(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.

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.

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.

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.