Genetics – Abnormalities of Chromosome number 105-113
Polyploidy
Euploidy- a cell that has a multiple of 23 chromosomes (46, 69, 92)
-Humans can be polyploid, complete sets of extra chromosomes. Humans can be triploid (69) or
tetraploid (92)
-Large surplus gene product causes multiple anomalies such as heart and CNS defects
-triploidy (69 XXX) is seen 1 in 10,000 live births
-triploidy is one of the most common causes of fetal loss at conception (spontaneous abortion)
-if they survive until birth, die shortly after.
-Triploidy has 3 main causes:
1.) Dispermy – fertilization of egg by 2 sperm
2.) fusion of an ovum and polar body + fertilization
3.) Meiotic failure – diploid sperm or egg can be produced
-Tetraploidy is very rare, only a few live births have been recorded, causes are
1.) mitotic failure of early embryo, all duplicated chromosomes migrate to 1 cell
2.) fusion of 2 diploid zygotes
Aneuploidy – cells that contain missing or additional individual chromosomes (not a multiple of 23)
-Usually only 1 chromosome is affected, mostly of autosomes
Monosomy – presence of only one copy of a chromosome in an otherwise diploid cell)
-almost always incompatible with life if in an autosome
Trisomy – three copies of one chromosome
-autosomal trisomies are seen quite a bit
Non-disjunction - Most common cause of aneuploidy, failure of chromosomes to disjoin normally during
meiosis
-Can occur either during meiosis 1 or 2
-both chromosomes migrate to one cell instead of splitting
Trisomy 21 – seen in approximately 1 out of every 800 to 1000 live births, most common aneuploidy
condition
-Produces Down Syndrome
-Features: low nasal root, upslanting palpebral fissures, small ears, flattened maxillary and malar
region, round cheeks, neck is short, skin is redundant at the nape of the neck
-50% of patients
-3% of infants develop duodenal atresia
-Respiratory problems are higher
-Increased risk for leukemia
Most Significant Medical Problem: 40% of Down Syndrome patients present with structural
heart defects
-Most common is atrioventricular (AV) canal defect (interatrial and interventricular
septa fail to fuse normally during development.
-Results in blood flow from left to right side of the heart and then to pulmonary
circulation, causing pulmonary hypertension
-Ventricular septal defects (VSD) are also common
-Can also have hearing loss, hypothyroidism, eye abnormalities
-Males are sterile, females an reproduce (high risk of producing Down’s offspring 50%)
-Mostly caused by nondisjunction, remainder by chromosome translocations
-Mother contributes the extra chromosome in 90% of the case
-Mosaicism- Patients with some normal somatic cells and other cells with trisomy 21.
-Nomenclature: 47, XY + 21[10]/46, XY[10] (number in brackets indicate cells counted
with the Down’s karyotype
-Most common cause is trisomic conception followed by loss of the extra chromosome
during mitosis in some embryonic cells
-results in milder clinical symptoms
Tissue-specific mosaicism – mosaicism confined only to certain tissues
-mosaicism in germline of parent causes recurrent risk for Down Syndrome in
patients
-Candidate gene for mental retardation in Down’s Patients is DYRK1A, a kinase gene that causes
learning and memory defects when overexpressed in mice
-Another candidate gene is APP (amyloid B precursor protein), a 3rd copy of APP in a trisomy 21
patient accounts for the Alzheimer’s symptoms seen in nearly all Down’s patients by age 40.
-Partial trisomies not affecting the APP region do not produce alzheimer’s symptoms.
Trisomy 18 – Also known as Edwards Syndrome, second most common trisomy (1:6000 live births)
-most common chromosomal abnormality among stillborns
-prenatal growth deficiency, characteristic facial features, and a distinctive hand abnormality
(index finger on top of middle finger)
-Congenital heart defects (VSD) are most common in 90% of children
-Omphalocele – protrusion of bowel into umbilical cord
-Radial Aplasia – missing radius bone
-Diaphragmatic hernia, and spina bifida
-50% of infants with trisomy 18 die within the first several weeks of life
-aspiration pneumonia, predisposition to infections, heart defects account for mortality.
