Chromosomal Disorders Chromosomes Coiled up DNA Humans have 23 pairs of chromosome Under normal conditions, all of the chromosomes

are inherited intact. Chromosomal Disorders Chromosomal Deletion- When cells go through meiosis, portions of the chromosome are lost Chromosomal Inversion- Chromosomes are flipped Chromosomal Translocation- Parts of the chromosome stick together and switch Chromosomal Non-disjunction- Do not separate correctly and are either passed lacking or too many Single Chromosome Disorders Deletion- Genetic material is missing Duplication- Genetic material is present twice Inversion- Genetic material is flipped Two Chromosome Disorders Insertion- Genetic material is added from another chromosome Translocation- Genetic material is swapped from another chromosome Downs Syndrome(Trisomy 21) About 95% of the cases have an extra chromosome 21, 4% are due to translocation and 1% are mosaics Children affected are born to old mothers, but sporadic or trisomic mongolism may also occur in young moms Overall incidence is 1:700 live births Marked variability depending on maternal age Younger than 20 years old: 1 in 1550; Over 40, 1 in 25 Paternal age does not seem to affect in cases where the gene is inherited from the father Downs Syndrome S/S Rarely cry Muscular hypotonicity Physical and mental development are retarded IQ varies from 25-50 Eyes are slanted, epicanthal folds usually present Bridge of nose is flattened Mouth is often held open due to large, protruding tongue, furrowed and lacks central fissure Hands are short and broad with a single palmar crease (Simian crease) Downs Syndrome S/S Brushfields spots gray to white spots resembling grains of salt around the periphery of the iris 40% affected by heart malformations There is a gap between the 1st and 2nd toe Predisposition to leukemia --- acute megakaryocytic leukemia Prognosis Life expectancy is decreased by heart dse and susceptibility to leukemia. Aging process seems to be accelerated with death occurring at 4th or 5th decade Edwards Syndrome (Trisomy 18) Additional chromosome 18 1:8000 live births with little maternal age defect Peculiar sex ratio 3 females : 1 male Edwards Syndrome Newborn is premature or small for gestational age Marked hypoplasia of skeletal muscle and subcutaneous fat Hypotonia Feeble fetal activity, polyhydramnios, small placenta and single umbilical artery Microcephaly, epicanthal folds, low-set malformed ears, cleft lip/palate are common Edwards Syndrome Peculiar clenched fist with the index finger overlapping the 3rd and 4th fingers is almost phathognomonic Absence of the distal crease on the 5th finger is common, low-arch dermal ridge pattern on the fingertips Micrognathia Edwards syndrome (small mouth, small, jaw, short neck, shield chest, short prominent sternum, wide set nipples, occiput is prominence, dysplastic or malformed ears, clenched hands with overlapping fingers, flex big toe, prominent heels) Prognosis Survival for more than a few mos is rare Mental retardation is severe on those who survive Pataus Syndrome(Trisomy 13) Trisomy of chromosome 13 1:5000 births and characterized by midline anomalies Pataus Syndrome (snall headf, absent eyebrows, cleft lip or palate, malformed ears, clenched hands or polydactyly, undescended testes S/S Small at birth Apneic spells in early infancy are freq Mental retardation is severe Many appear to be deaf Moderate microcephaly Sloping forehead

Wide sagittal sutures Widely patent fontanels are present Pataus Syndrome S/S Myelomeningocele in 50% of the cases Cleft lip, palate or both are present in most cases Ears are abnormally shaped and usually low-set Simian crease, polydactyly and hyperconvex narrow fingernails are common Fingers tend to be flexed but not the same as in trisomy 18 Dextrocardia is common 80% show congenital heart anomalies Cryptorchidism and abnormal scrotum Bicornuate uterus in female 70% die before age 6 mo. <20% survive beyond 1 year Trisomy 8 Normal height but slender Head is large and asymmetric Ears are low-set and dysplastic Strabismus Skeletal anomalies may involve ribs, vertebrae, patella and joint contractures and limitations are freq Unusually deep plantar and palmar creases Mild to moderate mental and motor retardation Delayed and poorly articulated speech Trisomy 9 Mental retardation Microcephaly Prominent nose High-arched palate Low-set ears Small penis Undescended testes Long flexed fingers Dislocation of the lips Congenital heart disease Partial Trisomy 22 Coloboma of the iris(cat eye) or anal atresia or both Extra chromosome 22 (22q+) Severe psychomotor retardation Eyes with an antimongoloid slant Abnormal ears with preauricular tags or fistulas Congenital heart dse. Full trisomy microcephaly, micrognathia and hypotonia Cri du chat Syndome 5p- syndrome Deletion of short arm of chromosome 5 High-pitched mewing cry Low birth weight Microcephaly Peculiar round or moon face with wide set eyes Antimonogoloid downward-sloping palpebral fissures with/without epicanthal folds Strabismus --- crossed-eyes broad-based nose Cri du chat Syndrome Ears are low-set and abnormally shaped Narrow external ear cannals, preauricular tags Short neck Varying degrees of syndactyly Heart defects are freq Hypotonic Mental and physical development are markedly retarded 4pExtremely rare Same as cat-cry syndrome without the cat-like cry 13q-(46, 13r or 46,13q-) Deletion of long arm of chromosome 13, often with formation of a ring chromosome Mental and physical retardation Broad, prominent, nasal bridge ptosis, Protruding upper incisors Short neck with lateral skin folds Large prominent low-set ears with facial asymmetry Imperforate anus or perineal fistulas

