Robertsonian Translocation

Structural Chromosomal Aberrations

Q. Discuss chromosomal translocations with examples.
(Or)
What is reciprocal translocation?
(Or)
Write a note on Robertsonian translocation.

Answer:

Structural chromosomal aberrations may occur either during mitosis or meiosis.

Types of chromosomal abnormality.

Numerical abnormalities

Aneuploidy

• Monosomy
• Trisomy
• Tetrasomy

Polyploidy

• Triploidy
• Tetraploidy

Structural abnormalities

• Translocations (exchange)
• Deletions (loss)
• Duplications
• Insertions
• Inversions
• Nondisjunction
• Ring chromosome

Read And Learn More: General Medicine Question And Answers

Structural Chromosomal Aberrations Isochromosomes

Mixoploidy

• Mosaicism
• Chimerism

Causes of structural alterations: It may occur spontaneously at a low rate and is increased by exposure to environmental mutagens, such as chemicals and ionizing radiation.

Types of Structural/Chromosomal Aberrations

Translocations: It is a structural alteration between two chromosomes in which a segment of one chromosome gets detached and is transferred to another chromosome.

There are two types of translocations.

1. Balanced reciprocal translocations: It is characterized by a single break in each of the two chromosomes with the exchange of genetic material distal to the break. There is no loss of genetic material.

A balanced reciprocal translocation between the long arm of chromosome 5 and the short arm of chromosome 10 would be written 46, XX, t (5; 10) (q31; p14).

Simple translocation: In this case, the terminal segment of a chromosome is integrated at one end of a non-homologous region.

Simple translocations are rather rare.

Shift: In shift, an intercalary segment of a chromosome is integrated within a nonhomologous chromosome.

2. Robertsonian translocation/centric fusion:

• This results from the breakage of two acrocentric chromosomes (i.e., chromosome 13, 14, 15, 21, 22) at or close to their centromeres and subsequent fusion of their long arms.
• The short arms of each chromosome are lost, this being of no clinical importance as they contain genes only for ribosomal RNA, for which there are multiple copies on various other chromosomes.
• The total chromosome number is reduced to 45.
• The overall incidence of this translocation is 1 in 1,000, the most common being 13q14Q
• The major practical importance is that this can predispose to the birth of babies with Down syndrome.

Inversion: When a segment of a chromosome is oriented in the reverse direction, such segment is said to be inverted and the phenomenon is termed inversion.

Isochromosomes: They are formed due to faulty centromere division. Normally, centromeres divide in a plane parallel to the long axis of the chromosome.

If a centromere divides in a plane transverse to the long axis, it results in pair of isochromosomes.

One pair consists of two short arms and the other of two long arms.

Deletion: It is the loss of a part of a chromosome.

It is of two types namely:

1. Interstitial (middle) and
2. Terminal (rare).

Interstitial deletion: It occurs when there are two breaks within a chromosome arm.

This is followed by the loss of the chromosomal material between the breaks and the fusion of the broken ends of the remaining portion of the chromosome.

It has to be specified in which region(s) and at what bands the breaks have occurred. For example, 46, XY, del (16)

(p11.2p13.1) describes breakpoints in the short arm of chromosome 16 at 16p11.2 and 16p13.1 with loss of material between breaks.

Terminal deletion: It results from a single break at the terminal part in a chromosome arm, producing a shortened chromosome bearing a deletion and a fragment with no centromere.

The fragment is then lost at the next cell division.

Ring chromosome: It is a special form of deletion. Ring chromosomes are formed by a break at both ends of a chromosome with a fusion of the damaged ends.

Insertion: It is a form of nonreciprocal translocation in which a fragment of the chromosome is transferred and inserted into a nonhomologous chromosome.

Mixoploidy

Mosaicism: Defined as the presence in an individual, or in a tissue, of two or more cell lines that differ in their genetic constitution but are derived from a single zygote, i.e., they have the same genetic origin. Seen in Down syndrome (1–2%) and Duchenne muscular dystrophy.

Chimerism: Defined as the presence in an individual, or in a tissue, of two or more cell lines that are derived from more than one zygote, i.e., they have different genetic origins.

