Patterns of Inheritance

INTRODUCTION

Human beings show a great degree of variation in their genetic patterns, which show classical patterns of inheritance. As these disorders follow the laws of Mendel, they are often referred to as Mendelian inheritance, though some exceptions are noted. Genes are responsible for a particular pattern, and alternative forms of genetic patterns at a specific locus are referred to as alleles. Some genes have only one pattern and this pattern is called the wild type, while some gene loci exhibit different forms called polymorphisms. Genetic patterns and disorders are transmitted from one generation to the other. The study of patterns of inheritance is important for the diagnosis, prognosis, and estimation of the recurrence risk in other family members. In order to study genetic diseases, certain terminologies and methods in history taking are used, which are described below.

The genetic constitution of a person is called a genotype, which may be considered collectively, or may be specific for a single locus. The phenotype is a term is used for expression of a genotype at a morphological, molecular or biochemical level. The term single gene disorder is used, when there is disorder arising from a mutation at a single locus on one or both members of a chromosome pair. A person having a pair of identical alleles is called a homozygote, and if the alleles are different, the person is called a heterozygote. Another term, compound heterozygote is used when two different mutant alleles are present at the same locus.

A family history is recorded by drawing a family tree. This is called pedigree charting. Various symbols are used in this process, and are described in Figure 1. The importance of taking a family history needs to be stressed in genetics, as this by itself can be useful as a screening test, or help in providing a diagnosis on the basis of pattern of inheritance or familial occurrence. An example is a disorder called osteogenesis imperfecta. In this condition, the child has a tendency to get fractures even with a history of minor injury, and the first fracture may be passed off as an accidental fracture. A detailed family history of a similar episode in another child with blue sclerae, would direct a geneticist towards the possibility of a genetic disorder. If such history is absent, it could be due to a new mutation. Confirmation of the diagnosis is not only important for the index case for management, but also for estimating a recurrence risk, and for planning future prenatal diagnostic tests.

Figs 1A and B: (A) Pedigree drawing and terminology used in history taking. (B) Pedigree symbolisation of assisted reproductive technology

Pedigree charting and symbols

Family history taking in genetics starts from an index case. The index case is the person through whom the family came to be investigated. This index case is called a proband, or propositus. A female propositus is called the propositi. The proband is indicated by an arrow in the pedigree chart. This means the whole family is studied through this case. The details of other family members, brothers, sisters, parents and relatives on both sides are noted.

Mendelian inheritance

There are over 8,000 genetic traits, which are known to follow the Mendelian pattern of inheritance, though some common familial traits or disorders do not follow this pattern. If a gene responsible for a disorder or a trait is located on an autosome, it is said to follow autosomal inheritance and if located on a sex chromosomes is said to follow a sex-linked inheritance.

These single gene inheritance patterns are further classified into autosomal dominant, autosomal recessive and X-linked (recessive and dominant). All such traits or disorders are enlisted in a catalogue entitled Mendelian inheritance in Man. This catalogue is now available on line.

Autosomal Dominant Inheritance

If a trait manifests itself in a heterozygous state, and only one copy of the mutant gene is needed for manifestation of disease. This means the affected person carries a single copy of the affected gene, and the other copy is normal. The disorder is transmitted vertically, and seen in every generation. In some cases, a dominant trait or a disorder may not have a family history, it is called a new mutation. The propositus may be the first person to manifest the trait. Some of the dominant conditions occur at a relatively high frequency, presumably because they have little effect on reproductive fitness and are passed on to next generation. There are however a few rare disorders, which can be incapacitating thus are not passed on by an affected individual (Table 1). The gametes from an individual with a dominant trait will contain one abnormal and one normal gene and therefore his chances of transmitting the affected gene to his progeny are 50%. It can affect both the male or female offspring equally, there is no sex preference (Fig. 2).

Table .1: Characteristic criteria of autosomal dominant inheritance

Fig. 2 : Autosomal dominant inheritance

Pleiotropy

Autosomal dominant traits can involve one organ, or different systems and different organs. This is called pleiotropy.

