isochromomes * Mosaicism + Chimerism karyotyping Chromosomal constitution of an individual/cell. Ploidy: Denotes number of chromosomal set N= 23 chromosomes. But all are eupioid Haploid cells contain (@)- ova, sperm Diploid ce\! (@fi)-somatic cells — Triploid (3n), tetraploid (4n)- in chromosomal abnormality Aneuploidy Aneuploidy is a chromosome number that is not a multiple of 23, the normal haploid number. It is caused most often by an addition of loss of one ot {wo chromosomes; this change may result from nondisjunetion or anaphase lag. a. Non disjunction (1) Nondisjunction is Meiotic nondisjunetion is the most common cause’of aneuploidy. (2) This process is responsible for disorders such as Anaphase lag (1) Anaphase lag results in i@O8SI6f@ chromosome. during meiotic or mitotic division. (2) in early embryonic life, this can result in mosaicism, in which an individual develops two lines of cells, one with a normal chromosome complement and another with monosomy, a single residual chromosome, for the affected chromosome pair Polyploidy it is a condition when the number is increased by multiple of haploid (23) chromosomes (other than diploid number) Triploidy is three times the haploid number, and tetraploidy is four times. |s rarely compatible with life and usually Suns spontaneous abortion Fb group: Road To PG Translocation This is an exchange of chromosomal segments between non-homologous chromosomes. + is denoted by a t followed by the involved chromosomes in numeric order. For example, the translocation form of Down syndrome is designated as t (14q:21q). a. Reciprocal or balanced translocation is a break in two chromosomes leading to an exchange of chromosomal material. Since no genetic material is lost, balanced translocation is often clinically silent 'b. Robertsonian translocation is a variant in which then long arms of two acrocenttric chromosomes, chromosomes in which the short arm is very short, are joined with a common centromere, and the short arms are lost. Example: (Vil) a) Acute promyelocytic leukaemia - (15:17) b) Burkits lymphoma - (8:14) ©) Mantle cell lymphoma > t(1 1:14) 4) Follicular cell lymphoma > (14:18) e) Philadelphia chromosome 1(9:22) in CML Deletion + Means loss of a segment of chromosome (which may be terminal or interstitial) + |s denoted by a minus sign following the number of chromosomes and the sign for the chromosomal atm involve For example, cri cu cat syndrome, characterized by Partial loss of short arm of chromosome 5 is designated. as 46 XY 5p- in males and 46,XX,5p-in females. Inser ns ‘An insertion occurs when a segment of one chromosome becomes inserted into another chromosome. Inversions. ‘An inversion is a two-break rearrangement involving a single chromosome in which a segment is reversed in position, i.e. inverted. if the inversion segment involves the centromere itis termed a pericentric inversion. if it involves only one arm of ‘the chromosome it is known as a paracentric inversion, ** Ring chromosomes A ting chromosome is formed when a break occurs on each arm of a chromosome leaving two ,sticky, ends on the central portion which reunites as a ring ‘The two distal chromosomal fragments are lost so ‘hat, if the involved chromosome is an autosome, the effects are usually very serious Isochromosomes ‘An isochromosome shows loss of one arm with duplication the other. This accounts for approximately 15% of all cases of Turner's syndrome. Mosaicism Mosaicism can be defined as the presence in an individual or in a tissue of two or more cell lines which differ in their genetic constitution but are derived from a single zygote, i.e. they have the same genetic origin Chimerism Chimerism can be defined as the presence, in an individual, of two or more genetically distinct cell lines derived from more than one zygote, ie. they have a different origin. Degrees of rel ns First-degree relatives are those who are related at the parent-offspring or sibling (brother and sister) level. ‘Second-degree relatives are those who are removed by one additional generational "step" (e.g grandparents and their grand-children, uncles and aunts and their nieces and nephews). Children, uncles and aunts and their nieces and nephews). ‘Third-degree relatives include one's first cousins great-grand parents and great-grand children Fb group: Road To PG GENETIC CODE The genetic code by which DNA directs transcription of RNA and its transiation into protein is a series of codons running 5' to 3’ along linear coding strand of DNA. + A codon is a three-nucleotide unit which specifies a particular amino acid to be incorporated into the mature protein, e.g. methionine: ATG. There are 43 (64) different triplets; 61 specify one of the 20 amino acids. Three TAA, TAG and TGA - are ‘nonsense’ codons which terminate the growing polypeptide chain. 1. SBEIIEHY - Genetic code is specific, e.a specific codon always codes for the same amino acid. Genetic code universal (with a few minor exceptions). 2. Universality Properties ‘3iRedUndaney - Genetic code is redundant (some- times called degenerate). In many conditions the age at onset is delayed: symptoms and signs may not appear until adulthood (as in Huntington disease), ‘Some other features: 1. Atleast one parent of a case is affected 2. Both male and female can be equally affected. Mer 3. Both male and female can transmit disease. 