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Author: Diana Bianchi, M.D.
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Mendelian Genetics


Jorde, Carey, Bamshad & White: Medical Genetics, 3rd edition

  • Single gene disorders
    • Chapter 4: Pages 57-76, 83-85
    • Chapter 5: Pages 88-101



The student should:

  1. Be familiar with Mendel’s basic principles of heredity;
  2. Know the difference between locus and allele;
  3. Know the difference between genotype and phenotype;
  4. Understand the patterns, and describe the characteristics of single gene inheritance;
  5. Recognize typical pedigree patterns;
  6. Know how to calculate recurrence risks for single gene disorders;
  7. Explain the occurrence of X-linked recessive traits in females;
  8. Understand the difference between expression and penetrance of a disorder;
  9. Be aware of the multiple explanations for variable expressivity of single gene disorders;
  10. Understand how to obtain updated information on the chromosomal location or cloning of a gene.

Definitions of Terms

  • Allele - Alternative form of a gene occupying the same locus on homologous chromosomes
  • Anticipation - The tendency of certain diseases to appear at earlier ages and with increased severity in successive generations.
  • Compound heterozygote - Two different abnormal alleles at one locus in one individual
  • Consanguinity - Term used if individuals are related by blood prior to marriage or mating (e.g., first cousins)
  • Dominant negative mutation - A mutation present in one copy, in which the abnormal gene product suppresses or destroys the normal gene product
  • Gene locus - The site on the chromosome at which a gene is located
  • Genotype - The precise allelic composition (i.e., letters in the genetic code) with respect to a particular gene
  • Gonadal mosaicism - This term is used when there is a mutation that occurs in the gonadal tissue (testes or ovaries) of an unaffected parent of a child with an “apparently” new mutation. This is usually discovered when both parents do not have the condition (usually dominantly inherited) but they have 2 affected children. Risk of recurrence depends on level of mosaicism in the gonads. Empirically, the recurrence risk is typically 2-5%.
  • Hemizygous - Males are hemizygous with respect to genes on the X chromosome, rather than homozygous or heterozygous, since they have only one X
  • Heterozygous - Both alleles at one locus are different (Aa)
  • Homozygous - Both alleles at one locus are the same (AA or aa)
  • Pedigree analysis - The method of recording family data to observe transmission of genetic disorders and mode of inheritance.
  • Penetrance - In an autosomal dominant condition, the proportion of individuals who carry a known gene mutation, who express any of the clinical symptoms associated with the genetic disease.
  • Phenotype - Traits or properties actually observed physically or clinically. The phenotype results from the interaction of the genotype with the environment.
  • Pleiotrophy - Genes having more than one discernible effect on the body. For example, mutations in the fibrillin gene are pleiotropic. They affect the heart, the skeletal system, and the eye.
  • Variable Expressivity - An identical genetic mutation can present with different clinical symptoms in related individuals.

Lecture Outline

Historical Perspective

(Johann) Gregor Mendel (1822-1864)

  • Austrian monk who discovered basic principles of heredity through his experiments with garden peas
  • Received no recognition for his work during his lifetime
  • Derived three laws from his experiments:
  1. Unit inheritance - parental phenotypes do not blend in offspring
  2. Segregation - two members of a pair of genes segregate and pass to different gametes
  3. Independent assortment - random recombination of maternal and paternal chromosomes in gametes.

What is Mendelian Inheritance?

Mendelian Inheritance refers to the transmission of inherited traits from generation to generation through the transmission of genes.

Four Basic Patterns of Single Gene Inheritance

Single Gene
  • A gene, which is expressed even when present in only one copy, is DOMINANT.
  • A gene expressed only when two copies are present is RECESSIVE.
  • In a male with an X-LINKED RECESSIVE disorder, only one copy of a gene is needed to produce the disease.

Victor A. McKusick, M.D. (1921 - present)

  • Tufts Undergraduate - never received a degree.
  • Professor Emeritus and former Chairman of Medicine at John Hopkins University School of Medicine
  • Established Catalog of Mendelian Inheritance in Man in 1962
    • initially X-linked traits (rare and common), then recessives in Old Order Amish.
    • Catalog has 12 editions in book format
    • Currently maintained on the world wide web - updated daily!
    • Web site address: http://www.ncbi.nlm.nih.gov/omim

What is OMIM?

Online Mendelian Inheritance in Man (OMIM TM) is a continuously updated catalog of human genes and genetic disorders. MIM focuses primarily on inherited, or heritable genetic diseases. It is also considered to be a phenotypic companion to the human gene project.