Reduced Penetrance

The mutant phenotype may or may not be expressed fully and identically in all disorders. When classical features of a syndrome are minimal, this may be due to reduced penetrance. If classical features are totally absent, it is called non­penetrance, a condition where the abnormal gene may be present but not expressed. The calculation of penetrance is done by studying the number of individuals expressing the disease divided by the total number of individuals inheriting the alleles. A common example of an autosomal dominant condition is Polydactyly. This is expressed in 65% of those inheriting the allele. Some autosomal dominant traits like Huntington’s disease need other influencing conditions factors like age. Huntington’s disease is a severe degenerative neurological disease caused by a triplet repeat expansion of the CAG trinucleotide repeat in the coding region of the Huntington’s gene on chromosome 4. The neurological condition is expressed in middle to late adult life, even though the individual is born with the mutation.

Variation in Severity, Dependent on Sex

The severity of a dominant condition may depend on the sex of an affected parent. For example, in individuals with myotonic dystrophy of early onset, it is usually inherited from an affected mother, while in Huntington’s disease those with early severe disease are likely to have an affected father.

Variable Expressivity

In many dominant disorders, there can be a wide variation between the clinical features of persons suffering from same trait or a disease. This is called variable expressivity.

New Mutations

Many autosomal dominant disorders can appear in an individual where parent is not affected. This is due to a new mutation arising in the offspring.

Co-dominance

This terminology is used for traits, which are expressed in the heterozygous state. For example, in a person with AB blood group it is possible to demonstrate that their red blood cells have both A and B blood group antigens. This is an example of co-dominance.

AUTOSOMAL RECESSIVE CONDITIONS

Every gene from one parent is matched with a gene with the same function on the matching chromosome of the other parent. The actual function controlled or directed by matching genes is a reflection of their combined action. If one of the matching genes inherited from one parent is defective, then the other normal gene provides half the needed function, usually enough to keep the functioning normally (called the carrier or heterozygous state). So a recessive gene may have no effect, if it is paired with a normal gene from the other parent, though the genetic function expected of this pair of genes (one defective, one normal) will probably be half of what is normally found. Autosomal recessive disorders are transmitted horizontally which means that in a particular family there may not be any affected member in the previous generation but the siblings of the proband may be affected (Fig. 3). Like autosomal dominant disorders both the sexes are affected equally. Thalassaemia is an autosomal recessive inherited genetic disorder, common in the Mediterranean region as well as in India (Table.2). A simple screening test for carrier detection, and prenatal screening can help reduce the incidence of such births. The risk of recurrence in recessive disorders is 1 in 25 for each pregnancy.

Fig. 3: Pedigree showing autosomal recessive inheritance

Table2: Characteristic criteria of autosomal recessive inheritance

Consanguinity

Many autosomal recessive traits occur due to consanguinity. Any individual though apparently normal, has 4-8 abnormal genes in his or her body. In random marriages it is a matter of chance that two individuals carrying the same abnormal gene will marry, thus reducing any chances of a recessively inherited genetic disorder in their progeny. Families with consanguine marriages are more likely to share the same abnormal gene resulting in an increase in the incidence of recessive genetic disorders. In the case of consanguine marriages, the more rare the recessive trait or disorder, the greater the chance of transmitting it to the progeny. In oculo-cutaneous albinism, 1 in 20 parents of the affected children are first cousins.

Pseudo-dominance

If an individual affected with an autosomal recessive disorder marries another carrier individual of the same disorder their progeny will have 50% risk of being affected. Such a pedigree is said to exhibit pseudo-dominance.

Genetic Heterogeneity

Many genetic disorders are inherited in a variety of ways due to genetic heterogeneity. Genetic heterogeneity may result from the existence of a series of different mutations at a single locus (allelic heterogeneity) or from mutations at different genetic loci (non allelic or locus heterogeneity). For example, phenotypes such as Charcot-Marie tooth disease, retinitis pigmentosa, and congenital sensory neural deafness all have autosomal dominant, autososmal recessive and X-linked forms. For example, in sensory neural hearing impairment, a couple with deaf mutism can have normal children, as their deaf mutism could be due to genetic heterogeneity. The normal offspring may be double heterozygotes for mutations in two different genes. If two homozygotes with deaf mutism marry all their children would be affected, as the offspring would have two copies of the affected genes. A number of genes can cause autosomal recessive sensory neural deafness, and to date several loci have been shown to be involved. A genetic disorder with a phenotype due to different genetic loci is known as a genocopy. If the same phenotype is due to an environmental cause, it is known as a phenocopy.