4. Heterozygotes are phenotypically affected. 5 6. Consecutive generations are affected. Half of offspring are affected, male= female 7. Unaffected individual cannot transmit disease 8. Father-son transmission may be observed 9. Risk remains the same for each successive 10.Can exhibit Anticipation (i.e. occurrence of disease with a progressively earlier age of onset in successive generations, e.g. in triplet repeat expansion diseases), 11. Conditions usually less Severe than autosomal recessive. 12. High nieWimidtation|rat. 13. Usually associated with StfUcturallabnormalities: (structural-type disorder), SEONG wea ge, SM A ora CRA RIANA STH EMA TE IRA ATS BOG wT | ‘Wl4- Tuberous sclerosis CI - Huntington disease, 481 -achondroplasia 12 — Ehler- Danlos syndrome — *ffetd - Polycystic kidney NICIA—myotonic dystrophy ‘ITA - hereditary spherocytosis HHT, WI'#- Marfan syndrome, GCH-VwWD ‘fifera— familial hypercholesterolaemia (Except- Famili Mediterranean fever) ‘WE - Osteogenesi imperfect 2&4 ACG—Neurofibromatosis BUG - Charcot marrie tooth disease TAUM—Burgada syndrome , Long QT syndrome | disease Autosomal Dominant Disease Nervous > Huntington system: disease > Neurofibromatosi s > Myotonic dystrophy > Tuberous sclerosis > CMT disease > Hereditary neuropathy with liability to pressure palsies Renal » Polycystic kidney disease GIT > FAP Metabolic > Familial hypercholesterol emia Haemopoe > Hereditary tic spherocytosis > VWD > HHT > Marfan syndrome > Osteogensis imperfect > Achondroplasia > Ehlers danlos syndrome Skeletal Cardiac > Long QT syndrome > Brugada syndrome Retinoblastoma. Melanoma. FAP- Familial adenomatous polyposis (APC), Neurofibromatosis 1 and 2 (NF-1, NF-2). MEN-1 MEN-2. Hereditary non polyposis colon cancer. Autosomal Recessive Diseases: Autosomal recessive traits make up thellargest GAtEGORY of Mendelian disorders. They occur WhEA ‘These disorders are characterized by the following features: 1 The trait does not usually affect the parents of the affected individual, but siblings may show the disease; siblings have one chance in four of having the trait (:e., the recurrence tisk is 25% for each birth); and if the mutant gene occurs with a low frequency in the population, there is a strong likelihood that the affected individual (proband) is the product of a The expression of the defect tends to be more uniform than in autosomal dominant disorders. Complete penetrance is common. Onset is frequently early in lfe Although new mutations associated with tecessive disorders do occur, they are rarely detected clinically. Since the individual with a new mutation is an asymptomatic heterozygote, several generations may pass before the descendants of such a person mate with other heterozygotes and produce affected offspring. 6. Many of the mutated genes encode enzymes. In heterozygotes, equal amounts of normal and defective enzyme are synthesized ‘Some other features: 1. Both sexes are equally affected. 2. Only manifests in HSM@z/GOUSTSTARE! ‘SIHeReFOAVPOHES are phenotypicaly cartier state exists unaffected, ie. 4. Parents are usually unaffected, healthy carriers 5. if both parents are carriers (ie. if carriers mary): 4.25% (one-quarter) of off spring are homozygous and affected. b.25% (one-quarter) of offsprings are genetically normal €.50% (one half) of offsprings are carriers 6. if one parent carries the gene: BISOISTGHOHSpTNGICATIENS . Asymptomatic carriers produce affected children. Those with the disease do not usually have affected children uniess they marry a carrier, ie. increased risk of disease among offspring of consanguineous marriages. 7 Onset is often early (first few years) in life and have Complete penetration is common Fb group: Road To PG Expression of defect tends to be more uniform. 8. Usually associated _— Variable expressivity less of a problem than with Autosomal dominant inheritance. 9. Horizontal transmission occur Re (Cystic fibrosis ) F4(Haemochromatosis, Homocystinuria) WIS (Alpha 1 antitrypsin deficiency ) FX ! (Sickle cell anemia) , CTT! (Storage disease) f2AT (Congenital adrenal hyperplasia) 811 (Thalassemia) COUT (Phenylketonuria, FMF( CE°G (Friedric ataxia) ‘BRATS (Wilson disease) FATT (Neurogenic muscular atropy) CF (Spinal muscul atrophy) CITT (Galactossemi syndrome ) NOTE: > Small penis + Small Testes = Klinefelter syndrome > Large testes + Large mouth = Fragile X syndrome > Microopthaimia +polydactyly= Pattau syndrome > Micrognathia (small mouth}+Rocker bottom feet =Edward syndrome Delayed puberty + ABGSHIId+ undescended testes-Kallman syndrome ¥ Tall structure: 1.Constitutional(most common) 2. Gigantism 3. Kinefelter syndrome 4. Kallman syndrome 5. Marfan syndrome 6. Homocystinura Autosommal Recessive Disease System Disease Metabolic Haemochromatosis | Homocystinuria Cystic fibrosis Wea Galactossemia Lysosomal storage disease Glycogen storage disease VVVVY VY v Sickle cell disease Thalassemia Hematopoetic viv v Endocrine Congenital adrenal hyperplasia Skeletal > Alkaptonuria > Ehlers Danlos syndrome Nervous > Neurogenic system muscular atropy Friedreich's