-developmental abnormalities – children not able to walk independently.
-very little mosaicism, mostly complete trisomy.
-Nondisjunction of maternal chromosome 18 in 90% of all cases
Trisomy 13 – also called Patau Syndrome, seen 1:10000 live births, 95% of infants die within first year of
life
-oral/facial clefts, micropthalmia (small eyes), polydactyly
-CNS malformations
-Heart defects
-Renal anomalies
-Cutis aplasia (scalp defect on posterior occiput)
-Can progress in development to communicate with parents, unlike trisomy 18
-80% of Patau syndrome patients have complete trisomy, with the other 20% having a
translocation of the long arm of chromosome 13
-95% of Patau patients spontaneously lost during pregnancy
Nondisjunction Risk and Maternal Age –
Less than 30 years – 1/1000
35 years
- 1/400
40 years
-1/100
45 years
-1/25
-the older the woman, the older her ova are, since they are arrested in prophase until ovulation.
Environmental factors (smoking, alcohol consumption, and radiation can play a role)
Turner Syndrome – phenotype associated with sex chromosome aneuploidy of a single X chromosome
(45X)
-usually female with the following characteristics:
-short stature
-sexual infantilism, ovarian dysgenesis (streaks of connective tissue seen instead of ovaries)
-major and minor malformations
-triangle shaped face, webbed neck, chest is broad and shield-like
-lymphedema of hands and feet
-congenital heart defects – most commonly obstructive lesions on left side of heart (bicuspid
aortic valve in 50% of patients)
-50% of patients have kidney defects
-50% of patients have 45,X karyotype, 30-40% of patients have 45,X/46,XX and less commonly
45,X/46,XY
-10% of patients have structural X chromosome abnormalities involving deletion of some or all
of XP.
-60-80% of cases involve loss of paternal X chromosome, occurring either in mitosis of embryo or early
meiosis of father
-1-2% of all conceptions are 45,X, but the low number of births with 45,X (1:1000) suggests majority are
lost prenatally.
-many survivors are mosaics, or placental mosaics (of placenta alone)
-mutations in SHOX gene, which encodes transcription factor for embryonic limbs, produces short
stature, thought to be associated with Turner’s Phenotype
-located on distal tip of X and Y short arms (escaping inactivation), thus 2 copies are normally
transcribed, Turner’s patients would only have one copy transcribed, resulting in
haploinsufficiency
-Pseudoautosomal Region: During normal meiosis, crossover occurs between tip of short arm of Y
chromosome and tip of short arm of X chromosome. These regions have homology, and therefore
behave similar to autosomes. Distal portion of Y chromosome is called Pseudoautosomal region
-SRY gene is just proximal to pseudoautosomal region (determines male phenotype)
-Acts antagonistically against DAX1, which normally represses differentiation of embryo into a
male
-absence of SRY causes DAX1 to act unopposed, producing females
-males produced when SRY upregulates SOX9
Klinefelter Syndrome (47, XXY) – 1/500 to 1/1000 births
-primary cause of hypogonadism in males
-taller than average, sterile, testosterone levels are low
-Gynecomastia is common (breast development)
-reduction in verbal IQ
-Extra chromosome is mostly derived maternally, and mosaicism can be seen in 15% of patients
-Can also be XXXY and XXXXY – degree of mental and physical deficiency increases with more X’s
-Can be treated with testosterone therapy
Trisomy X (47, XXX) – 1/1000 females, benign consequences, sometimes suffering from sterility,
menstrual irregularity, mild mental retardation, can be found with XXXX or XXXXX
47, XXY Syndrome – males with this karyotype tend to be taller, lower IQ, few physical irregularities,
found with high prevalence in prisons, minor behavioral disorders, hyperactivity, ADD< and learning
disabilities