Numbering system: Each OMIM entry is given a unique six-digit number whose first digit indicates the mode of inheritance of the gene involved.

OMIM Numbering and Symbols

1 (100000-) Autosomal dominant

2 (200000-) Autosomal recessive

3 (300000-) X-linked

4 (400000-) Y-linked

5 (500000-) Mitochondrial

6 (600000-) Autosomal locus or phenotype created after May 15, 1994

An asterisk (*) before an entry number indicates a gene of known sequence.

A plus sign (+) before an entry number indicates a gene of known sequence and phenotype.

No symbol before an entry number means that the mode of inheritance has not been proved, although suspected, or that the separateness of this locus from that of another entry is unclear.

A number symbol (#) indicates that this is a descriptive entry and does not represent a unique locus.

A percent sign (%) before an entry number means that there is a confirmed Mendelian phenotype but the underlying molecular basis is not known.

Number of Recognized Single Gene Disorders

1966 1978 1988 1990 1994 Online
Autosomal Dominant 837 1489 2557 3047 4458 Autosomal (all)
Autosomal Recessive 531 1117 1477 1554 1730 15,311
X-Linked 119 205 310 336 412 910
Y-Linked 19 56
Mitochondrial 63
TOTAL 1487 2811 4344 4937 6678 16,340

Examples of Single Gene Disorders

Autosomal Dominant Population Frequency
Neurofibromatosis I 1:3,000-5,000
Marfan syndrome 1:10,000-15,000
Huntington disease 1:15,000-20,000
Hypercholesterolemia 1:500
Autosomal Recessive Population Frequency
Sickle cell anemia 1:600 African Americans
Cystic fibrosis 1:1,600 N. European Caucasians
Tay-Sachs disease 1:3,500 Ashkenazi Jews
Phenylketonuria 1:10,000 N European Caucasians
X-Linked Population Frequency
Hemophilia 1:10,000 males
Fragile X 1:1,500 males; 1:2,500 females
Duchenne muscular dystrophy 1:3,500 males
Color blindness 1:12 males
G6PD deficiency 1:8-10 African American males
  • Most disorders caused by enzyme defects are RECESSIVE.
  • Disorders caused by non-enzymatic or structural proteins are usually DOMINANT.
  • There are exceptions to these rules.

Where are the Genes Located?

Total Mapped Loci as of 10/22/05
chromosome 1: 890
chromosome 2: 583
chromosome 3: 505
chromosome 4: 355
chromosome 5: 448
chromosome 6: 586
chromosome 7: 429
chromosome 8: 327
chromosome 9: 334
chromosome 10: 321
chromosome 11: 591
chromosome 12: 487
chromosome 13: 174
chromosome 14: 283
chromosome 15: 269
chromosome 16: 359
chromosome 17: 539
chromosome 18: 139
chromosome 19: 613
chromosome 20: 220
chromosome 21: 127
chromosome 22: 233
chromosome X: 550
chromosome Y: 46
Total # of Loci: 9408

To get up to the minute information, go to: http://www.ncbi.nlm.nih.gov/omim/stats/mimstats.html

Note that the autosomal chromosomes involved in the live born trisomies (13,18,21) have the fewest mapped loci.

Why is this significant?

Answer: Three copies of too many genes is lethal. The only trisomies that allow survival through pregnancy involve the chromosomes with the fewest genes and hence, the fewest “extra” genetic information. The exception is the sex chromosome abnormalities, in which one can have three copies of the X chromosome and be relatively asymptomatic.

Autosomal Dominant Inheritance

  1. Only one copy of a mutant allele is necessary for expression of the trait.
  2. A heterozygote has a 1 in 2 chance to pass on the mutant allele. Therefore, offspring have a 50% chance of being affected.
  3. Homozygous normal offspring have no risk of the disorder or of passing on the mutant allele to their children.

Characteristics of Autosomal Dominant Pedigrees

  1. Transmission is vertical (from generation to generation)
  2. Number of affected males and females is equal
  3. Male-to-male transmission is observed
  4. Unaffected individuals have unaffected children (exception is decreased penetrance).
  5. Disorder may arise as a new mutation.
  6. Phenotype can vary from affected person to affected person in same family

Hypothetical pedigree showing AD disorder:

AD Disorder

Both Parents Affected

One Parent Affected

Illustrations adapted from Counseling Aids for Geneticists, 2nd edition, Greenwood Genetic Center, copyright 1989, Jacobs Press

Clinical Characteristics of Autosomal Dominant (AD) Disorders

Characteristics of Autosomal Recessive Pedigree

  1. The disorder is rarely present in the parents, collateral relatives or ancestors, but may appear in siblings.
  2. Number of affected males and females is equal.
  3. Consanguinity is more likely to be present in AR pedigrees.

