1. Chromosomal aberrations

2. sex determination

Dr. Bheem Prasad

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vEach cell (except RBO) contain all of the chromosomes from both parents in the nucleusv23 pairs of chromosomes come from each

parentvAutosome: one of the 22 pairs of

chromosomes that is not responsible for determining the sex of the childvSex Chromosome: X and Y chromosomes

responsible for sex determination

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Chromosomal Defects• Abnormal Number

– Monosomy: one less than the diploid number (45)– Trisomy: one more than the diploid number (47)

• Mosaicism: some cells have the correct number of chromosomes and some have more or less than the correct number of chromosomes

• Abnormal Structure– Deletion: loss of a chromosomal segment– Translocation: the occurrence of a chromosomal segment at an

abnormal site either on another chromosome or in the wrong position on the same chromosome

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Trisomy 21• Incidence

– 1 : 650 – 1000 live births, parental age related– 75 % abort spontaneously– Sex ratio: 3 males / 2 females– Most common autosomal chromosomal disorder causing mental

retardation

• Risk Factors– maternal age– Parental carrier of translocation

• Prenatal Testing– Triple screen (alpha-fetal protein decreased, estriol decreased, beta-

HCG increased)– If positive, amnio or CVS may be indicated

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Clinical Presentation•Size: small, 20% are premature•Skull: short and round with a flat occiput, separated sutures•Eyes: slant upward and outward•Prominent epicanthal fold•Moon-shaped face•Brushfield’s spots•Cheeks: red•Palate: narrow and short•Nose: short with flat bridge

•Tongue: protrudes, tongue thrusting•Skin loose around lateral and dorsal aspects of neck•Hands: fingers are short, hands are square, thumbs are low set, separated more than usual from second finger, 5th

finger is short and curves inward, single/bilateral simean crease•Ears: low-set, posteriorly rotated ears

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Clinical Presentation•Umbilicus: herniated•Feet: wide space between great toe and 2nd toe, deep crease between great toe and the 2nd toe, flat feet•Heart: VSD•Duodenal atresia•Muscular hypotonia•Retarded psychomotor development•Hyperlaxity of ligaments

•Velvety, loose adhering mottled skin in infancy, coarse skin in adolescence•Mouth frequently open/frequently open mouth•Visual and/or hearing impairment

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Trisomy 21

Trisomy 18

• Edward’s Syndrome, Trisomy E, Trisomy 16 –18

• Caused by an extra chromosome 18

Normal Karyotype Edward’s Syndrome (47,XY, +18)8

Trisomy 18

• Incidence– 1 : 6000 – 8000 live births– F > M (4 : 1)– Most die in embryonic or fetal life

• Risk factors– Increased paternal and maternal age

• Prenatal screening– Good indicator is if in maternal serum during mid trimester have

low human chorionic gonadotrophin and low unconjugatedestriol

– Ultrasound– If anomalies seen, amnio or CVS may be indicated

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Types of Trisomy 18

• Full Form– Every cell in the body has 3 chromosome 18 instead of

2– Severe form

• Mosaic Form– Some cells have 3 chromosome 18 and others have 2– Less severe form

• Partial Form– In some cells there may be an extra copy of part of

chromosome 18– Severity dependent on anomalies

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Clinical Presentation•Prenatal hx: feeble fetal activity, polyhydramnios, small placenta, single umbilical artery•Post-dates•SGA•Weight: low birth weight in term infant•Weak cry•Response to sound decreased•Ears: low set and/or abnormal shape

•Mouth: micrognathia, microstomia, cleft lip, cleft palate•Mental retardation•Heart: VSD, PDA, ASD•Feet: rocker bottom, big toe shortened and dorsiflexed, clubfeet•Crossed legs•Diastasis recti•Pectus carinatum•GU defects: horseshoe kidneys, hydronephrosis, polycystic kidneys

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Clinical Presentation•Hands: clenched and with flexed fingers (usually where index finger overlaps 3rd and 4th fingers),flexion contraction of the two middle digits, underdeveloped or absent thumb, simian crease, arches on seven or more fingers, nails underdeveloped•Syndactyly•Eyes: ptosis of one or both eyelids, epicanthal folds

•Head: abnormally prominent occiput, microcephaly•Hernias: umbilical, inguinal•Redundant skin folds esp. over the back of the neck•Males: cryptorchidism

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Trisomy 18

Trisomy 13

• Patau’s Syndrome, 13+ Syndrome, 13 – 15 D Syndrome, Trisomy Syndrome

• Caused by an extra chromosome 13

Normal Karyotype Trisomy 13 (47,XX,+13)14

• Incidence– 1 : 5000 live births– Male = Female

• Risk Factors– Increases with maternal and paternal age– Increases with increased parity– Parental carrier of balanced translocation

• Prenatal Screening– Ultrasound– If anomalies seen, amnio or CVS may be indicated

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Clinical Presentation•Severe mental and psychomotor retardation•Ears: malformed, low-set•Hands: flexion deformities; polydactyly, simian crease, clenched hands•Heart: VSD, PDA, ASD, rotational anomalies (dextrocardia)•Eyes: microphthalmos, colobomas of iris, cataracts, retinal dysplasia, close set (may fuse into one)

