Genetic disorders — line by line

Genetic disorders fall broadly into two categories: Mendelian disorders and chromosomal disorders.

The split is the same one flagged at the end of yesterday's portion — altered genes versus altered chromosomes. Every disorder in these pages belongs to one bucket or the other, and questions frequently just ask which.

Mendelian disorders are mainly determined by alteration or mutation in a single gene.

One gene, hence "Mendelian" — they are transmitted to offspring along exactly the lines studied in the principles of inheritance earlier in the chapter.

The most common and prevalent Mendelian disorders named by the book: Haemophilia, Cystic fibrosis, Sickle-cell anaemia, Colour blindness, Phenylketonuria, Thalassemia.

Six names in the list, though only five are described in detail. Cystic fibrosis is named but never explained anywhere in the chapter — which is exactly why it appears in questions.

Mendelian disorders may be dominant or recessive, and a trait may also be linked to the sex chromosome, as in haemophilia.

Two independent axes, and both must be stated for any disorder. "Sickle-cell anaemia is recessive" is an incomplete answer; "autosome-linked recessive" is the complete one.

Haemophilia is an X-linked recessive trait, and it shows transmission from a carrier female to male progeny.

That transmission route — carrier mother to affected son — is the signature of every X-linked recessive disorder, and it is the reason such disorders appear to skip the females while striking the males.

Figure 4.14 shows representative pedigrees: (a) an autosomal dominant trait, example myotonic dystrophy; (b) an autosomal recessive trait, example sickle-cell anaemia.

Myotonic dystrophy appears nowhere else in the chapter — only in this figure caption, as the example of an autosomal dominant trait. That single-mention status makes it a favourite one-mark question.

Asked as — "which is an example of an autosomal dominant disorder?" → myotonic dystrophy. Learn to read the two pedigrees too: in (a) the trait appears in every generation; in (b) it skips generations and reappears.

Colour blindness is a sex-linked recessive disorder, caused by a defect in either the red or the green cone of the eye, resulting in a failure to discriminate between red and green colour.

Note it is specifically the red-green form. Cones, not rods — rods handle dim light and have nothing to do with colour.

Asked as — "colour blindness is due to a defect in ___" → the red or green cones. "Rods" is the standard distractor.

It occurs in about 8 per cent of males and only about 0.4 per cent of females.

The reason is given right there in the text: the genes are on the X chromosome, and males have only one X while females have two. A male needs just one defective copy; a female needs two.

Asked as — the two percentages are asked directly, and are also swapped between the sexes as a trap. 8 and 0.4 — the male figure is twenty times the female figure.

The son of a woman who carries the gene has a 50 per cent chance of being colour blind.

She has one normal and one defective X. Each son receives one or the other at random, and his Y carries no counterpart, so whichever X he gets is expressed.

The mother herself is not colour blind, because the gene is recessive — its effect is suppressed by her matching dominant normal gene.

This is the definition of a carrier: heterozygous, unaffected, but able to transmit. The word to use in answers is carrier.

A daughter will not normally be colour blind unless her mother is a carrier and her father is colour blind.

She needs two defective X chromosomes, one from each parent. So both conditions must hold simultaneously — which is why the female frequency is so low.

Asked as — numerical pedigree questions. Two crosses are worth working out on paper today, writing X with a superscript for the allele:
• Carrier mother × normal father → daughters: half normal, half carriers, none affected. Sons: half normal, half colour blind.
• Normal mother × colour blind father → all daughters are carriers, all sons are normal. This is the classic criss-cross pattern: the father's X goes only to his daughters.

Haemophilia is a sex-linked recessive disease, showing transmission from an unaffected carrier female to some of the male progeny.

"Some of the male progeny", not all — each son independently has a 50 per cent chance.

In this disease, a single protein that is part of the cascade of proteins involved in the clotting of blood is affected.

The word cascade matters — clotting proceeds as a chain of proteins activating one another, and knocking out one link stops the chain.

Consequently, in an affected individual a simple cut will result in non-stop bleeding.

The one-line symptom to quote. Prolonged, uncontrolled bleeding from even a minor injury.

A heterozygous female (a carrier) may transmit the disease to her sons.

Same route as colour blindness, since both are X-linked recessive. The two disorders behave identically in pedigrees.

A female becoming haemophilic is extremely rare, because her mother would have to be at least a carrier and her father would have to be haemophilic — and the book notes that this is unviable in the later stage of life.

Both conditions again, as with colour blindness, but rarer still because affected males historically seldom survived to reproduce.

Asked as — "why is haemophilia rare in females?" Answer with both requirements: carrier or affected mother, and affected father.

The family pedigree of Queen Victoria shows a number of haemophilic descendants, as she was a carrier of the disease.

She was a carrier, not affected. That distinction is the exam point.

Asked as — "the royal pedigree associated with haemophilia" → Queen Victoria. It is the only named pedigree in the chapter.

Sickle-cell anaemia is an autosome-linked recessive trait, transmitted from parents to offspring when both partners are carriers (heterozygous).

