Medical Genetics

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Translocation

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Genetic abnormality caused by rearrangement of parts between non-homologous chromosomes.
Two types: reciprocal (transfer of genetic material between non-homologous chromosomes), and non-reciprocal (Robertsonian)

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Robertsonian translocation

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Involves two acrocentric chromosomes (where the p arm is too smal to be observed) that fuse near the centromere. Namely, this occurs only in chromosomes 13, 14, 15, 21, and 22.
The resulting karyotype will have 45 chromosomes since two have fused together.

Carriers have no phenotypic abnormalities, but there is a risk for unbalanced gametes which result in miscarriage or abnormal offspring. For example, an offspring can get translocation Down's syndrome.
Whether the translocation is reciprocal or Robertsonian, if no chromosomal material is lost, the translocation is said to be balanced.

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Acrocentric chromosome

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Centromere is near the end. Have very short p arms which end in structures called satellites.

Chromosomes 13, 14, 15, 21, and Y are acrocentric.

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Array Based Comparative Genomic Hybridization (CGH)

Describe. Uses. Limitation.

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This technique is used to test copy number changes in the DNA. This is especially useful to detect cancer by comparing the cancer genes with reference (normal) genes, and identification of copy number variants (CNV) where large segments of the chromosome is involved.
Limitation: cannot detect balanced translocations.

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Aneuploidy

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Any chromosome number that is not an exact multiple of the haploid number. Example: trisomy and monosomy.
Can result from nondisjunction.

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At what stage of the cell cycle are the chromosomes maximally condensed?

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Metaphase. Think metaphase plate!

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Haplotype

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Common pattern of human genetic variation.
A combination of alleles at adjacent locations on the chromosome that are transmitted together. A haplotype may be one locus, several loci, or an entire chromosome depending on how many genes underwent recombination.

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Epigenetics

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Imprints, methylations, and environmental factors affecting the genes.

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Pseudoautosomal points

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Matching sequences on the X and Y chromosomes where crossing over may take place.

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During oogenesis, when is the first meiotic division complete?

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At the time of ovulation.

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How long does it take to complete spermatogenesis?

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Approximately 60 days.

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When does prophase start for an oocyte?

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It starts in fetal life and remains in suspended phase until ovulation.

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During oogenesis, when does the second meiotic division take place?

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ALmost immediately after the completion of the first meitoc division (after ovulation), but is only completed if fertilized in the fallopian tube.

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How do you distinguish nondisjunction that happens during meiosis I and II?

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If the two chromosomes are identical: nondisjunction in meiosis II.
If non-identical: meisosis I.

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Isochromosome

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The complete absence of one of the arms on a chromosome. Usually the short arm is lost.

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Trisomy 21 (Down Syndrome)

Physical characteristics

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Physical characteristics: hypotonia (poor muscle tone), slanted palpebral fissures, poor moro reflex, anomolous ear auricles, hyperflexibility of joins, dysplasia of pelvis (malformed), dysplasia of the midphalanx of hte fifth finger, Single palmar (Simian) crease, excess skin on back of neck, flat facial profile.

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Trisomy 21 (Down Syndrome)

Major cause of mortality

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Major cause of mortality is congenital heart defects. 44% of Down syndrome individuals die of heart problems in infancy.

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Atresia

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Body orifice or opening is abnormally closed or missing.

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What is the etiology of trisomy 21?

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Main etiology is nondisjunctional trisomy 21 (more likely with advanced maternal age).
Trisomy 21/normal mosaicim.
Translocation (not associated w/maternal age)

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Recurrence risk of trisomy 21.

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First, need to know etiology.
Nondisjunction: 1% or the mother's maternal age relative risk.
Translocation: both parents need to be karyotyped to see if which parent(s) is a balanced carrier. Risk is 10-15% if the mother is a balanced carrier, but 5% if the father is a balanved carrier.

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Trisomy 18 (Edward Syndrome)

What are some of the features before birth?

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Second most common multiple malformation syndrome.

Features before birth: polyydramnios, rocker-bottom feet, intrauterine growth retardation, decreased fetal activity, and single umbilical artery.

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Trisomy 18 (Edwards Syndrome)

Sx at birth, and prognosis. Etiology.

