Mendelian Inheritance and Inheritance Patterns : High Yield Notes with Mnemonics

Some important terms related to inheritance and genetics

Gene:  a functional part of the DNA molecule of a chromosome which directs the synthesis of a specific polypeptide chain.

Allele (allelomorph): alternative form of a gene found at the same locus on a pair of homologous chromosomes.

Homozygous: the presence of two identical alleles at a particular locus on a pair of homologous chromosomes.

Hybrid: individual having two different allele at a locus.

Dominant: a trait which is expressed in individual who are heterozygous for a particular allele.

Recessive: a trait which is expressed in individuals who are homozygous for a particular allele but not in those who are heterozygous.

Codominance: when both alleles are expressed in the heterozygote.

Genotype: the genetic constitution of an individual.

Phenotype: the appearance(physical,biochemical,physiological) of an individual which results from an interaction of the environment and the genotype.

Mutant: a gene which has undergone a change or mutation.

Mutation: a change in genetic material,either of a single gene,or in the number or structure of the chromosomes. A mutation which occurs in the gametes is inherited,a mutation which occurs in the somatic cells(somatic mutation) is not inherited.

Mosiac: an individual with two different cell lines derived from a single zygote.

Mendal’s first law: Law of uniformity

It refers to the fact that:

When two homozygotes with different alleles are crossed, all the offsprings of the F1 (first filial) generation are identical and heterogygous.

The characteristics do not blend and reappear in the later generation.

Mendal’s second law: Law of segregation

• Refers to the observation that each individual possesses two genes for a particular characteristic,only one of which can be transmitted at any one time.
• Rare exceptions to this rule can occur when two allelic genes fail to separate because of chromosome nondisjunction at the first meiotic division.
• A hereditary disease or trait transmitted by a single gene is called Mendelian trait.

Mendal’s third law: Law of individual assortment

• Refers to the fact that members of different gene pairs segregate to offspring independently of one another. However, genes that are close together on the same chromosome tend to be inherited together, i.e. they are linked.

Features:

• Genes are transmitted in different chromosomes.
• Transmission of one gene does not influence that of another.
• Meiotic events explain independent assortment.
• Example:

If a male having following features-

• Passing yellow urine (Bb)
• Colored eyelid (Hh) and
• Normal fingers (ee)

Mates with a female having following features:

• Passes red urine (bb)
• Normal eyelids (hh) and
• Short fingers (Ee);

Then the chances of a child having the following features- who passes red urine (bb) x colored eyelids (Hh) x short fingers (Ee) are  ½ x ½ x ½ = 1/8.

Features of Mendelian trait:

• A Mendelian trait is caused by a single gene.
• Mode of inheritance reveal whether a Mendelian trait is dominant or recessive and whether the gene that controls it is carried on an autosome or a sex chromosome.
• Mendelian trait or single gene disorder can be in herited in five ways : autosomal dominant, autosomal recessive, X linked dominant, X linked recessive and Y linked.
• Mendel’s second law which can predict the probability that a child will inherit a Mendelian trait,applies anew to each child.

Criteria and Features of an Autosomal Dominant Traits:

• Both males and females can be affected. Can have male to male transmission.
• Male and female transmit the trait with equal frequency.
• Successive generations are affected.
• Transmission stops if a generation arises in which no one is affected.
• Can arise from fresh mutations.
• Autosomal dominant inheritance: when a parent is affected and the other is not,each offspring has a 50% probability of inheriting the mutant allele and the condition.

Criteria and Features of an Autosomal Recessive Traits:

• Both males and females are affected.
• Affected males and females can transmit the trait, unless it causes death before reproductive age.
• The trait can skip generation.
• Parents of affected individual are heterozygous or also have the trait(carriers).
• Probability: normal(25%) and affected(25%) chance.
• Genotypic ratio: 1:2:1.
• Phenotypic ratio: 3:1.

Criteria for X-linked Dominant trait:

• Males as well as females can be affected but often with an excess of females.
• Females are less severely affected than males.
• Affected males can transmit the disorder to their daughters but not to their sons.
• Some of the traits are:
  • Vitamin D resistant rickets.
  • Charcot –Marie tooth disease (hereditary sensory and motor neuropathy)

Criteria for X-linked Recessive trait:

• Males are usually only affected.
• Transmitted through unaffected females.
• Males cannot transmit the disorder to their sons ie,no male to male transmission can occur.

Y linked inheritance; also called Holandric inheritance:

• Males are only affected.
• Affected males must transmit it to their sons.
• Y linked inheritance (trait):
  • Porcupine skin, hairy ears, webbed toes.

Now coming on to the more volatile stuff. Let’s discuss the diseases and their inheritance patterns.

First, remember the general rules.

1. X-linked dominant, mitochondrial and Y-linked conditions are rare. You need to remember them.

2. Usually inherited in autosomal dominant pattern are:

• Mostly mutations in non-enzymatic structural proteins (e.g. collagen, fibrillin, cytoskeletal proteins of RBC) or in membrane receptors (e.g. LDL receptor)
• Diseases due to diminished feedback inhibition by end-product due to enzyme deficiencies e.g. Porphyria
  • Except Congenital Erythropoietic Porphyria which is autosomal recessive
• Conditions prefixed “hereditary” or “familial”
• Hereditary cancer syndromes
• ‘Gain of function mutations’ like Achondroplasia, Huntington’s disease, Proto-oncogenes, etc.