•Nose: broad and flattened•Mouth: cleft lip and palate•Hernias: umbilical hernia, inguinal hernia•Kidneys: polycystic•Skin: cutaneous hemangiomas•Head: dermal sinus on scalp, microcephaly•Brain: gross defects, grand mal seizures, myoclonic jerks, seizures, holoprosencephaly

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Turner’s Syndrome

• Turner’s Syndrome, Monosomy X, Gonadal Dysgenesis, Bonnevie-Ullrich Syndrome, XO Syndrome Is the absence of one set of genes from the short arm of one X chromosome

Normal Karyotype Turner’s Syndrome (45,X) 18

• Incidence– 1 : 2000-3000 live-born females– Females only affected– 98% of pregnancies with TS spontaneously abort– 10% of pregnancies that spontaneously abort have TS

• Risk Factors– Increased paternal age– Mother with mosaic or deletional Turner’s Syndrome

• SHOX gene association– SHOX gene provides instructions for making a protein that

regulates activity of other genes

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Clinical Presentation•Short stature; mean birth weight 2.9 kg; average height: 4’7”•Webbed neck•Low posterior hairline•Micrognathia•Ears: low-set, sometimes malformed, prone to otitis media•Widely spaced hypoplastic nipples on a shield-shaped chest•Increased carrying angle at the elbow

•Heart: coarctation of the aorta, aortic vavular stenosis, bicuspid aortic valve, aortic dissection•Eye: ptosis, strabismus, amblyopia, cataracts, epicanthal folds, dry eyes, red-green color blindness•Congenital hip dislocation•Abnormal growth patterns•Congenital lymphedema of hands and feet

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Clinical Presentation

•Absent or retarded development of secondary sexual characteristics that normally appear at puberty•Absent menstruation•Absence of normal vaginal moisture•infertility

•Gonadal dysplasia•Horseshoe kidney•Unilateral renal agenesis•Intelligence: not at risk for mental retardation, better verbal then visuospatial abilities•Broad nasal bridge

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Klinefelter Syndrome

• Incidence = 1/1000• Usually taller than average• Disproportionately long limbs• 30-50% gynaecomastia• Infertility / Azoospermia• I.Q may be reduced relative to sibs

Example karyotypes = 47,XXY47,XXY/46,XY

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Klinefelter Syndrome

• Phenotype very variable – some patients are not diagnosed until they try for a family

• Mosaics 47,XXY/46,XY may have milder phenotype and may be fertile

• Therefore always carry out mosaicism check as infertility is the main clinical problem

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Cri-du-chat Syndrome

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Fragile X Syndrome

• Moderate to sever mental retardation• Speech delay, short attention, hyperactivity• Poor motor coordination and mouthing

objects• Poor socialization, temper tantrum• Mood disorder (bipolar), schizophrenia

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Fragile X syndrome

• Long protruding ears• Long face and prominent jaw• Flattened nasal bridge• High arch palate• Macroorchidism• Genetic is complex, 80% penetration in male

and 30% penetration in female

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Fragile X syndrome

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Angelman syndrome

• Sever mental retardation• Inappropriate laughter• Decrease pigmentation of choroid or iris (pale blue

eyes)• Ataxia and jerky eye movement• Sever speech proplem• Deletion of b15q11q13, maternal in origin• Paternal uniparental disomy

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Prader-willi syndrome

• (A fat red faced boy in state of somnolency) Charles Diickens

• Early hypotonia• Obesity• Short stature as adult• Almond shaped blue eyes• Mental retardation (mild to moderate)• Narrow hands

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Prader Willi Facial Features

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clinically recognized pregnancies

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-20 20-24 25-29 30-34 35-39 40+maternal age

% tr

isom

icChromosome abnormalities and maternal age

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Sex determination

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• The Y chromosome contains far fewer genes than the X chromosome.

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• Pseudoautosomal Regions (PARs)

– regions on Y chromosome that share homology with regions on the X chromosome

– synapse and recombine with it during meiosis

– Presence of such a pairing region is critical to segregation of the X and Y chromosomes during male gametogenesis

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• Y chromosome contains:– the male-specific

region of the Y (MSY)

– a sex-determining region of the Y (SRY)

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• Testis-determining factor (TDF)– a protein encoded by a gene in the SRY that

triggers testes formation.

• The MSY consists of three regions: – X-transposed region– X-degenerative region– ampliconic region

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• Dosage Compensation Prevents Excessive Expression of X-Linked Genes in Humans and Other Mammals

• Dosage compensation balances the dose of X chromosome gene expression in females and males.

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• The inactive X is highly condensed, can be observed in stained interphase cells, and are referred to as Barr bodies.

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• The Lyon hypothesis states that X-inactivation occurs randomly in somatic cells.

• This is evident in the calico cat.

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• The X-inactivation center (Xic) is active on the inactive X.

• It consists of the X-inactive specific transcript (XIST) gene.

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THANK YOU43