ataxia > Spinal muscular atrophy Vv Others ARPKD Kartagener syndrome > Pendred’s syndrome > Gilbert's syndrome Mevalonic aciduria Benign recurrent intrahepatic cholestatsis vv vv [Comparison between autosomal dominantandrecessvedisorder —] linked Recessive Disease ~D aR Stem Disorder T Afeedpenonisulyiasan |i Parneandoteranceronare] | Blood Haemophilia A&B fected parent. normal G6PD deficiency T itiscausedbyastnglecopyot |2 Here bat copes ofthe alesare (Chronic granulomatous disease mutation a heterorygotes mate (ie only homorygotes are areaffected) affected) 3. Usual recurrence risk50% _|3. Usual recurrence are affected - Musculoskeletal Duchenne Muscular dystrophy zo% Immune ‘Agammaclobulinaeria + Ta 3 Tranaission pater “Sarna cmt ep [a eke enerationaher generation |inonemoresiblings butusialynot | [Nervous sytem Fragile Ksyndrome thereisnoskippingot —_|incarler generations. ee ary Alport’ syndrome 5 Sexratio-equalmumber of |S. Sexratio—equal fafected males affected malesand females _| and females (usually) {usu A we, et mT & Father sontransmissiono? — | Consanguinity maybe present disease gene's possible ¥%(Duchenne Musculardystrophy) fia DI- Nephrogenic) enendcn hgieey [AP umotexnMorm than | | eats Agammaglobuinaemia) ,#8(Chronie granulomatous piste ume [eaypmmnamomewmn| | Hsta8e) CPP (Fri X syndtome)cr 66RD defen) te preset . al Lassie eaiyearsater it) Moresevee |_| ®H(HaemophiiaA & B) 3. Affected males cannot transmit the ‘condition to their'sons (but all their daughters would be carriers). 4. The risk of a female carrier having an affected child is 25% or hall of her male | offspring. Several genes are located in the “male specific region of Y*; al of these are related 5. Only females are carriers. to spermatogenesis! Males with mutations affecting the Y-linked genes are usually infertile, and hence 6. The heterozygous female usually does not there is no Y-linked inheritance, express the full phenotypic change because of the paired normal allele. Charecterstics: 7. in heterozygous females (offspring from a 1. Affected cases are usually males carrying carrier female and normal male): the gene and homozygous females (rare) 50% of daughters carriers 2. The gene can be transmitted from female: b.50% of daughters normal carriers (o their sons: in families with an X- 50% of cons:afiggO) linked recessiv condition, there are often a 4.80% of sone normal/ number of affected males related through unaffected females. 8. Inaffected male: a) All daughters are carriers b) All sons are normal (no male-male transmission) 9, When female is a carrier and mal affected: a. 50% of sons are affected b.50% sons are healthy ©.50% of daughters are affected 4.50% daughters are carriers. * Affected cases have affected brothers and maternal uncles. ‘+ Since females have two copies of the X chromosome and males have only one (hemizygosity), X linked recessive diseases are much more common among males than females. Characteristics: 4. Affects both sexes, but fif/ESIRiSR=A 2. In homozygous females all children are affected 3. Inheterozygous females: a.50% of sons normal, b.50% of sons affected, €.50% of daughters normal, 4.50% of daughters affected 4. Inaffected males: all daughters affected; all sons transmission normal (no male-male transmission) 5. No carrier state X linked Dominant Disorder | 1. Vitamin D resistant ricket | 2. Rett syndrome 3.Retinitis pigmentosa — X linked 4. Incontinentia pigmenti 5. Coffin lowry syndrome 6. Oral-facial- digital syndrome type 1 7. Periventricular heterotropia — X_linked Marfan syndrome is caused by a mutation in thé which is required for structural integrity of connective tissues and regulation of TGF-8 signaling. The major tissues affected are the skeleton, eyes, and cardiovascular system. Clinigal features ma) aneurysm, and aortic dissection. Most common cardiac anomaly associated is A heterogeneous group of genetic disorders with connective tissue problems. Marfan patients are tall, with very long extremities, and long fingers ("arachnodactyiyi)! Doubie-jointed. Chest deformities. (Pectus excavatum /carinatum) Funny-looking face. Bones siim, muscles wiry, body habitus slender. “Ectopia lentis" of eye (lax suspensory ligaments). Elongate globe, flat cornea (progressive myopia). Weak central area of thoracic aortic media predispose to aortic sissection (‘cystic medial necrosis"). ‘BSTOWIRIIFEIWEIE. Lax ligament around SBAIG ‘valve, (calises regurgitation later in life. One gene is {ibrilin, a connective tissue protein. Semi-Marfan's abound Related to Marfan's: (1) Kathigrisen (2) Menke's kinky hair disease, on the X- chromosome, which prevents normal handling of copper, prevents function of lysine oxidase. (3) Stickler's, a common Marfan variant, results from a premature termination codon on the type | procollagen gene. ("Rubber man", "human pretzels") is a family of variably-inherited diseases which leave a person with poorly woven collagen; easy to hurt, poor healers. Some have overly- extensible (even "cigarette-paper") skin; most have overly-mobile joints which often slip out of place. Type IV: various problems with type _ Il collagen ("reticulin"); colon and arteries often rupture. Type VI: reduced lysyl hydroxylase (autosomal recessive), ruptured corneas, detached retinas. Type VII: inability to turn type | procollagen into collagen. Ehlers-Danlos Syndromes There are six variants of Ehlers-Danlos syndromes, all characterized by defects_in_collagen__synthesis or assembly. Each of the variants is caused by a distinct mutation involving one of several collagen genes or genes that encode other ECM proteins like tenascin-X. Clinical features may include fragile, hyperextensible skin _vulnerable_to trauma, _hypermobile _joints, _and ruptures involving colon, cornea, or large arteries. Wound healing is Poor. Fb group: Road To PG 1. TRISOMIES Karyotype: 47 XY#21, 47XX421 Incidence strongly affected by maternal age: ~ 1:1200 live births (mothers under 30 years)/1:800, - 1:100 live births (mothers aged 39 years) Note: Maternal age affects birth rates of: Down syndrome, Edward syndrome, Patau syndrome, hydrocephalus, anencephaly, achondroplasia (patemal age also); increased frequency with age Causes: Nonzajsunction (aurea cases) Sporadic incidence related to matemal age Mosaicism (2% of cases). Less marked physical or intellectual dysfunction. Robertsonian translocation (40% of cases). Abnormalities in parents’ chromosomes. Mnemonics: Down syndrome pathology DOWN: -Decreased alpha-fetoprotein and unconjugated estriol (maternal). *** -One extra chromosome twenty-one. -Women of advanced age. -Non-disjunction during matemal meiosis. Clinical features Down's syndrome features: complete "My CHILD HAS PROBLEM": -Congenital heart disease/ Cataracts -Hypotonia / Hypothyroidism -Incure 5th finger/ Increased gap between 1st and 2nd toe -Leukemia risk x2/ Lung problem -Duodenal atresia/ Delayed development/Dental abn. -Hirshsprung's disease/ Hearing loss -Alzheimer's disease/ Alantoaxial instability Arched palate -Squint/ Short neck -Protruding tongue/ Palm crease -Round face/ Rolling eye (nystagmus) -Occiput flat/ Oblique eye fissure -Brushfield spot/ Brachycephaly -Low nasal bridge/ Language problem -Epicanthic fold/ Ear folded -Mental retardation/ Myocionus ‘Screening: + Antenatal screening in the first and second trimester identities fetuses at risk of Down's syndrome. Tests which currently have sensitivity > 60% and specificity > 91% include: + First timester (11-14 weeks): HUGH ‘{fASIUEBAEY; or nuchal translucency, human. chorionic gonadotrophin (HCGYan@ BrESHEREy: + Second timester (13-20 weeks): ffipleltest i. hCG: High ii. a-fetoprotein: Low ili, Unconjugated oestriol, UES: Low Trisomy 18 , E for Election. Vote FATS ATA st TAR | eine al features. * Mental retardation, craniofacial abnormalities (prominent occiput, low-set ears, foot deformity, contraction of finger, CHD, dies within few Edwards’ syndrome: characteristics EDWARDS! Eighteen (trisomy) Digit overiapping flexion -Wide head -Absent intellect (mentally retarded) -Rocker-bottom feet Diseased heart -Small lower jaw Trisomy 13 Clinical features + Mental retardation, cleft palate and lip, Hare lip, Ciett palate, polydactyly and microphthaimia. Deletions a) Cri du cat syndrome (Cries like a cat): Partial deletion of short arm of chromosome 5 Karyotype: 421 ‘Mnemonics: chromosomal deletion GaUsing)itis and starts with a P? (Answer: pussy) Why is the cat crying? Missing its P. [source: Genesis sheet] Clinical features: + Mental retardation, spasticity, high-pitched cry cranio-facial abnormalities (Round face with hypertelorism, Micrognathia, low-set ears, epicanthic folds) b) Prader-Willi syndrome and Angelman syndrome Deletion of chromosome 15 Fb group: Road To PG Clinical features + Prader-Willi (paternal inheritance): Neonatal hypotonia, facial obesity, low IQ, short stature and genital hypoplasia ‘Angelman (maternal inheritance) Hypertonia, ataxic gait, prominent jaw, deep-set eyes, absent speech and mental retardation Chappy puppet syndrome’) CYTOGENETIC DISORDERS INVOLVING SEX CHROMOSOMES Present in 25-30% of early abortions and 7% of deaths in first year of life. incidence 1:550 live births. Karyotype: 45X 0 [SBA, FCPS] i.e. no sex chromatin body Incidence 1:2000 live female births Causes: “Non-disjunction of sex chromomes Mosaicism (XO/XX, XO/XY or XO/KXX) Clinical features: Phenotypically female, short stature, wide carrying nal ing of neck, short 4thfrefacarpals (retarded bone age). sexual infantilism (lack of breast development with widely spaced nipples scanty pubic and axilary hai Primary amenorrhoea (occasional menstruation ‘occurs in mosaicism), high gonadotrophin levels, low oestrogen level. Associated anomalies iOSteomimonly With Bicuspi aortic valve (15%) & coarctation of the aorta (10%) , and renal abnormalities |Horseshoe kidneys. [SBA] Fusion of the lower poles of the right and left kidneys has formed a horseshoe-shaped organ. Horseshoe kidneys usually function normally Various kinds of kidney malformations, including horseshoe kidney, are common in Turner syndrome. Mnemonics: Turner syndrome: ‘components CLOWNS: Cardiac abnormalities -Lymphoedema -Ovaries underdeveloped (causing sterility) -Webbed neck -Nipples widely spaced Klinefelter syndrome is best defined as male hypogonadism that occurs when there are two or more X chromosomes and one or more Y chromosomes. Affects approximately 1 in 100 males ‘Common karyotype 47XXY, [SBA] also 46 X y/47XXy Mosaicism. One or two sex chromatin bodies. eee + The principal pathological abnormalit seminiferous tubules dysgenesis. This is evident from infancy (and possibly even in utero) and progresses with age. By adolescence, hyalinization and fibrosis are present within seminiferous tubules and Leydig-cell function is impaired, resulting in hypogonadism. Diagnosis is typically made in adolescents when presented with gynaecomastia failure to progress normally through puberty, iS/@onfifmied by Kalyotype analysis, Subject is male Barr Body in male. Clinical features: Tall, obese, bilateral gynaecomastia and infertility (decreased crown-pubis: pubis-heel ratio, modified eunuchoid). Small, prea-sized, firm azoospermic testes. Increased incidence of mental subnormality (Related to number of X chromosome) High urinary gonadotrophins with 17-ketosteroid content. The sex of an individual can be defined on several levels. Genetic sex is determined by the presence or absence of a Y chromosome. No matter how many X chromosomes are present, a single Y chromosome dictates testicular development and the genetic male gender. The initially indifferent gonads of both the male and the female embryos have an inherent tendency to feminize, unless influenced by Y chromosome dependent masculinizing factors. Gonadal sex is based on the histologic characteristics of the gonads. Ductal sex depends on the presence of derivatives of the millerian or wolffian ducts, Phenotypic, or genital, sex is based on the appearance of the external genitalia. Sexual ambiguity is present whenever there is disagreement among these various criteria for determining sex. ‘The term true hermaphrodite implies the presence of both ovarian and testicular tissue. In contrast, a pseudohermaphrodite represents a disagreement between the phenotypic and gonadal sexi i.e., a female pseudohermaphrodite has ovaries but male extemal genitalia; a male pseudohermaphrodite has testicular tissue but female-type genitalia). The genetic bases of these conditions are quite variable. Karyotype 45xY Clinical features: Similar features to Tumer's syndrome but phenotypically male Complete absence of testicles, cryptorchidism Gonadal function may be normal Karyotype 46 XY, ie. one sex chromatin body -al features: + Main cause of male pseudohermaphroditism, Inadequately virlized due to target organ failure. Phenotypically female, well-developed breasts and female contours but lacking body hair, with samall, blind vaginas. No uterus or fallopian tubes. Gonads are testes, producing testosterone. tearation [Mest comman genetic cause of mental "eardaton-> Down syndrome ) ‘Associated with a fragile site on the long arm of the X chromosome, and shows modified X-linked inheritance + There is an expansion of the molecular level of the CGCiftiplet repeat, which can exist as a permutation or a full mutation +» Affected males are. moderately to severely mentally retarded, carrier females can show mild mental retardation. + Macro-orchidism, Mnemonics: Fragile X syndrome: features FEMALES DS M-4: FMRi gene Exhibits anticpation Macro-orchidism ‘Autism Long face with large jaw Everted eyes ‘Second most common casue of genetic mental retardation Discontinued chromosome staining ‘Shows anticipation Male (male more affected) Fb group: Road To PG Mental retardation (2nd most common genetic cause) ‘Macrognathia (bnormally lange jaw). (MactOGrchidism [Large Testes] (MULTIFACTORIAL INHERITANCES Muttifactorial inheritances are more common than monogenic inheritances. Characteristics resulting from a combination of genetic and environmental factors are said to be multifactorial; those involving multiple genes can also be said to be polygenic. Expression determined by number of genes. Overall 5% chance of 1st degree relatives having it. Identical twins >>>5%, but way less than 100%. ‘This 5% is increased if more children have it. Expression of continuous traits (e.g., height) vs. Discontinuous traits (e.g., diabetes) [Very important } 1. Cleft lip with or without cleft palate 2. Neural tube defects (anencephaly spina bifida) 3. Congenital dislocation of the hip 4. Congenital heart defects 5. Gout 6. Pyloric stenosis 7. Talipes (club foot) 8. Diabetes 9. Hypertension prenatal diagnosis: [Very Important] 7. Adult 6 71. G6PD Polycystic kidney | Phenylketonur disease ja 2. Beckers 7. 12, muscular Osteogenesis | Huntington’ dystrophy imperfect s disease 3. Cystic fibrosis | 8. Sickle cell | 13. disease Hunter's syndrome. 4.Down 9. 14. syndrome Thalassemia | Menke's Syndrome 5. Duchenne | 10. 15 muscular Haemophilia | Myotonic | dystrophy dystorphy 16. 17. Neural 18. Neurofibromatos | tube defect | Niemann- is Pick disease Indications: [Very Important] 1. Women aged over 35 years 2. Raised maternal serum alpha-fetoprotein 3. Strong family history of neural tube defects, e.g previous affected child 4. Strong family history of chromosomal abnormality. 