3. Usually inherited in autosomal recessive pattern are:

• Most enzymatic defects and inborn errors of metabolism except few exceptions
• Transport proteins like globin or channel related mutations
  • Exception: Copper transporting ATPase in Menke’s disease (X-linked recessive)
• Mutation in DNA repair genes like  Ataxia Telangiectasia, Bloom Syndrome, Fanconi’s Anemia, Xeroderma Pigmentosum
  • Exception: Hereditary Nonpolyposis Colon Cancer (HNPCC)

4. Usually inherited in X-linked recessive pattern are:

• Enzyme deficiencies that are exceptions from autosomal recessive pattern like Fabry’s disease, Phospoglycerate kinase 1 deficiency form of Glycogen storage disease, Hunter’s syndrome, G6PD deficiency, HGPRT deficiency, OTC deficiency
• Most of the inherited inmmunodeficiencies except:
  • Autosomal recessive:
    • ADA-SCID
    • Chronic Granulomatous disease (some forms)
  • Autosomal dominant:
    • Job’s syndrome
    • DiGeorge syndrome
• Common forms of muscular dystrophies: DMD and BMD

X-linked Dominant

Mnemonic: FAIR

• Familial hypophosphatemic rickets (Vitamin D resistant rickets)
  • PHEX gene mutation
• Fragile X syndrome
  • FMR1 gene mutation
• Alport syndrome (most of the cases)
  • COL4A gene mutation
• Incontinentia pigmenti
  • IKK-gamma gene mutation
• Rett’s syndrome
  • MeCP2 gene mutation

Y-linked Inheritance

1. Swyer syndrome
   • Mutation in SRY gene on Y chromosome
2. Jacob’s syndrome
   • Extra Y i.e XYY
3. Auricular hypertrychosis

Mitochondrial Inheritance

1. Leigh disease
2. MELAS (Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes)
3. Leber’s Hereditary Optic Neuropathy (LHON)
4. Myoclonic Epilepsy with Ragged Red Fibers (MERRF)
5. Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)

Now, by exclusion let us learn the examples for other modes of inheritance.

Autosomal Dominant Inheritance

Key Idea:

1. Most diseases caused by mutations in non-enzymatic structural proteins (e.g. collagen, fibrillin, cytoskeletal proteins of RBC) or in membrane receptors (e.g. LDL receptor)
2. Uncommon forms of muscle dystrophy
3. Diseases due to diminished feedback inhibition by end-product due to enzyme deficiencies e.g. Porphyria
4. Conditions prefixed “hereditary” or “familial”
5. Hereditary cancer syndromes
6. Blue-yellow color blindness

These are characterized by:

1. Reduced penetrance: individuals inherit the gene but can be phenotypically normal
2. Variable expressibility: the trait is seen in the individuals carrying the mutant gene but is expressed differently among individuals, e.g. patients of neurofibromatosis have variant from brownish skin spots to multiple skin tumors in different patients.
3. Gain of function e.g. Huntington’s disease or Loss of function (Dominant negative mutant allele) e.g. Collagen disorders (single mutant collagen chain and normal collagen trimers cannot be formed e.g., Osteogenesis imperfecta, Ehler Danlos, Marfan syndrome).

Examples:

1. Achondroplasia
2. Ehlers-Danlos Syndrome (most; type 6 is autosomal recessive) – type 3 (hpermobility type; most common), type 4 (vascular type; most dangerous)
3. Facioscapulohumeral, Oculopharyngeal, Limb-girdle and Emery-Dreifuss muscular dystrophy
4. Familial Adenomatous Polyposis
5. Familial hypercholesterolemia (LDL receptor defect)
6. Hereditary spherocytosis (Spectrin and ankyrin defect)
7. Huntington disease
8. Marfan syndrome (Mutation of fibrillin gene on 15q21)
9. Myotonic dystrophy
10. Neurofibromatosis type 1 and 2
11. Porphyrias (except congenital erythropoietic porphyria which is autosomal recessive)
12. Tuberous sclerosis
13. Von Willebrond Disease except type III vWD (autosomal recessive)

Mnemonic: Autosomal DOMINANT Hunts Vulnerable Family.