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Sx at birth: hypertonia, microcephaly, low-set malformed ears, small jaw (micrognathia), cleft lip and/or palate, small nails of hands and feet, shortened sternum, inguinal or umbilical hernia, diaphragmatic hernia and heart defects.

Prognosis: very limited capacity for survival. Only 10% survive to the first year.

Etiology: nondisjunction, and rarely translocations.

Recurrence risk is much lower than trisomy 21.

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Trisomy 13 (Patau Syndrome)

Features. Prognosis. Etiology. Recurrence.

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Clinical features: hallmark is abnormalities of midfacial and forebrain development, holoprosencephaly (prosencephalon fails to develop), Intrauterine growth retardation, congenital deafness, microcephaly, polydactyly and syndactyly, cardiac defects, polycystic kidneys, duplication of the ureters, males with cryptorchidism, and hypospadius.

Px: only 5% survive first six months.
Etiology: nondisjunctions, and rarely translocations.
Recurrence is lower than trisomy 21.

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Triploidy

Features. Prognosis. Etiology.

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Placentas are very large and contain the characteristic cystic hydatiform changes (mass tissue resembling a bunch of grapes= hydatid cyst), Simian crease and syndactyly of 3rd and 4th digits, congenital heart defects, hypospadias, micropenis, cryptochidism.

All cases of triploidy have been stilborns or died within months.
Etiology: mostly paternal from dispermy, fertilization by diploid sperm. Sometimes a diploid ovum is involved.

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Diploid/triploid mosaicism

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Individuals with diploid/triploid mosaicism usually survive with varying degrees of psychomotor retardation and skeletal asymmatry.

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Contiguous Gene Syndrome

Definitions. Examples.

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Abnormalities of 2 or more genes which are located next to each other on a chromosome. Usually deletion of multiple genes at closely linked loci. Examples:

Prader-Willi/ Angelman Syndrome (15q11-q13)
Williams Syndrome (7q11.23)
Velocardiofacial syndrome (22q11)
Smith-Magenis syndrome (17p11.2)

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Velocardiofacial Syndrome

Synonyms. Clinical features.

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Synonyms: VCFS, DiGeorge Syndrome, 22q deletion syndrome, CATCH-22.
Prefix velo is for velum (soft palate)

Clinical features: velopharyngeal incompetance (VPI), cleft palate, speech and feeding problems, cardiac defects, tetrology of Fallot, facial appearance (assymetric crying, overfolded ears, long face), hypocalcemia, learning difficulty, immunodeficiency due to absence or small thymus

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Velocardiofacial Syndrome.

Etiology. Dx

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Greater than 95% have deletion in 22q11 (microdeletion). Most of this deletion is denovo.
Other etiology include smaller 22q11, chromosomal rearrangement, or mutation in the TBX1 gene.

Dx: karyotyping, FISH, or CGH.

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XYY Syndrome

Features. Transmission to offspring risk. Etiology.

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Features are very subtle, so rarely detected. Males are phenotypically normal and fertile.

Some observed features: accelerated growth in mid childhood, dull mentality, explosive behavior, distractibility, severe nodulocystic acne in adolescence. facial asymetry with large teeth, long ears, and prominent glabella, increased length vs. breadth, relative muscle weakness.

Transmission of this karyotype is rare, so mostly it results from de novo nondisjunction events.
Etiology: Extra Y chromosome is from nondisjunction during meiosis II.

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XXY Syndrome (Klinefelter Syndrome)

Features. Etiology.

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Hypogonadism and infertility. Gynecomastia. Low IQ, moderate intention tremor, behavioral problems (immaturity, insecurity, shyness), tall slim stature, tend to be obese without testosterone replacement.

Etiology: Meiotic nondusjunction (equal maternal and paternal).

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45 XO (Turner Syndrome)

Features. Etiology.

EXAM

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Small stature, sexual infantilism, webbed neck, puffiness over the dorsum of the hands and transient congenital lymphedema, low posterior hairline. Elbow anomalies, broad shield chest, cardiac anomalies, hearing deficiency.

Etiology: often paternal chromosome is minssing.

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Laparotomy

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Large incision through the abdominal wall to gain access to the abdominal cavity.