5. Carriers of X-linked recessive diseases. who have decided to terminate male fetuses. +E + DYoearewememe lol EElimnnol Denice ' ¢- ¢ + eeu dl Sto Toomer: ardiovascular disease} Cue ernie) Moco iP= Phenylketonuria| o-¢ Meee eres deficiency, alpha | antitrypsin icone! Sites exert T= Thalassaemia| sees ¢ + Box: 3.3 [Infinity star] > Karyotyphing or chromosomal analysis is indicated in Chromosomal abnormality. Doers snore eo ME ao021 4720021 11m 800 Carat tie, uly <0, conn eat asm, reamed fe ctr ward! sycrome Orsony 18) AT Y-818 04790618 1196000 _Eany nhaiy, Serine at and aces, east ‘rtarmabots of ea, hey ar Sor Pat's syorome erry 13) ar13 6470013 any tay aw ane aap, ral ead. 12000, Reqnt conpena hawt case anaes sero any Teo Fhenonpic ma, intray, gynacomasta, smal testes © too, » anxn 11m 1000 sy asymptomatic, sme impute conte preter TeX sare Sion {in 1000 Ususty sorta. ray he foaucod 1 Tamer ecrome x 11h 5000 Phenobp Tomate shat sare, welbed neck coarctation of (to sons pany amenorns i 65) SPetiqeoenccncat rons eee Mn 4000 Cardacoutow act cect, tinctve facia appearance, ‘xine tte Tae eda defects ace pla) Prager sare sat at tn ‘tSmcine facet pearance, hype sa has ae 18000 Keer dsnettatavoura pct, Imre epon, ons tn paternal stem TO% of cases ‘ogetnan's sya tsati-at3 tn rate tal oppearnn sent 1S000 —_ictemengnsogam fF) abrormanty.charactenstc gat pred og, dors on matra s rcrean tens strome rat 20 tn Dearne fel sppearnee, supine su ston, 1000 kearung asa ane wearaie ryprescaemar Major pone fo Siprawiwiar sore tense te ease Srp Magen syne vot2 tn Desc ta appearbnn an thao nenetoe 25000 sattmuy ana raps eye movement FEN) sep arama ‘igor anne seems tobe RA? See Inheritance pattern + Autosomal recessive Genetic cause © Two common mutations in the SERPINAT gene: p.Giu342Lys and p.Gu264Val Prevalence 1 in 1500-3000 of European ancestry Clinical presentation Variable presentation from neonatal period through to adulthood «+ Neonatal period: prolonged jaundice with conjugated hyperblirubinaemia or (rarely) Wer disease ‘© Adulthood: pulmonary emphysema and/or cirrhosis. Rarely, the skin disease, panniculitis, develops Disease mechanism «+ SERPINAT encodes a-antinysin, which protect the body from the effects of netohilelastase. The symptoms of, -antthypsin Cefiency rsut rom the ects ofthis enayme attacking normal tsa © M variant: if an individual has normal SERPINAT genes and ‘produces normal levels of c.-antitypsin, they are said to have an M variant © variant: p.Gu264Val mutation results inc, antirypsin levels ‘reduced to about 40% of normal © Z variant: p.Giu342Lys mutation results in very litte cx, -antitrypsin ‘© PIZZ: individuals who are homozygous for the p.Glu342Lys mutation are likely to have ct, -antitrypsin deficiency and the associated ‘symptoms : individuals who are compound heterazygous for p.Giu342Lys snp wey abe ee especialy # they smoke, 5 Sey ae ee eer ees SEG wee ge st ‘eter noma hem orc ‘rome ape ae orp ay a de nt = aorta ea oe ‘athens pn Sr ‘eer on wt apm Sted tetra eM ‘ce aout ed ie es woth oem ear eet ry Taste tena ere ape a ‘Sev eot sca coped ee cocaine Mnemonic! BAPP (aL BI) The Ss a ‘Wain MWe Doses TW amas se 7 TELS, Mata site wok UO, mya trex nouns Patan gh gnaw te rear eso iy 1 eae 7 z Termes ae WJ pscioe eer —10 7 Paes ELS, co, ay ea petoreaneppeapenaay 1) icon an 10 3 itd en tes sn dee oe rit 1a nae Zz {eg nue, We! il ess “i a= wt a lg a a eb a Mt, Smid te ants AS ay cn a ea lt NRE = teron nape tana ne ms acapegRA heal Seema oer nce WT fey Mane oer 29 The advantages and disadvantages of whole-genome sequencing, whole-exome sequencing and gene panels Test. Advantages Disadvantages ‘Whole-genome The most comprehensive aaj ofthe genome avaiable More expensive to gererae and store sequencing (WGS) More even coverage of genes, allwng beter dentfcaton” Wil ect milion of variant in nan-cotng ONA, whic can af dosage abnomalties ‘be vey cial to inteet Wil potently detect al gene mutans, icing nomic Associated with a greater Tsk of identyeg ince dogs mutations ‘Shalow sequencing fe reads per gene and so ess sense ‘and less abl to detect mosaicism ‘Whole-erome Cheaper han whole genome sequencing Les even coverage ofthe genome and so dosage Sequencing (WES) Aras sno restricted o only those gees known to —_abnormalis are mare dict to detect cause a gen canon Less comprehensive ans (-2% othe genom than WS ener varans detected than in WGS and so easier Increased kof ienting niet cigs oe larpeted Interpretation ene sequencing Deeper sequencing tan WGS increases senstty and detection of mosaics Gene panels ——asteectve ‘Wl nly detect vari in genes known to cause a gen ery dep sequencing, increasing the chances of mosaicsm —conion tring detect Dita ox new ganas othe pana as they ce severed Fever varans detected and so data easier to interpret ‘As ana) is ested to known genes, he tkeltood of Yerant being pathogen great inceased Syndromic baby CHa SCHBAS common feature ATF | 1, Mental Retardation 4, GiT abnormality 2. Cranio-facial abnormality 3. Congenital heart disease [__Disease Causing Mutation | WePointmutatation=s Haemochromatosis FAP Cystic fibrosis ADPKD ‘Achondroplasia ‘Alpha 1 antitrypsin deficiency viv > Cystic fibrosis [Deletion] > Hereditary motor and sensory neuropathy type 1 Cardiovascular , CNS , Connective Tissue disease 4 GIT disease Get AMATO Autosomal Dominant. 1. All GIT disease is AD except Cystic fibrosis 2. Al CNS disease is AD except Friedrech’s ataxia, Neurogenic muscular atrophy, Spinal muscular atrophy. 