Clinical Characteristics of Autosomal Recessive (AR) Disorder

  • AR disorders cluster in ethnic groups with relative geographic or religious isolation and increased consanguinity.
  • Penetrance is usually complete and there is little phenotypic variability.
  • Most AR disorders are enzyme abnormalities.
  • Heterozygotes may be detectable by presence of about 50% of normal enzyme activity, resulting from the presence of only one normal gene or by DNA mutation analysis, or by DNA linkage analysis, or by protein testing.

Heterozygote Detection By Enzyme Analysis Example:

Tay Sachs Disease

Frequency: 1:3,500 Ashkenazi (Eastern European) Jews

Features: Caused by absence of the lysosomal enzyme, hexosaminidase A (hex A), with subsequent accumulation of GM2 ganglioside in the CNS. Onset of symptoms at 4-6 months with progressive neurologic deterioration and death by 2-3 years.

Tay-Sachs is 10 times more frequent in Ashkenazi Jews (1/30 carrier frequency) than in other ethnic groups in North America (1/300 carrier frequency). A simple, inexpensive carrier test is available and prenatal diagnosis is possible, based on Hex A enzyme assay or DNA mutation assay.

The gene is on chromosome 15q2. There are multiple abnormal alleles

Heterozygote Detection by DNA Mutation Analysis Example:

Cystic fibrosis (CF)

Frequency: 1:1,600 whites

Features: Pancreatic insufficiency, respiratory disease with recurrent pneumonia due to thick, inspissated mucous secretions.

CF is the most common AR disorder in Caucasians. Carrier frequency is about 1/20. The gene for CFTR protein is located on chromosome 7. There are several hundred known mutations (alleles), with wide variation in the clinical symptoms. About 70% of cases have the same mutation (delta F508). Carrier screening and prenatal testing can be as accurate as 85-90% (depending on ethnic group) even in the absence of an affected relative. Carrier screening is being offered routinely to all prenatal diagnosis clients at some facilities. All newborn infants in Massachusetts are tested for cystic fibrosis.

Heterozygote Detection by Electrophoresis Example:

Sickle cell disease

Frequency: 1:600 African Americans

Features: Sickling of red blood cells, leading to vascular occlusion and hemolysis. Clinical features include pain, reduced ability to fight infection, leg ulcers, poor growth, and reduced life expectancy. The single base pair alteration in the “B” subunit of hemoglobin is on chromosome 11p11. Diagnosis and carrier screening are possible without linkage analysis. Carrier frequency is 1/12 in African Americans. Carriers have both hemoglobin A and hemoglobin S.

Heterozygote Detection by Linkage Analysis Example:

Phenylketonuria (PKU)

Frequency: 1:10,000

Features: “Classic” PKU is due to phenylalanine hydroxylase deficiency. If not treated by a low phenylalanine diet, it results in mental retardation and seizures. Newborn screening detects infants with hyperphenylalaninemia. However, there are other enzyme defects, which can result in hyperphenylalaninemia (genetic heterogeneity). Some of these other conditions will not respond to the PKU dietary treatment. Carrier detection is possible. Prenatal diagnosis is possible for some cases using restriction fragment length polymorphisms (RFLPs) and linkage analysis, or DNA detection of specific mutations.

The gene is located at 12q24.1. There are multiple alleles, some of which do not result in clinical disease.

Risk Determination for Recessive Conditions

Parents of an affected child - 25% recurrence risk in subsequent pregnancies.

Siblings of affected individuals - risk to their children:

  1. Risk of being a carrier is 2/3
  2. The risk is calculated by multiplying the probability that the sibling is a heterozygote (2/3) times the probability that the spouse is a carrier (population carrier frequency) times the probability that they will both pass the recessive gene to their offspring (1/4). Sample calculation for AR disorder with 1/100 carrier frequency:

Risk Determination

Risk of affected offspring = 2/3 x 1/100 x 1/4 = 1/600 or .16%

X-Linked Recessive Inheritance

  1. Hemizygous males are affected
  2. Heterozygous female carriers are usually unaffected
  3. Heterozygous females have 50% chance for having heterozygous carrier daughters and 50% chance for having hemizygous affected sons.
  4. Affected males will have all normal sons and all heterozygote (carrier) daughters.

