5.1. Single gene disorders

What is a carrier in autosomal recessive inheritance?

An individual with one affected allele and one normal allele who does not display the disease phenotype

What is a compound heterozygote?

An individual with two affected alleles but with different alterations at each

What is a true homozygote in autosomal recessive inheritance?

An individual with two identical affected alleles

What is Phenylketonuria (PKU)?

An autosomal recessive disorder caused by a deficiency in the enzyme phenylalanine hydroxylase, leading to a build-up of phenylalanine

What is the UK prevalence of classical PKU?

1 in 10,000 children born

What are the symptoms of PKU?

Mental retardation, defective myelination of nerves, and organ damage

What is cystic fibrosis and what causes it?

An autosomal recessive disease caused by loss of function mutations in the CFTR gene, identified in 1989

What is the UK prevalence of cystic fibrosis at birth?

1 in 2,600

What proportion of the UK population are carriers of CFTR?

1 in 25

What is the most common fatal homozygous recessive disorder?

Cystic fibrosis

Can carriers express disease-related traits?

Yes — carriers can express some disease-related traits that distinguish them from the normal population

How does sickle cell anaemia demonstrate a recessive disease with a dominant trait?

Affected individuals are homozygous for the beta-globin mutation; carriers have co-dominant expression and mild anaemia, and can experience sickling under stress

What happens to RBCs in sickle cell anaemia?

They adopt a rigid sickle shape and have a shorter lifespan

What happens to heterozygotes with sickle cell under stress?

Sickling can occur, e.g. during infection

What is a Barr body?

An inactivated X chromosome in female cells

What is the Lyon hypothesis?

All but one X chromosome in any sex chromosome genotype is inactivated

At what stage is the X-inactivation decision made?

In the preimplantation embryo at approximately the 8-cell stage

Is the pattern of X-inactivation inherited?

Yes — it is inherited by all descendant cells

What is Klinefelter's syndrome?

A Barr body syndrome in males with XXY chromosomes

What is Turner's syndrome?

A Barr body syndrome in females with XO chromosomes

What is Triple X syndrome?

A Barr body syndrome in females with XXX chromosomes, also called Superwoman syndrome

What are the features of X-linked recessive inheritance?

Affected individuals are mostly males, born to unaffected/carrier parents, no male-to-male transmission

Who can be an affected daughter in X-linked recessive inheritance?

A daughter with an affected father and a carrier mother

What determines disease severity in X-linked recessive conditions?

Which X chromosome is inactivated

What are the features of X-linked dominant inheritance?

Can affect either sex, usually at least one parent is affected, more females affected, no male-to-male transmission, milder phenotype in females

What happens in some X-linked dominant disorders in males?

They are embryonic lethal

What is the pseudoautosomal region?

Regions on the X and Y chromosomes where recombination occurs during male meiosis, with X-Y gene pairs acting as effective alleles

What does a KAL mutation cause?

Kallmann syndrome

What does a SHOX mutation cause?

Leri-Weill dyschondrosteosis (heterozygote) and Langer mesomelic dysplasia (homozygote)

What are the features of Y-linked inheritance?

Only males are affected, exclusive male-to-male transmission

What is the relative size of the Y chromosome compared to X?

Approximately 38% of the size of X

How many proteins does the male-specific region of the Y chromosome produce?

Only 31 proteins

What is a single gene disorder?

A disorder where the genetic abnormality is the major, if not sole, cause of symptoms

What is a multifactorial disease?

A disease where genetic variation interacts with a wide variety of other factors to cause disease

What is a chromosomal disorder?

A disorder caused by aberrant numbers of chromosomes or abnormal chromosome structure

What is a mitochondrial disorder?

A rare disorder caused by mutations in non-chromosomal mitochondrial DNA (mtDNA)

What is the frequency of autosomal dominant disorders per 1000 live births?

1.8-9.5

What is the frequency of autosomal recessive disorders per 1000 live births?

2.2-2.5

What is the frequency of X-linked disorders per 1000 live births?

0.5-2.0

What is the frequency of chromosomal disorders per 1000 live births?

6.8

What is the frequency of congenital malformations per 1000 live births?

19-22

What is autosomal dominant inheritance?

A pattern where an affected person is normally a heterozygote at the disease locus

What is Huntington's disease?

An autosomal dominant disorder affecting the HTT gene, causing expansion of a polyglutamine tract leading to a toxic gene product

What is the prevalence of Huntington's disease?

3-7 per 100,000 people aged 30-50

What are the symptoms of Huntington's disease?

Huntington's chorea, emotional problems, and cognitive problems

What codon codes for glutamine in Huntington's disease?

CAG

What is the normal number of CAG repeats in the HTT gene?

10-35 repeats

What number of CAG repeats indicates increased chance of Huntington's disease?

36-39 repeats

What number of CAG repeats causes Huntington's disease?

40 or more repeats — producing a toxic gene product

What is men are constitutionally hemizygous mean?

Men have only one copy of most genes on the X chromosome, so whatever allele they carry is automatically expressed