Compound Heterozygotes

Heterogeneity can occur at an allelic level. For example, in beta thalassaemia a large number of mutations have been identified. Individuals having 2 different mutations at the same locus are known as compound heterozygotes. The heterozygosity can be common to a particular community.

Sex-linked Inheritance

Sex-linked inheritance is a type of inheritance occurring as a result of mutant genes located on the X or Y chromosomes. The disorders, which occur due to mutant genes located on one of the X chromosomes, are referred to as sex-linked disorders. The Y chromosome does not have any such genes, but has certain traits that are passed from father to son. This is called holandric inheritance.

X-linked Recessive Inheritance

A female can pass either her normal X or the X carrying the abnormal gene to her sons. Thus half the sons will be normal and the other half affected. The female offspring of such carrier females will have one normal X from the father to balance the defective gene. They will therefore be carriers like their mothers. There is also a 50% chance of daughters getting a normal gene and being totally normal (Table 3). An example of an X linked recessive disorder is Haemophilia A. The carrier mother has an abnormal gene on one of her X chromosomes. This gene on her X chromosome is expressed only in males. The female child who receives the mutant gene from the mother also receives a matching normal gene from the father and will be a carrier. The inheritance pattern in X linked disorders in males can be summarized as disorders being transmitted from the affected person to his carrier daughters and then to his grandsons (Fig. 4).

Fig. 4: Pedigree showing X-linked recessive inheritance

Table 3: Characteristic criteria of sex linked inheritance

Some X linked genetic recessive disorders such as Duchenne muscular dystrophy (DMD) are not transmitted through affected males, as the affected male does not survive up to reproductive age. 2/3 of DMD cases are new mutations. In most cases, symptoms in the affected males start in early childhood by the age of three and as the muscular weakness progresses the child is confined to the wheel chair. Death is commonly due to affection of the respiratory muscles.

Variable Expression in Heterozygous Females

There are several X-linked recessive disorders in which heterozygous females show a mosaic phenotype (mixed features of normal and mutant alleles) e.g. X-linked ocular albinism. In this condition affected males totally lack pigment in their iris and ocular fundi. Mothers of such children show a mosaic pattern of pigmentation. Such a pattern is explained by the process of X-inactivation in females and is based on the Lyon Hypothesis. In the pigmented areas the normal gene is on the active X chromosome and in the depigmented area mutant allele is on the inactive X chromosome.

Homozygosity for X-linked Recessive Disorders

Red green colour blindness is a condition, which affects about 8% of males while in females its incidence in 1 in 150. This shows that females do get affected with X-linked recessive trait. Homozygosity in a female is due to an affected father and carrier mother or a new mutation occurring in the father’s X chromosome and carrier mother.

Symptomatic Carrier Female (Skewed X-inactivation)

This can occur due to the possibility of inactivation of the normal X chromosome in most cells of a female and expression of X chromosome with a mutant allele. A carrier female can then show symptoms of the disease. This has been reported in female carriers of haemophilia and Duchenne muscular dystrophy (DMD).

X-chromosomal Abnormalities and X-linked Inheritance

A female can manifest an X-linked disorder in a carrier stats if she has only one X chromosome, as in Turner syndrome. Haemophilia and DMD in Turner females has been reported in the literature.

X-autosome Translocation

If a break point in an X-autosome translocation occurs at a position where the gene in question is located on the X- chromosome, females can be affected with an X-linked recessive disorder. This happens because the X-chromosome involved in the translocated chromosome maintains the functional disomy of the autosomal genes. Mapping of the gene for Duchenne Muscular Dystrophy was aided by this observation in females with X-autosome translocations (Fig. 5).