Characteristics of X-Linked Recessive Pedigree

  1. Incidence is much higher in males than females.
  2. No male-to-male transmission.
  3. Trait is passed from an affected male to all of his daughters and then to ½ of the daughter’s sons.
  4. Carrier females may show variable expression of the trait.

Typical X-linked recessive pedigree:

X-linked Recessive

Mother Carrier

Father Affected

Illustrations from Counseling Aids for Geneticists. 2nd edition, Greenwood Genetics Center, Copyright 1989, Jacobs Press.

Hemophilia Example:

Frequency: 1:10,000 males

Features: Classic hemophilia with Factor VIII deficiency. Bleeding tendency with minimal trauma. Intra-articular bleeds with deformity and subsequent handicap. Risk of fatal bleed. About 2/3 carrier females will have abnormal Factor VIII levels. DNA markers are available in the vicinity of the gene. Most families have “private” mutations, so carrier testing and prenatal diagnosis often require linkage analysis.

Duchenne Muscular Dystrophy (DMD) Example:

Frequency: 1:3500 males

First symptoms by 5 years of age with calf hypertrophy; progressive muscle weakness; death usually occurs by 20 years of age. Female carriers may show subtle clinical signs. CPK levels are increased in about 2/3 of carrier females. It is important to obtain blood samples from possible carriers before the age of 10 years whenever feasible, because the levels of CPK are likely to be more abnormal in the first decade. During pregnancy, the levels of CPK may fall, limiting its usefulness at this stage. DMD is an example of a genetic lethal (males do not reproduce and, therefore, do not transmit the gene). 1/3 of individuals with DMD are new mutations, 2/3 of cases are inherited through carrier mothers. The gene for DMD has been identified, as well as its protein product, dystrophin. The gene is very large, and most families have their own “private” mutations. If the mutation in a family is known, DNA analysis may be utilized for carrier detection and prenatal diagnosis. If not, linkage analysis may be possible if there are living affected relatives. Because of so many mutations, population screening is not possible. Sixty percent of the mutations are deletions, with the remainder being point mutations or duplications.

Becker Muscular Dystrophy Example:

Mutations in the DMD gene which interfere with but do not knock out dystrophin cause a milder phenotype, clinically diagnosed as Becker muscular dystrophy. Most are point mutations in the dystrophin gene.

Duchenne and Becker muscular dystrophy are allelic, meaning that both diseases are caused by different mutations in the same gene.

Risk Determination in X-Linked Recessive Disorders

Sons of obligate carriers have a 50% risk of being affected.

  1. Obligate carriers include:
    • Mothers of one affected male with a previous family history of the disorder
    • Mothers of more than one affected male
    • All daughters of an affected male
  2. For other female relatives of the affected male, the risk of carrier status can be determined using:
    1. A priori risk based on relationship to proband
    2. Laboratory tests for possible carrier status:
      • DNA - direct or linkage
      • Enzyme analysis - accuracy can be affected by X-inactivation of lyonization

Lyon Hypothesis:

In the somatic cells of female mammals, only one X chromosome is active. Inactivation occurs early in embryonic life. The inactive X can be either the paternal or maternal X. After inactivation in a given cell, any cells derived from that cell have the same inactivated X (i.e., inactivation is random; but fixed).

Sporadic cases: other could be heterozygous or it could be the result of a de novo mutation. Laboratory studies (enzyme levels; search for common mutations) in the mother may help distinguish between these possibilities.


Possible explanations:

  1. The affected female is homozygous for the mutant allele (has an affected father and carrier mother).
  2. Cells with the normal X inactivated could be present in disproportionate numbers.
  3. The affected female has a 45,X karyotype, an X chromosome with deletion of a normal gene, or preferential inactivation of the normal X.
  4. An epistatic gene (other gene at another location), which affects the level of activity of the gene product from a normal allele.
  5. The disorder is genetically heterogeneous, with X-linked and autosomal recessive forms.


Sex Limited Trait: A trait that is autosomally transmitted, but expressed in only one sex (e.g., precocious puberty).

Sex Influenced Trait: An autosomally transmitted trait that is expressed in both sexes, but with widely different frequencies (e.g., hemochromatosis, male pattern baldness, congenital adrenal hyperplasia).