3. All CVS disease is AD except Long QT syndrome (BOTH AD & AR) ¢ DOea 8 GPO Sy aH ate wen TETAS AR 1. Metabolic diseases are AR except Familial hypercholesterolaemia (AD), ‘Acute intermittent porphyria 2. Hematological all disease are AR except Haemophilia (XLR) 3. Renal all disease are AR except Polycystic kidney disease (Both AD & AR), Alport syndrome (XLR) 4. Hepatic all disease are AR except Polycystic liver disease & Gilbert syndrome (Both AD & AR) 5. Respiratory all disease are AR # AD diseases occur due to structural /Protein abnormality # AR diseases occur due to metabolic cause/enzyme deficiency NOTE: Table 6-2 Biochemical Basis and Inheritance Patsern for Selected Mendelian Disorders Disease ‘Abnormal Protin Protein TypefFuncion Fara npecroeerlena Lowest Ippreen receptor Receptor rasport ota sntrme pein Srvcarl pore extract matric ler: Dinar sndrome! Cotager Struc prt extracel mara Haradaryspherocons Specein. ano prot Sirucaral upprere bod el membrane Newstin Newer (NI) Growth epson ‘ase ply hey ease Pobyen| PRON) Cleland ce rar areions jae fro Cyc foros tanamembrane regitor lon cna Pheretonr Frannie Exayne Tpit dseae Herons Enyne Severe cmbned emunodsoency ‘Aterosine damase name 1 and Thame Hemodotin Conger uaspert Side cet arama Hemorotin Oxygen uanport. Hemophia | Face ‘Coapuvon Duchemne/ecker muta opty Drarophn Srvc suppor cl marrane Frage X syndrome ro RNA wanton Sore rans ef ers Darl pore hae adoreal recess Wace pase {altug uk hown stems reqare Bac msatorshetoargtes for Gusset and ke cel anemia may reset wih mil crc die, Tha Tose dere sot re copra tana ederan ies SUMMARY Transmission Patterns of Single-Gene Disorders + Autosomal dominant disorders are characterized by expression in heterozygous state; they affect males and females equally, and both sexes can transmit the disorder. + Enzyme proteins are not affected in autosomal dominant disorders; instead, receptors and structural proteins are involved. * Autosomal recessive diseases occur when both copies of a gene are mutated; enzyme proteins are frequently involved. Males and females are affected equally. + X:linked disorders are transmitted by heterozygous females to their sons, who manifest the disease. Female carriers usually are protected because of random inactiva- tion of one X chromosome. SUMMARY ae + Marfan syndrome is caused by a mutation in the FBN/ gene encoding fibrillin, which is required for structural integrity of connective tissues. + The major tissues affected are the skeleton, eyes, and cardiovascular system. + Clinical features may include tall stature, long fingers, bilat- eral subluxation of lens, mitral valve prolapse, aortic aneu- rysm, and aortic dissection. + Clinical trials with drugs that inhibit TGF-B signaling such as angiotensin receptor blockers are ongoing, as these have been shown to improve aortic and cardiac function in mouse models. Ehlers-Danlos Syndromes There are six variants of Ehlers-Danlos syndromes, all characterized by defects in collagen synthesis or assembly. Each of the variants is caused by a distinct mutation. Clinical features may include fragile, hyperextensible skin vulnerable to trauma, hypermobile joints, and ruptures involving colon, cornea, or large arteries. Wound healing is poor, CF is an autosomal recessive disease caused by mutations in the CFTR gene encoding the CF transmembrane regulator. The principal defect is of chloride ion transport, resulting in high salt concentrations in sweat and in viscous luminal secretions in respiratory and gastrointestinal tracts. CFTR mutations can be severe (AF508), resulting in multi- system disease, or mild, with limited disease extent and severity. Cardiopulmonary complications constitute the most common cause of death; pulmonary infections, especially with resistant pseudomonads, are frequent. Bronchiectasis and right-sided heart failure are long-term sequelae. Pancreatic insufficiency is extremely common; infertility caused by congenital bilateral absence of vas deferens is a characteristic finding in adult patients with CF Liver disease, including cirrhosis, is increasing in frequency due to improved survival. PKU is a disorder of autosomal recessive inheritance caused by a lack of the enzyme phenylalanine hydroxylase and consequent inability to metabolize phenylalanine. Clinical features of untreated PKU may include severe mental retardation, seizures, and decreased pigmentation of skin, which can be avoided by restricting the intake of phenylalanine in the diet. Female patients with PKU who discontinue dietary treat- ment can give birth to children with malformations and neurologic impairment resulting from transplacental passage of phenylalanine metabolites. Galactosemia Galactosemia is caused by an inherited lack of the GALT enzyme, leading to accumulation of galactose-I-phosphate and its metabolites in tissues. Clinical features may include jaundice, liver damage, cata- racts, neural damage, vomiting and diarrhea, and E. coli sepsis. Dietary restriction of galactose can prevent at least some of the more severe complications. “Table 64 Lynne Serge Doda ‘rina oso drose elect ‘Porurtons processing dele of sso ‘emes Ieticene