Mode of inheritance of genetic defects

Modes of inheritance of genetic defects:

Mendelian inheritance:

                       Disorders caused by a single gene defect follow inheritance patterns described by Mendel(Father of modern genetics), and since 1901 the term mendelian inheritance has been used to denote unifactorial inheritance.

Gregor Mendel

1.Autosomal Dominant inheritance:

Ø It affects both males and females almost equally.

Ø Here the defect is not transmitted by the family unaffected members.

Ø Important features shown by this type of inheritance are:

·Late onset disorders: ( affected individuals may remain asymptomatic till adult life)

·  Variable expressivity (difference in the severity of the expression of the defect)

·  Lack of Penetrance

·  New mutations

        Examples:

                        Achondroplasia, Acute intermittent porphyria, Charcot–Marie–Tooth disease, Facioscapulohumeral dystrophy, Doyne honeycomb retinal dystrophy (DHRD), Familial adenomatous polyposis, Familial breast cancer (BRCA 1, 2), Familial hypercholesterolemia, Huntington disease, Myotonic dystrophy, Noonan syndrome, Neurofibromatosis (types 1 and 2), Osteogenesis imperfect, Spinocerebellar ataxia, BIRT-HOGG-DUBE SYNDROME, Tuberous sclerosis…..

2. Autosomal recessive inheritance:

v There is homozygosity of the mutated gene in the affected individual.

v Both the parents of the affected individual will have a single allele copy of the mutated gene( heterozygous carriers).

v Many of the inborn errors recognized follow this type of inheritance.

v The recessive disorders can be found out by proper prenatal investigations.

v Important features:

·  Variability

·  Uniparental disomy

·  New mutations

·  Heterogeneity

·  Consanguinity (Increases the risk of recessive disorders)

  Examples:

                 Congenital adrenal hyperplasia, Gaucher's disease (for more info visit), Cystic fibrosis, Deafness (some forms), Friedreich ataxia, Galactosaemia,  Hemochromatosis, Homocystinuria, Hurler syndrome (MPS I), Oculocutaneous albinism, Phenylketonuria, Sickle cell disease, Tay–Sachs disease, Thalassaemia.

3. X linked recessive inheritance:

Ø Males are almost always affected because of the hemizygosity of the X-chromosome.

Ø Females are almost always acting as carriers.

Ø The inheritance from an affected male is always to the daughters and never to the sons.

Ø Important features:

§ Manifesting carriers:

ü Heterozygous females are affected occasionally, because of non-random X-inactivation.

Examples:

               Anhidrotic ectodermal dysplasia, Becker muscular dystrophy, Choroideraemia, Colour blindness, Duchenne muscular dystrophy, Emery–Dreifuss muscular dystrophy, Fabry disease, Fragile X syndrome, G-6-P-D deficiency, Haemophilia A, B, Hunter syndrome (MPS II), Ichthyosis (steroid sulphatase deficiency), Lesch–Nyhan syndrome, Menkes syndrome, Ocular albinism, Ornithine transcarbamylase deficiency, Retinitis pigmentosa (some types), Testicular feminization syndrome, Norrie’s disease.

4. X linked dominant inheritance:

v Both hemizygous males and heterozygous females are affected equally but more severe in males.

v Inheritance is same as X-linked recessive (affected male to daughters but never to sons)

Examples:

                 X linked hypophosphatemia (vitamin D-resistant rickets) ,  oculomotor nystagmus, focal dermal hypoplasia (Goltz syndrome), incontinentia pigmenti, Rett syndrome.

5.Y-linked inheritance:

·  Also known as, “Holandric inheritance”

·  Exclusively affects only males associated with infertility

·  It was postulated that this mode of inheritance is actually, autosomal dominant inheritance with sex limitation.

Examples:

                Porcupine skin, hairy ears, webbed toes

Unusual inheritance:

1. Uniparental disomy:

                                    ·  Both copies of a particular chromosome are inherited from the same parent.

                                    ·  Usually due to a phenomenon called trisomy rescue ( loss of one chromosome in a zygote which is originally  trisomic)

         o  Because of trisomy rescue, there can be,

                                                                                                                i.  Normal ( one chromosome from each parent)

                                                                                                                ii.  Iso-disomy 

                                (Two identical chromosome from the same parent)

                                                                                                              iii.  Hetero-disomy 

                                (Two different chromosome from the same parent)

                                     ·  It can also occasionally occur due to Monosomy rescue.

2. Imprinting:

·           It is the physiological silencing of genes based on parental origin.

·           It can be :

o   Paternal or

o   Maternal

·        Chromosomes mostly commonly involved here are 7,11,15.

 Examples:

                 Prader–Willi syndrome,  Angelman syndrome

3. Mosaicism:

                         ·  It is the presence of two or more types of cell lines in an individual.

                          ·  Can be either:

             o   Somatic mosaicism (Not transmissible)

             o   Germline mosaicism ( transmitted to next generation but may be clinically silent in the individual where initiation of the mosaicism took place).

Examples:

Ø Somatic mosaicism: segmental neurofibromatosis type 1

Ø Germline mosaicism: Duchenne muscular dystrophy

4. Mitochondrial inheritance disorders

                                    ·  The inheritance is from mother to all the children( because only the egg contributes mitochondria and cytoplasm of the zygote...

                                    ·  It is often sporadic.

Examples:

                 Leber hereditary optic neuropathy (LHON), MERRF, Kaerns-Sayre syndrome, MELAS

5. Unfavorable lyonization:

                                     ·  Selectively more number of normal X-chromosome undergoes inactivation.

Examples:

                 Alport syndrome, Fragile X-syndrome.

6. Trinucleotide repeat disorder:

                                     ·  The repeats will be converted to full mutations only when they reach a certain number.

                                     ·  Because of this reason, it is also called as unstable mutation.

Examples:

·  Gain of function mutations (due to CAG repeat):

         Huntington disease, Kennedy syndrome, Spinocerebellar ataxias( Machado-Joseph disease), Dentatorubropallidoluysian atrophy.

·  Loss of function mutations:

Fragile XA (site A) ( CGG repeats)

Fragile XE (site E) ( CCG repeats)

Friedreich ataxia (FA) ( GAA repeats)

Myotonic dystrophy : (CTG repeats)

Spinocerebellar ataxia 8 (CTG repeats)

     Follow us on:

        

For more information visit the links below:

1.Classic Mendelian Genetics (Patterns of Inheritance):    

2. INHERITANCE PATTERNS

3.Autosomal Recessive vs. Autosomal Dominance

4.X Linked Recessive 

5.Pedigrees, Patterns of Genetic Inheritance, Autosomal Dominant Recessive X-Linked Mitochondrial