Down Syndrome (Trisomy 21)

Question 3. Write a short essay/note on Down syndrome and its clinical features.
Answer: The best-known and most common chromosome-related syndrome. Formerly known as “Mongolism”.

It is the most common chromosomal disorder and is a leading cause of mental retardation.

The incidence of Down syndrome in newborns is about 1 in 700 live births.

Etiology and Pathogenesis

Maternal age: It has a strong influence on the incidence of trisomy 21. Children of older mothers have a much greater risk of having Down syndrome.

The risk for mothers < 25 years of age to have trisomy is about 1 in 1,500 births. At 40 years of age, 1 in 100 births. At 45 years, 1 in 40 births.

Other factors: Increased incidence may be associated with exposure of the mother to pesticides, electromagnetic fields, anesthetic drugs, alcohol, and caffeine.

Mechanism of trisomy 21: The three copies of chromosome 21 in somatic cells cause Down syndrome.

It may be due to:

About 95% of these individuals have nondisjunction during the first meiotic division of gametogenesis.

Robertsonian translocation of an extra long arm of chromosome 21 to another acrocentric chromosome causes about 5% of cases.

About 1% of mosaicism has two different cell lines, one with the normal chromosomal constitution and the other with an extra chromosome 21.

Down Syndrome (Trisomy 21) Clinical Features

Craniofacial and Skeletal Features

• Flat face and occiput, with a low-bridged nose, reduced interpupillary distance, and oblique palpebral fissures.
• Epicanthal folds of the eyes impart an almond shape to the eyes and an oriental appearance (obsolete term mongolism).
• A speckled appearance of the iris (Brushfield spots), and enlarged and malformed ears.
• A protruding furrowed tongue (macroglossia), which typically lacks a central fissure and protrudes through an open mouth (scrotal tongue).
• Broad, short neck, brachycephaly, Simian crease-single palmar flexion crease (50% cases), clinodactyly-incurved fifth finger with hypoplastic mid phalanx (60%), short stature, hypotonia, and space between the first and second toes (sandal gap).

Brain: Mild to moderate intellectual disability, attention-deficit hyperactivity disorder, autism, dementia, atlantoaxial dislocation.

Heart: Congenital cardiac anomalies are responsible for the majority of deaths in infancy and early childhood.

The genetic band in the 21q22 critical region is considered responsible for the cardiac anomalies.

Complete atrioventricular septal defect (CAVSD)—37%, ventricular septal defect (VSD)—31%, atrial septal defect (ASD)—15%, partial atrioventricular septal defect (PAVSD)—6%, and patent ductus arteriosus (PDA)—4%.

Gastrointestinal tract: It may show esophageal/duodenal stenosis or atresia, imperforate anus, and Hirschsprung disease p(megacolon).

Genitourinary: Hypospadias, cryptorchidism. Males are infertile due to impaired spermatogenesis.

Immune system: Affected children are susceptible to infections due to defective immunity.

Endocrine system: Antithyroid antibodies may cause hypothyroidism and type 1 diabetes.

Hematologic disorders: They have an increased risk of acute myeloid or lymphoblastic leukemia.

Polycythemia, macrocytosis, leukopenia, and leukemia (acute megakaryoblastic, and acute lymphoblastic).

Other features: Refractive errors, strabismus, sensory neural hearing loss, obesity, obstructive sleep apnea, palmoplantar hyperkeratosis, juvenile idiopathic arthritis.

Down syndrome screens

Triple screen (75% sensitive): Maternal serum alpha-fetoprotein, estriol, and human chorionic gonadotropin.

Quad screen (79% sensitive): Maternal serum alpha-feto-protein, estriol, human chorionic gonadotropin, and high inhibin-alpha (INHA).

Nuchal translucency/free beta-hCG>/PAPPA screen (91% sensitive): Ultrasound to measure nuchal translucency in addition to the free Beta-hCG and PAPPA (pregnancy-associated plasma protein A).

The full integrated test (first-trimester nuchal translucency and PAPPA plus second-trimester quadruple markers) detects 85% of Down syndrome fetuses.