aging of ted pote to “he notome elec Isotomal eye protection Defcn sole nonenzymatic osama rcs “Taramenbrane nenerzymae) pron defeny ‘Gucher dese So nosis “TySuds diese Sind dese Fabry diese ete ee ‘ona deve pes ané 8 Macnutdovs (wane won) ucatp ype and apt Gat don Go stor poten decency arnt AB ‘Spiga cota prota Gene) [Nena dane ype C (NC) Sia dase (reese 4 org) Gucocaeesee Gnfincosde oronmiaie.cbune Hevesi sure ‘eGactoudne A {Gatorade Sitar ple sunases ‘Hesse ghccarine eho Pretciv prte apn A ‘Drplncoave and newense) Ge actor ren Sig corer protean 2c ana nner Sahn Lysosomal Storage Diseases + Tay-Sachs disease is caused by an inability to metabolize Gyn gangliosides due to lack of the B subunit of lysosomal hexosaminidase. Gra gangliosides accumulate in the CNS and cause severe mental retardation, blindness, motor weakness, and death by 2 to 3 years of age. + Niemann-Pick disease types A and B are caused by a defi- ciency of sphingomyelinase. In the more severe, type A variant, accumulation of sphingomyelin in the nervous system results in neuronal damage. Lipid also is stored in phagocytes within the liver, spleen, bone marrow, and lymph nodes, causing their enlargement. In type B, neuro- nal damage is not present. + Niemann-Pick disease type C is caused by a defect in cho- lesterol transport and resultant accumulation of choles- terol and gangliosides in the nervous system. Affected children exhibit ataxia, dysarthria, and psychomotor regression. + Gaucher disease results from lack of the lysosomal enzyme glucocerebrosidase and accumulation of glucocerebroside in mononuclear phagocytic cells. In the most common, type | variant, affected phagocytes become enlarged (Gaucher cells) and accumulate in liver, spleen, and bone marrow, causing hepatosplenomegaly and bone erosion. Types I and Ill are characterized by variable neuronal involvement. + Mucopolysaccharidoses result from accumulation of muco- polysaccharides in many tissues including liver, spleen, heart, blood vessels, brain, cornea, and joints. Affected patients in all forms have coarse facial features. Manifesta- tions of Hurler syndrome include corneal clouding, coro- nary arterial and valvular deposits, and death in childhood. Hunter syndrome is associated with a milder clinical course. SUMMARY eee oe meee + In females, one X chromosome, maternal or paternal, is randomly inactivated during development (Lyon hypothesis). + In Klinefelter syndrome, there are two or more X chromo- somes with oneY chromosome as a result of nondisjunc= tion of sex chromosomes. Patients have testicular atrophy, sterility, reduced body hair, gynecomastia, and eunuchoid body habitus. It is the most common cause of male sterility. + In Turner syndrome, there is partial or complete mono- somy of genes on the short arm of the X chromosome, most commonly due to absence of one X chromosome (45.X) and less commonly from mosaicism, or from dele- tions involving the short arm of the X chromosome. Short stature, webbing of the neck, cubitus valgus, cardio- vascular malformations, amenorrhea, lack of secondary sex characteristics, and fibrotic ovaries are typical clinical features. ay SSP Pea eee ‘The molecular basis for fragile X syndrome is beginning to be Understood and relates to silencing of the product of the FMRI gene, familial mental retardation protein (FMRP). The normal FMRI gene contains CGG repeats in its §° untrane lated region. When the number of trinucleotide repeats in the FIARI gene exceeds approximately 230, the DNA of the entire 5” region of the gene becomes abnormally methylated Methylation also extends upstream into the promoter region of the gene, resulting in transcriptional suppression of FAIR ‘The resulting absence of FMRP is believed to cause the phe. notype changes, FMP is widely expressed in normal tissues, but higher levels are found in the brain and the testi. Current evidence suggests that FMRP is an RNA-binding protein that 's transported from the cytoplasm to the nucleus, where it binds spectic mRNAs and transports them to the axons and dendrites (Fig, 6-18). Its inthe synapses that FMRP-mRNA complexes perform critical roles in regulating the translation of specific MRNAS. The absence of this fnely coordinated “shutle” function seems to underlie the eausation of fagle X syndrome. As noted, in addition to fragle X syndrome, many other neurodegenerative diseases related to trinucleotide repeat ‘expansions are recognized. Some general principles follow. + Inall cases, gene functions are altered by an expansion of the repeats, but the precise threshold at which premutatons are converte to full mutations fers with tach dra, + Wi te xan fog Xsytoeocis ig ogeeds. nother orders sacha Hunton deus remains are converted to fil mutton dng Fpermarogenesi +The expation may vo any prt ofthe gee, andthe range of posses canbe ded int two Broad tomes: those that fect untrandated regions an age Syndrome) or coding repone (xn Hung sare) (Fig 6-19) When mucatons sec nono reions thm no incon ana pte or pressed (eg, FMRO). By contr, mutations ivong Uranalte pars ofthe gene ue eto mafelded protons tater wh itn arora pn, Ungon dese). Many of thee so-

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