X-linked Dominant Inheritance Disorders

This is an uncommon pattern. However there are X-linked dominant traits, which manifest in the heterozygous female as well as in the male having a mutant allele on his X chromosome. This condition appears as an autosomal dominant trait since both male and female offspring are affected. An important point to note here is in all X-linked dominant conditions the affected male will transmit the disorder to female offspring only and never to a male (Fig. 5). Some X-linked disorders are lethal in utero in males and severely or completely impair reproduction in females. An example of an X-linked dominant disorder is incontinentia pigmenti.

Fig. 5 : X-autosomal translocation

Y-linked Inheritance

Y linked or holandric inheritance suggests that, only males are affected. The Y chromosome is exclusively transmitted from father to son, and the daughters are not affected (Fig. 6). The commonest known traits are hairy pinna and baldness. Ongoing research on the Y chromosome clearly indicates that H-Y histocompatibility antigen and genes responsible for spermatogenesis are located on the Y chromosome.

Fig. 6: The human mitochodrial genome with various gene positions

Partial Sex Linkage

This refers to the linkage of genes located on the homologous portion of the X chromosome with that of Y chromosome. At meiosis these homologous regions on the X and Y pair at the pseudo-autosomal region. Due to this, during crossing over, genes located on X chromosome can transfer to the Y chromosome.

Some confusing patterns of ‘X’ or ‘Y’ linked inheritance have utilised this possible explanation for diseases like colour blindness and rare skin disorders, though more work and family studies are necessary in these areas.

Influence of Sex on Inheritance Patterns

Sex-influenced patterns of autosomal dominant inheritance are observed in conditions like gout and pre-senile baldness, males being affected the most. This may occur through the effect of male hormones. In females, gout is rarely seen before menopause.

Mitochondrial inheritance

Mitochondria are small organelles located in the cytoplasm of all eukaryotic cells, and are mainly responsible for the generation of ATP in the body, which is the main source of energy for all metabolic activities. As per the metabolic and energetic requirements of the organ, the number of mitochondria in the respective cells varies. This means organs showing high metabolic activity such as brain, liver, germ cells, skeletal muscles, have the largest number of mitochondria. These organs are mainly affected by dysfunctioning of mitochondria. Mitochondria possess their own genome, mitochondrial DNA (mtDNA) that is responsible for ATP synthesis and different RNA forms such as mitochondrial ribosomal RNA (rRNA) and transfer RNA (tRNA). The size of the mitochondrial genome is 16-17 kb and it is circular and double stranded.

Mitochondria contain several (2 to 10) copies of circular chromosomes (mtDNA) that contain genes. The cytoplasmic localization and high copy numbers of mtDNA result in a characteristic non-Mendelian inheritance pattern termed “maternal” or mitochondrial inheritance. Because the sperm contains hardly any cytoplasm the mitochondria in a zygote originate almost exclusively from the cytoplasm of the ovum. Therefore mitochondrial inheritance of a trait is exclusively maternal, inherited by all offspring, with males and females being equally affected. However mutations are only present in a proportion of cellular mitochondrial chromosomes (heteroplasmy) and cellular function is affected only if a significant proportion is mutated (threshold expression).

Dysfunction of mitochondria leads to degenerative diseases. Clinical manifestations due to mitochondriopathies depend not only on mutation of genes, but also upon energy requirement of organs. Mitochondrial diseases are mainly classified into two categories: 1) deficiencies that arise due to disturbance in respiratory chain function leading to mitochondrial myopathies, 2) deficiencies of enzymes for metabolic functions and substrate transport across the mitochondrial membrane. Several diseases have been identified that result due to mitochondrial mutations. Diseases such as myoclonic epilepsy and ragged red fibres (MERRF), mitochondrial encephalomyelopathy with lactic acidosis and stroke like episodes (MELAS), aminoglycoside-induced deafness (AID) are due to mitochondrial tRNA mutations. Leber’s hereditary optic neuropathy (LHON), neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) are as a result of mutations in the coding sequence. Point mutations in the ATPase 6 gene leads to Leigh syndrome, which is maternally inherited. Pearson disease, Wolfram syndrome, Kearns-Sayre syndrome and ocular myopathies are due to deletions.

References

Purandarey , H. (2009) . Essentials of Human Genetics. Second Edition. Jaypee Brothers Medical Publishers (P) Ltd.