Autosomal, not sex-linked — the single most common error students make in this section, because it sits between two X-linked disorders in the book. Both parents must be carriers for an affected child to be possible.

The disease is controlled by a single pair of alleles: HbA and HbS.

Three possible genotypes follow: HbAHbA, HbAHbS and HbSHbS.

Of the three genotypes, only the homozygous HbSHbS shows the diseased phenotype.

Which is what "recessive" means here in practice — one normal allele is enough to keep a person out of disease.

Heterozygous HbAHbS individuals appear apparently unaffected but are carriers, with a 50 per cent probability of transmitting the mutant gene to their progeny — they exhibit the sickle-cell trait.

"Sickle-cell trait" is the specific term for the heterozygous condition, as opposed to sickle-cell anaemia for the homozygous disease. Both terms get asked, and they are not interchangeable.

Asked as — the cross of two carriers is a standard numerical: HbAHbS × HbAHbS → 1 normal : 2 carrier (trait) : 1 diseased. So 1/4 of children are affected, 1/2 are carriers, and 3/4 appear healthy.

The defect is caused by the substitution of glutamic acid (Glu) by valine (Val) at the sixth position of the beta globin chain of the haemoglobin molecule.

Four elements, all examinable: which amino acid is replaced, which replaces it, the position, and which chain. Glu → Val, position 6, β-chain.

Asked as — the direction of the substitution is reversed as a trap (Val → Glu), and "α-chain" is offered instead of β. Position 6, β-chain, Glu out, Val in.

The amino acid substitution results from a single base substitution at the sixth codon of the beta globin gene, changing GAG to GUG.

This is the point mutation from yesterday's section, now with its molecular detail. GAG codes for glutamic acid; GUG codes for valine. One base changed, one amino acid changed, one disease.

Asked as — note carefully that GAG → GUG is stated at the mRNA level. In Figure 4.15 the gene is shown as GAG (with CTC on the complementary strand) changing to GTG (with CAC). If a question asks about the DNA it is GAG → GTG; if about the mRNA, GAG → GUG. Reading the word "gene" or "mRNA" in the question is the whole trick.

Figure 4.15 — the amino acid sequence of the relevant portion of the β-chain, positions 1 to 7.

Only position 6 differs. Position 7 remains glutamic acid in both, which is what makes "the sixth position" worth stating precisely rather than saying "a glutamic acid".

Asked as — the figure also shows micrographs of the red cells, normal biconcave discs against elongated sickled cells. Both halves of the figure are examinable.

The mutant haemoglobin molecule undergoes polymerisation under low oxygen tension, changing the shape of the red blood cell from a biconcave disc to an elongated sickle-like structure.

The trigger is low oxygen tension — the cells sickle when oxygen is scarce, not all the time. Learn the mechanism as a chain: base substitution → amino acid change → abnormal haemoglobin → polymerisation at low O₂ → sickled cell.

Asked as — "under what condition does sickling occur?" → low oxygen tension. And the shape change, both from and to.

Phenylketonuria is an inborn error of metabolism, inherited as an autosomal recessive trait.

The phrase "inborn error of metabolism" is the book's own and is worth reproducing. Autosomal recessive — not sex-linked.

The affected individual lacks the enzyme that converts phenylalanine into tyrosine.

On page 69 the chapter named that enzyme: phenyl alanine hydroxylase. Bring the two mentions together — the name comes from the pleiotropy section, the function from here.

As a result, phenylalanine accumulates and is converted into phenylpyruvic acid and other derivatives.

The blocked pathway backs up. Phenylalanine cannot go forward to tyrosine, so it is diverted down a side route.

Accumulation of these compounds in the brain causes impaired mental development (the book's term is mental retardation). They are also excreted through the urine, because of their poor absorption by the kidney.

Two consequences, in two different organs. The urinary excretion is what gives the disease its name — phenylketones in the urine.

Asked as — "phenylpyruvic acid is excreted in urine because ___" → it is poorly absorbed by the kidney. Also remember PKU's double role in this chapter: the example of pleiotropy in section 4.5, and an autosomal recessive Mendelian disorder here.

Thalassemia is an autosome-linked recessive blood disease, transmitted from parents to offspring when both partners are unaffected carriers (heterozygous).

The same transmission requirement as sickle-cell anaemia, and the same autosomal recessive pattern.

The defect arises from either mutation or deletion, and ultimately results in a reduced rate of synthesis of one of the globin chains (α or β) that make up haemoglobin.

Note both causes — mutation or deletion. Sickle-cell arises from substitution only.

Thalassemia is classified by which chain is affected. In α-thalassemia the production of the α globin chain is affected; in β-thalassemia the production of the β globin chain is affected.

Simple and worth stating explicitly, because the gene and chromosome details in the next two items hang off it.

α-thalassemia is controlled by two closely linked genes, HBA1 and HBA2, on chromosome 16 of each parent, and arises from mutation or deletion of one or more of the four genes. The more genes affected, the fewer alpha globin molecules produced.