18qRetarded physical and mental growth Microcephaly Atretic or narrow ear cannals without dysplastic auricles are hallmarks Variable anomalies of the extremities, heart and face Leukemia In most patients with chronic, myelogenous leukemia, bone marrow cells of the myeloid series contain the Philadelphia chromosome, deleted chromosome no. 22 Turners Syndrome Complete or partial absence of one of the two X chromosomes Incidence: 1:3000 Affected newborns present with: dorsal lymphedema of hands and feet Lymphedema or loose folds of skin over the posterior aspect of the neck Older child: Short stature Webbing of neck Low hairline on back of neck Ptosis Wide chest with broadspaced nipples Multiple pigmented nevi Short 4th metacarpals Coarctation of the aorta Amenorrhea Failure of breast development Juvenile external genitalia Triple X syndrome (47, xxx) Discovered in about 1:1000 apparently normal females Sterility sometimes occurs, but several normal XXX females had offspring who are both phenotypically and chromosomally normal Klinefelters syndrome (47, xxy) 1:700 live male births 1:50 incidence of mentally retarded males Tall and eunuchoid, small firm testes and gynecomastia Most are normal in apprarance and intellect Scarce beard Longer fingers and arms Sterile Delicate skin Low mental ability Normal lifespan 47 XYY First described in 1961, in a 6-ft white male with no particular problems A number of males have been found in institutions for criminals with subnormal IQ It has been suggested that the extra Y chromosomal material predisposes the males to criminal aggressive tendencies. Intersex States True Hermaphrodites May be 46,XY or 46,XX Chromosomal studies on gonadal tissue show the ovotestis to be XX in the ovarian section and XY in the testicular section Testicular Feminization Syndrome Affected individuals are phenotypic females Gonad is testicular, defect lies in the cell membrane binding site for testosterone or in the production pathway of the active male sex hormone Inherited as an X-linked recessive trait Karyotype is 46,XY

MULTIFACTORIAL DISORDERS Inheritance controlled by many genes with small additive effects (polygenic) plus the effects of the environment Environmental influences act on a genetic predisposition Clinical clue: One organ system affected MULTIFACTORIAL DISORDERS Cause combination of genetic predisposition and environmental influences Pattern more affected people in family than expected from incidence in population but doesnt fit dominant, recessive or X-linked inheritance patterns MULTIFACTORIAL DISORDERS Factors close relationship to proband high heritability of disorder severe or early onset of disease proband of more rarely affected sex multiple family members affected

MULTIFACTORIAL DISORDERS Characteristics may occur in isolation lifestyle and environmental influences NOT a sex-limited trait incidence in relatives is lower than for single gene disorder but higher than in general population occurs more frequently in a specific ethnic group incidence falls rapidly in more distant relatives incidence in relatives rises as the manifestations become more severe in the index case risk to relatives higher when index case is of the least commonly affected sex observed risk rises following the birth of two affected children MULTIFACTORIAL DISORDERS Liability In multifactorial disorders, the liability curve is made up of genetic and environmental factors MULTIFACTORIAL DISORDERS Threshold In multifactorial disorders, there is a threshold, above which a person will develop the multifactorial disorder Frequency of pyloric stenosis in relatives For a female to be affected with pyloric stenosis, she must have a particularly strong genetic susceptibility COMMON DISEASES Congenital malformations Cleft lip/palate Congenital hip dislocation Congenital heart defects Neural tube defects Pyloric Stenosis Talipes Adult onset disorders Diabetes mellitus Epilepsy Glaucoma Hypertension Ischaemic heart disease Manic depression Schizophrenia MULTIFACTORIAL DISORDERS Recurrence Risks determined through family studies FAMILIAL RISKS TWIN STUDIES ADOPTION STUDIES POPULATION & MIGRATION STUDIES Do both twins show the same characteristic or trait? Comparing MZ/DZ twins can give evidence for genetic and/or environmental influences MZ twins share all their genes and environment DZ twins share 50% genes and environment Major effort to identify common disease susceptibility genes underway Risk factors for coronary artery disease Uncontrollable (but identifiable) Family history (genetics) Age Male sex Potentially controllable or treatable Fatty diet Hypertension Smoking High serum cholesterol Low serum HDL High serum LDL Stress Insufficient exercise Obesity Diabetes