1. Autosomal – ADPKD
2. D – Dystrophia myotonica
3. O – Osteogenesis imperfecta
4. M – Marfan syndrome
5. I – Intermittent porphyria
6. N – Neurofibromatosis type 1 (von Recklinghausen disease – more common 90%; Lisch nodules; Juvenile myelomonocytic leukemia; mutation of neurofibromin on chromosome 17)
7. A – Achondroplasia
8. N – Neurofibromatosis type 2 (less common 10%; bilateral acoustic neuromas, multiple meningioma; Lisch nodules absent; mutation of merlin on chromosome 22)
9. T – Tuberous sclerosis
10. Hunts – Huntington’s disease, Hereditary spherocytosis
11. Vulnerable – vWD disease
12. Family – Familial hypercholesterolemia

Autosomal Recessive Disorders

Idea:

1. Most enzymatic defects and inborn errors of metabolism except few exceptions
2. Transport proteins like globin, channel or cilia related mutations
3. Mutation in DNA repair genes like  Ataxia Telangiectasia, Bloom Syndrome, Fanconi’s Anemia, Xeroderma Pigmentosum
   • Exception: Hereditary Nonpolyposis Colon Cancer (HNPCC) which is Autosomal Dominant.
4. Congenital bleeding disorders except the common ones:
   • Hemophilia A and B (X-linked recessive)
   • Von Willebrond Disease Type 1 and Type 2 (Autosomal dominant)
   • Wiskott-Aldrich syndrome (X-linked recessive)

Suspect uniparental disomy if affected child is born to one carrier and other normal parent.

Examples:

1. Albinism (except ocular albinism which is X-linked recessive)
2. ARPKD
3. Ataxia Telangiectasia
4. Barter syndrome
5. Bloom syndrome
6. Congenital adrenal hyperplasia
7. Criggler Najar Syndrome (Severe form)
8. Cystic fibrosis
9. Dubin-Johnson Syndrome
10. Familial Mediterranean fever
11. Fanconi anemia
12. Friedrich ataxia
13. Galactosemia
14. Glycogen storage disorders (except phosphoglycerate kinase 1 deficiency)
15. Gilbert syndrome
16. Gitelman syndrome
17. Hartnup disease
18. Hemochromatosis
19. Homocystinuria
20. Kartagener syndrome
21. Laurence Moon Biedl Syndrome
22. Leukocyte adhesion defect
23. Mucopolysaccharidoses (except Hunter syndrome)
24. Myeloperoxidase deficiency
25. Pendred syndrome
26. Phenylketonuria
27. Rotor syndrome
28. Sickle cell anemia
29. Sphingolipidoses (except Fabry disease)
30. Spinal muscular atrophies
31. Usher syndrome
32. Beta-thalassemia
33. Wilson disease
34. Xeroderma pigmentosum
35. Ehler danlos type 6 (kyphoscoliosis type – mutation in lysyl hydroxylase)

Mnemonic: ABCDEFGH KLMNoP RSTuVWX

1. Abetalipoproteinemia, Alkaptonuria, Albinism, Alpha-1-antitrypsin deficiency
2. Bernard soulier syndrome, Bloom syndrome
3. Carpenter syndrome, Chediak-Higashi syndrome, Cystic fibrosis, Criggler-Najar syndrome, CAH, Cystinuria, Cystinosis
4. Dubin-Johnson syndrome
5. Ehler Danlos syndrome type 6, Endocardial fibroelastosis
6. Familial Mediterranean fever, Fanconi anemia, Freidrich’s ataxia
7. Gaucher’s disease, Glanzmann’s thrombasthenia, Glycogen storage diseases, Gastroschisis
8. Hartnup disease, Hemochromatosis, Homocystinuria
9. Krabbe disease, Kartagener syndrome
10. Leukocyte adhesion defect (LAD)
11. Mucopolysaccharidoses (except Hunter syndrome which is X-linked), Muscular atrophy (SMA)
12. Niemann-Pick disease
13. Orotic aciduria
14. Phenylketonuria
15. Rotor syndrome
16. Shwachman-Diamond syndrome, Sickle cell disease
17. Tay-Sachs disease, Thalassemia
18. Urofacial syndrome
19. vWD disease type 3
20. Wilson’s disease
21. Xeroderma pigmentosum

X-linked Recessive Disorders

Idea:

1. Enzyme deficiencies that are exceptions from autosomal recessive pattern like Fabry’s disease, Phospoglycerate kinase 1 deficiency form of Glycogen storage disease, Hunter’s syndrome, G6PD deficiency, HGPRT deficiency, OTC deficiency
2. Most of the inherited inmmunodeficiencies except:
   • Autosomal recessive:
     • ADA-SCID
     • Chronic Granulomatous disease (some forms)
   • Autosomal dominant:
     • Job’s syndrome
     • DiGeorge syndrome
3. Common forms of muscular dystrophies: DMD and BMD
4. Red-green color blindness

Examples:

The exceptions of Autosomal recessive disorders:

1. Fabry’s disease
2. G6PD deficiency
3. Hunter syndrome
4. Ornithine transcarbamylase deficiency
5. Lesch-Nyhan syndrome (HGPRT deficiency)

Muscular dystrophies:

1. Duchenne muscular dystrophy (DMD)
2. Becker muscular dystrophy (BMD)

Others:

1. Charcot-Marie-Tooth disease
2. Wiskott-Aldrich syndrome
3. Ocular albinism
4. Bruton agammaglobulinemia
5. Hemophilia A and B
6. X-linked SCID
7. Menke’s disease
8. Red-green color blindness

This is a comprehensive review of the topic of Mendelian inheritance and inheritance patterns. This is frequently asked in exams.

Bookmark this article and revise it every week, and definitely before the exams.
Hope you enjoyed the article. Let us know in the comments.
Happy studying 🙂

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