Chromosomes, chromosome abnormalities and birth defects

Question 1

Explain the classification of congenital defects, and how non-genetic factors may lead to such defects

Answer 1

Congenital abnormality;

• every abnormality that an individual has ( both chromosomal and non-chromosomal)

Classification;

1. Single
   
   1. Malformation; ​
      
      • Has abnormality from the beginning
      • It is a primary structural defect
      • single organ showing multifactorial inheritance
      • ex. cleft clip
   2. Disruption;
      
      • was originally normal but due to an event an abnormality was acquired
      • It is a secondary structural defect of an organ/tissue
      • caused by ischemia (extrinsic factor affects development)
      • ex. amniotic band leading to digital amputation
   3. Deformation
      
      • Abnormal form, shape or position of the body due to a mechanical force
      • It happens later in pregnancy because the organ works but it was deformities
      • ex. club foot, hip dislocation
   4. Dysplasia;
      
      • It is the abnormal organization of cells into tissues and its morphological results
      • ex. thanatophoric dysplasia (a severe skeletal disorder in which the fetus has a disproprtionalty small ribcage, very short limbs, extra skin on arms + legs)
2. Multiple;
   
   1. Sequence;
      
      • a pattern of multiple abnormalities derived from a single known/presumed abnormality (initiated by primary factor which can be genetic)
      • ex Potters sequence(atypical appearance of baby due to oligohydramnios (clubbed feet, pulmonary hypoplasia, cranial abnormalities))
   2. Syndrome;
      
      • pathogenetically related abnormalities with specific underlying cause
      • ex. Downs syndrome
   3. Association;
      
      • non- random occurrence of abnormalities which cannot be explained by a syndrome (unknown cause)
      • ex. VATER association

(affects many systems: cardiac defects, renal, limb abnormalities, fistulas tracheo-oesophageal etc)

How do non-genetic factors lead to congenital defects?

Problems with chromosomes;

1. Numerical;
   
   1. defined by the loss or gain of chromosomes(aneuploidy) (monosomy, trisomy, tetrasomy)
   2. ex. Trisomy 13; Patau syndrome, Trisomy 18 Edwards syndrome, Trisomy 21; Down syndrome
2. Structural;
   
   1. Duplications; deleted from one chromosome and attached to the homologous chromosome
   2. Deletion
   3. Translocation; lost from one chromosome and attached to a non-homologous chromosome (swapping material which results in a disrupted gene and a fused product)
      
      • Robertsonian translocation; fusion of two chromosomes that have little to short arm.
        
        • what are the odds of a parent with Robert translocation on chromosome 21 to have an offspring with trisomy 21 –> 100% since 50% will have the trisomy and the other 50% are not compatible with life
   4. Inversions; lost, rotated 180* and re-installed
   5. Insertions
   6. Rings
3. Mosaicism; different numbers or arrangement of chromosomes caused by mitotic non-disjunctions

Question 2

Recall the normal human karyotype, chromosome banding and nomenclature; explain what is meant by the terms “aneuploidy”, “chromosome translocation”, “copy number variant” and their possible biological effects

Answer 2

Aneuploidy; loss or gain of a chromosome

Trisomy 16; is the most common but it is fatal in utero (chromosomal cause of miscarriage)

Trisomy 13 Patau syndrome

• heart defects
• mental retardation
• holoprosencephaly (cleft lip/palate)

Trisomy 18 Edwards syndrome

• heart defects
• kidney malformation
• mental retardation
• digestive track defects

Trismoy 21 Down syndrome

• craniofacial abnormalities (small ears macroglossia)
• heart defects (septal defects)
• Low IQ but advanced social skills
• short statue
• during newborn period; hypotonia, lethargy, excess nuchal skin

Copy number variation (CNV);

is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals in the human population

Normal karyotype;

• 46 chromosomes (22 autosomal, 1 sex)
• Males: 46,XY Females:46,XX

Question 3

Recognise the increased genetic risks associated with advanced maternal and paternal age

Answer 3

Question 4

Explain how three different chromosome aberrations lead to Down syndrome and the clinical features of that condition

Answer 4

There are 3 different chromosme aberrations that can lead to Downs syndrome

1. Non-disjunction of homologus chromosomes in meiosis 1 (3 copies instead of 2)—> 90% of the cases
2. Translocation; number of total chromosomes is still 46 but a part of chromosome 21 attaches to another chromosome ( usually 14)
3. Mosaicism; diagnosed with a mix of two types of cells–> some containing 46 and others with 47–> less than 1% of the cases

Question 5

Define dosage compensation and explain why sex determination is not solely based on sex chromosome karyotype

Answer 5

Dosage compensation; it is the process by which organisms equalize expression of genes between members of biological sexes

Mechanisms;

1. Random inactivation of single X chromones in females (most mammals)
2. Increased (2x) expression of X chromosome genes in males
3. Decreased (0.5x) expression of both X chromosome genes in hermaphrodites

Turner’s syndrome;

1. shorT statue
2. delaUed puberty
3. feRtility issues
4. heariNg loss
5. averagE IQ
6. heart Risks

Treatment; growth hormone, oestrogen replacement

Klinefelter’s syndrome; 47XXY (1:1000)

1. phenotypically male
2. gynecomastia
3. taller than average
4. infertility
5. learning disabilities
6. rarer variants; 48 XXXY, 49XXXXY

SRY gene;

• it is the gene responsible for the “formation” of gender
• It usually found on the Y chromosome
• there are cases where someone is phenotypically male and chromosomally female ( in this case the gene moved from Y chr, to X) –> they develop testes but they are infertile because other genes needed for spermatogenesis are in the Y chr
• XY females are infertile

Question 6

Genetic Disease

Answer 6

Monogenic disorders

1. Clear inheritance
2. No environment
3. Individually rare
4. Ex. Huntingtons, CF, Haemophilia

Complex disorders

1. No clear inheritance
2. Environment essential
3. Common
4. Ex. Type 2, Schizophrenia, Crohn’s

Allele; alternate form of gene

Mutation; heritable change in DNA sequence

Polymorphism; mutation at >1% frequency in given population.

• Polymorphisms can contribute to complex disease
• Only called mutation if contributes to monogenic disease

Point mutation; missense + nonsense

Frameshift mutation; insertions or deletions

Question 7

Explain the basic principles of meiosis and non-disjunction