Mendelian Inheritance

A good understanding of the fundamental laws of inheritance helps us to understand the different patterns of disease transmission. The inheritance patterns of single gene diseases are referred to as ‘Mendelian inheritance’ after Gregor Mendel, the first person to observe the different patterns of gene segregation for selected traits in garden peas. From his observations, he was able to determine the probabilities of recurrence of a trait for subsequent generations.

Many genes have more than one version, caused by mutations or polymorphisms, and these are referred to as alleles. People can carry a ‘normal’ allele and/or a ‘mutated’ allele. The expression of the mutated allele with respect to the normal allele can be characterised as dominant, co-dominant, or recessive. There are five basic modes of inheritance for single-gene diseases:

Autosomal dominant
Autosomal recessive
X-linked dominant
X-linked recessive
Mitochondrial

Autosomal dominant inheritance

Autosomal dominant inheritance is characterised by disease transmission to both heterozygous and homozygous offspring. Only a single mutated copy of the gene is necessary for a person to be affected and each affected person usually has only one affected parent.

Each child of an affected parent will have a 50% chance of inheriting the mutated gene:

The following are examples of autosomal dominant conditions:

Achondroplasia
Acute intermittent porphyria
Adult polycystic kidney disease
Ehler’s-Danlos syndrome
Familial adenomatous polyposis coli
Familial hypercholesterolaemia
Huntingdon’s chorea
Hereditary haemorrhagic telangiectasia
Hereditary multiple exostoses
Hereditary spherocytosis
Hypertrophic obstructive cardiomyopathy
Hypokalaemic periodic paralysis
Gilbert’s syndrome
Marfan’s syndrome
Myotonic dystrophy
Neurofibromatosis types 1 and 2
Noonan’s syndrome
Osteogenesis imperfecta
Retinoblastoma
Tuberous sclerosis
Von-Hippel-Lindau syndrome
Von Willebrand’s disease

Autosomal recessive inheritance

Autosomal recessive inheritance is characterised by the disease only being transmitted to homozygous offspring. Two copies of the abnormal mutated gene are necessary for a person to be affected. Heterozygous individuals that carry only one affected gene become carriers. They are unaffected but can pass the abnormal gene to their offspring.

Children of two unaffected carriers have a 50% chance of inheriting one abnormal gene and becoming a carrier themselves and a 25% chance of inheriting two abnormal genes and being affected by the disease:

The following are examples of autosomal recessive conditions:

Alkaptonuria
Ataxia telangiectasia
Beta-thalassaemia
Congenital adrenal hyperplasia
Congenital erythropoietic porphyria
Cystic fibrosis
Dubin-Johnson syndrome
Familial Mediterranean fever
Fanconi anaemia
Friedreich’s ataxia
Galactosaemia
Gaucher’s disease
Glucose-6-phosphatase deficiency
Homocystinuria
Haemochromatosis
Hartnup disease
Phenylketonuria
Sickle-cell disease
Situs invertus
Spinal muscular atrophy
Tay-Sach’s disease
Wilson’s disease
Xeroderma pigmentosa

X-linked dominant inheritance

X-linked disorders, which are also referred to as sex-linked disorders, are caused by a mutation in the X chromosome of a sufferer.

In X-linked dominant disorders, both male and female mutation carriers are affected by a mutation on the X chromosome. Females tend to be less severely affected because of X-inactivation (also called lyonisation), which is a process by which one of the copies of the X-chromosome present in a female is inactivated. These disorders are frequently much more severe, or even lethal, in males, because they only have a single X-chromosome.

All offspring of an affected female have a 50% chance of being affected. If the condition is lethal in males (e.g. incontinentia pigmenti), a skewed birth ratio may be observed resulting in a higher proportion of live females with the condition.

The following are examples of X-linked dominant conditions:

Charcot-Marie-Tooth disease (type X)
Fragile X syndrome
Hypophosphataemic vitamin D resistant rickets
Rett’s syndrome
Incontinentia pigmenti
Periventricular nodular heterotopia

X-linked recessive inheritance

In X-linked recessive disorders, only males are affected. Heterozygous females are clinically unaffected but are carriers of the affected gene.

The following family pedigree chart shows the transmission of the affected mutated gene in white:

The following are examples of X-linked recessive conditions:

Alport’s syndrome
Becker muscular dystrophy
Duchenne muscular dystrophy
Fabry’s disease
Glucose-6-phosphate dehydrogenase deficiency
Haemophilia A and B
Hunter’s syndrome
Lesch-Nyhan syndrome
Red-green colour blindness
Testicular feminisation syndrome
Wiskott-Aldrich syndrome

Mitochondrial inheritance

Mitochondria are exclusively maternally inherited as they are derived from the mitochondria present in the cytoplasm of the ovum. Mutations in mitochondrial DNA can result in biochemical problems due to the absence or impairment of enzymes involved in the respiratory chain and reduced supply of ATP.

Within cells, there can be a mixed proportion of normal and abnormal mitochondria, which is referred to as heteroplasmy. Different proportions of abnormal mitochondria may be required to cause disease, and this is referred to as the threshold effect.

The following are examples of mitochondrial conditions: