2 Patterns of inheritance

AD disorders are encoded on the autosomes (i.e. not the X or Y chromosome) and the disorder manifests in heterozygotes, i.e. when a single copy of the mutant allele is present. AD disorders are characterized by inter- and intrafamilial variability. Factors influencing this variability may include modifier genes (the expression of which can influence a phenotype resulting from a mutation at another locus) and environmental exposure.

Some AD disorders, particularly cancer susceptibility disorders such as retinoblastoma and von Hippel–Landau disease (VHL) ( see Chapter 7, Retinoblastoma and von Hippel–Landau disease, pp. 284 and 288) are recessive at the cellular level. The mutation confers increased susceptibility to tumours because of a heritable mutation in one allele, but cell behaviour appears normal in the heterozygous state. Tumorigenesis requires inactivation of the second allele (‘second-hit’).

AR disorders are encoded on the autosomes (i.e. not the X or Y chromosome) and the disorder manifests in homozygotes (two identical mutations) and compound heterozygotes (two different mutations), i.e. when both alleles at a given locus are mutated. Heterozygotes (single mutation) do not manifest a phenotype (e.g. cystic fibrosis (CF)), or if they do, this is very mild in comparison with the disease state (e.g. sickle cell trait vs. sickle cell disease). Affected siblings often follow a broadly similar clinical course which is more similar than for many autosomal dominant (AD) disorders.

Mitochondrial DNA (mtDNA) has unique genetic features that distinguish it from nuclear DNA. The mtDNA genome of humans is a double-stranded circular DNA, 16.6kb in length and encoding 13 proteins (all subunits of respiratory chain complexes involved in oxidative phosphorylation), two ribosomal RNAs, and 22 transfer RNAs. There are no introns and most of the mitochondrial genome is coding sequence. Mitochondria typically contain several copies of mtDNA and a typical human somatic cell can contain up to 1000 mitochondria (i.e. 5000–10 000 copies of mtDNA) representing >1% of the cell’s total DNA. Mature oocytes contain a staggering ~100 000 copies of mtDNA, whereas sperm contain only 7100 copies.

The organs most often affected in mitochondrial disorders are highly energy-demanding tissues, such as the central nervous system (CNS), skeletal and cardiac muscle, pancreatic islets, liver, and kidney.

Many genetic disorders result in every cell in the body having the same mutation. However, it is possible, if a somatic mutation occurs early in embryogenesis, for one individual to have two, or more, cell lines that differ in their genetic constitution ( see Fig. 2.7). It occurs in two forms:

This would be suspected in either:

An adult with germline mosaicism may appear to be phenotypically normal, but has two or more children with an autosomal dominant disorder, such as tuberous sclerosis. This can be explained by the parent having germline mosaicism with a proportion of his/her sperm or egg cells carrying the gene mutation.

From a clinical perspective there is a continuous spectrum of disease from, at the one end, disorders that are strictly genetic and caused by fully penetrant mutations with minimal contribution from the environment to, at the other extreme, those caused predominantly by environmental factors (e.g. teratogens) with minimal contribution from genetic factors. Between these two extremes lie the incompletely penetrant and the polygenic disorders, creating a smooth transition from strictly genetic to multifactorial illnesses ( see Fig. 2.8).

The disease processes mentioned above do not generally follow a Mendelian pattern of inheritance, nevertheless they share a tendency to cluster in families, more than would be expected by chance. Many of these conditions probably depend on a mixture of major and minor genetic determinants, together with environmental factors: multifactorial inheritance. Diseases inherited in this manner are termed complex diseases. Multifactorial inheritance may involve a small number of loci (oligogenic), many loci (polygenic), or a single major locus with a polygenic background.

In multifactorial inheritance, disease occurrence is attributable to the interaction of the environment with alleles at many loci interspersed throughout the genome. The mapping and identification of these genes, though now a huge research area, is difficult because the disease-associated alleles occur almost as commonly in patients as in healthy individuals; even the highest-risk genotypes confer only modest risk of disease. Thus there are, currently, few susceptibility genes known to play a role in multifactorial diseases.

Traits such as intelligence, behavioural traits, height, and weight approximate to a normal distribution in the general population ( see Fig. 2.9). A large number of loci are involved in determining these characteristics, together with environmental factors. For example, factors influencing height include parental height, nutrition, and chronic illness, and in total >100 genetic loci contribute to height.

This is based on the assumption that liability to a condition is multifactorial and follows a normal distribution in the population, and that the disease occurs when a particular threshold value is exceeded. The normal distribution for liability is shifted in close relatives of an affected individual; hence a greater proportion of them will exceed the critical threshold value and be affected ( see Fig. 2.10). For first-degree relatives the expected incidence approximates to the square-root of the population incidence.

For a condition affecting 1/1000 individuals (0.1%), the risk to sibs, parents, and children is ~1/30 (3%), falling to 1/100 (1%) for second-degree relatives, and close to population risk for third-degree relatives. This is fairly close to the figures observed for neural tube defects and cleft palate.

Gender predisposition. For most multifactorial disorders males or females have a greater frequency. If the disorder does occur in the less likely gender then there is a greater recurrence risk implying more genes and/or environmental factors are present in that family.

Several general principles affect the risk:

A standard approach to all consultations in which there may be a genetic element, is to take a full family history, going back three generations, also referred to as a ‘pedigree’ (from the French pied á grue = crane’s foot). As genetic knowledge increases, the taking of such a history may be indicated in an increasing number of consultations, whether there is an obvious genetic component or not.

Some genetic specialists have access to sophisticated pedigree computer software which enables easy tabulation of the family history, and can be shared with relevant professionals. Despite this, nearly all consultants and genetic counsellors in the UK approach family history taking with pen in hand, and the great majority of genetic consultations in the UK are based on hand-drawn family trees. One approach is shown on the next page ( see Fig. 2.12).

PCPs will need a pen and paper, and a working knowledge of both the basic symbols and the correct understanding of genetic nomenclature ( see inside back cover).

The first individual identified in a family tree (pedigree) who has been identified clinically as being affected by a genetic disorder, is known as the proband. The individual who is seeking advice is called the consultand.

Guidelines for PCPs (e.g. NICE) commonly require the reader to quantify the number of first- or second-degree relatives with the target condition:

Such history-taking has attendant difficulties:

This will require empathic, but focused, responses from the history-taker who must be constantly diplomatic and gentle, and recognize the need for confidentiality.

XL disorders are encoded on the X chromosome. An XL recessive (XLR) disorder manifests in males who have one X chromosome, but generally not in carrier females who have two X chromosomes (one normal and one mutated copy). Some X-linked disorders are almost never expressed in females. In some disorders females have symptoms infrequently, e.g. Duchenne muscular dystrophy (DMD)/Becker muscular dystrophy (BMD), whereas for others, e.g. X-linked hereditary motor and sensory neuropathy (X-HMSN) and fragile X syndrome (FRAXA), manifestation in female carriers is fairly common but is usually less severe than in affected males. Disorders, in which heterozygotes commonly manifest, e.g. X-HMSN, may be said to follow X-linked semi-dominant inheritance.

In order to fully understand sex chromosome inheritance patterns, it is important to divert briefly into epigenetics. This term means ‘on top of genetics’. Epigenetics studies processes, e.g. methylation that turn genes ‘on’ or ‘off’.

The sex chromosomes differ from the autosomes:

A normal male will have a single Y and a single X chromosome, whereas a normal female complement is two X chromosomes. In order to prevent overexpression of the X chromosome in a female, only one copy of the X chromosome is active in a female cell, the other being, mostly, inactivated. This process, X-inactivation, occurs in every cell in a developing female embryo 1–2 weeks after conception. It is also referred to as Lyonization in honour of its proposer, Dr Mary Lyon.

The early events in X-inactivation are under the control of the X-chromosome inactivation centre (Xic). The XIST gene (X Inactivation Specific Transcript), located at Xq13.3, plays an essential role in the initiation of X-inactivation by spreading an inactivation signal. Initiation of X-inactivation involves a counting step in which the number of X chromosomes in the cell is counted such that only a single X chromosome is functional per diploid adult cell, i.e. in a female with three X chromosomes (47,XXX), two X chromosomes are inactivated and in a male with two X chromosomes (47,XXY), one is inactivated.

A small region of the inactivated X chromosome remains unaffected by this process and is found at the tip of the short arm—the pseudoautosomal region (PAR) ( see X-linked dominant inheritance, p. 57).

X-inactivation in the embryo is a random process, which should therefore result in ~50% of cells containing the maternal X inactive and ~50% of cells containing the paternal X inactive.

Hence a karyotype is indicated in these circumstances.

An XLD disorder manifests very severely in males, often leading to spontaneous loss or neonatal death of affected male pregnancies. Hence the disorder appears to affect females exclusively and there is often a history of miscarriage and a predominance of females in the pedigree. XLD disorders are uncommon and examples include the rare genetic disorder Rett syndrome.