Why four: two genes on the chromosome 16 inherited from each parent, so two from the mother and two from the father. The severity is graded by how many of the four are hit.

Asked as — the number four is asked directly, and so is the pairing of HBA1 and HBA2 with chromosome 16.

β-thalassemia is controlled by a single gene, HBB, on chromosome 11 of each parent, and occurs due to mutation of one or both of the genes.

One gene per parent, so two in total — against four for the alpha form. Keep the pairs locked: α → HBA1 + HBA2 → chromosome 16 → four genes; β → HBB → chromosome 11 → two genes.

Asked as — chromosome 16 and chromosome 11 are swapped between the two forms as the standard trap. A memory hook: alpha is the first letter but takes the larger chromosome number, 16.

Thalassemia differs from sickle-cell anaemia in that thalassemia is a quantitative problem — synthesising too few globin molecules — while sickle-cell anaemia is a qualitative problem — synthesising an incorrectly functioning globin.

Too few versus wrong. This one sentence is asked more often than any other in the section, sometimes with the two words reversed.

Asked as — the crispest way to hold it: thalassemia = quantity, sickle-cell = quality.

Chromosomal disorders are caused by the absence, excess or abnormal arrangement of one or more chromosomes.

Three causes in the definition. Contrast with Mendelian disorders, which come from a single altered gene.

Aneuploidy: failure of segregation of chromatids during the cell division cycle results in the gain or loss of a chromosome.

The cause is a failure of chromatid segregation. The result is one chromosome too many or too few — not a whole set.

The two examples given for aneuploidy: Down's syndrome — gain of an extra copy of chromosome 21; and Turner's syndrome — loss of an X chromosome in human females.

One gain, one loss, both aneuploidy.

Polyploidy: failure of cytokinesis after the telophase stage of cell division results in an increase in a whole set of chromosomes. This condition is often seen in plants.

Different cause, different scale, different organisms. Aneuploidy is one chromosome; polyploidy is an entire set.

Asked as — the aneuploidy/polyploidy pair is a certainty. Fix both causes: chromatid segregation failure → aneuploidy; cytokinesis failure after telophase → polyploidy. "Often seen in plants" belongs to polyploidy.

The total number of chromosomes in a normal human cell is 46 (23 pairs) — 22 pairs of autosomes and one pair of sex chromosomes.

Repeated from page 71, and repeated here for a reason: every karyotype in the next section is read against this baseline.

Rarely, an individual may carry an additional copy of a chromosome, or may lack one of a pair. These conditions are called trisomy and monosomy respectively, and lead to very serious consequences.

Trisomy = three copies where there should be two (2n + 1). Monosomy = one copy where there should be two (2n − 1). Down's is a trisomy; Turner's is a monosomy of X.

Asked as — "Turner's syndrome is an example of ___" → monosomy. Students who have only memorised the karyotype 45, X0 miss this framing.

Down's syndrome is caused by the presence of an additional copy of chromosome number 21 (trisomy of 21). It was first described by Langdon Down, in 1866.

Chromosome 21, and the total becomes 47. The name and the year are both examinable, and 1866 gets confused with 1865 (Mendel's publication) in options.

Features of Down's syndrome as listed in the text: short stature, small round head, furrowed tongue, partially open mouth; the palm is broad with a characteristic palm crease; and physical, psychomotor and mental development is retarded.

Three types of development are named — physical, psychomotor, mental. Questions do ask for all three, and psychomotor is the one usually forgotten.

Klinefelter's syndrome is caused by the presence of an additional copy of the X chromosome, giving a karyotype of 47, XXY.

47 chromosomes, with the sex chromosome set XXY. This is a trisomy of the sex chromosomes.

Such an individual has overall masculine development, but feminine development is also expressed — development of breast, i.e. gynaecomastia. Such individuals are sterile.

The term gynaecomastia is asked by name. Figure 4.17 (a) describes the appearance as tall stature with feminised character.

Turner's syndrome is caused by the absence of one of the X chromosomes, giving 45 with X0.

45 chromosomes, a single X and nothing in its place. The zero in X0 means absence, exactly as in the XO type of sex determination on page 70.

Such females are sterile as the ovaries are rudimentary, and they also lack other secondary sexual characters.

Figure 4.17 (b) describes the appearance as short stature with underdeveloped feminine character. Note the contrast with Klinefelter's, where stature is tall.

Asked as — the two syndromes are constantly paired and swapped. Anchor them by number: Klinefelter 47, XXY, tall, gynaecomastia; Turner 45, X0, short, rudimentary ovaries. Both are sterile.

The Summary's closing lines on chromosomal disorders, compactly stated: Down's syndrome is trisomy of chromosome 21 with the total becoming 47; in Turner's syndrome one X is missing and the sex chromosome constitution is XO; in Klinefelter's syndrome the condition is XXY. All three can be studied readily by karyotype analysis.

The term karyotype appears here as the method for studying these disorders — a one-word answer that students often cannot supply.