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Genetic Disorders : Causes, Classification : NEET PG Pathology

May 24, 2023

Genetic Disorders

Chromosomal disorders are Disorders where the entire chromosome is affected either chromosome number or structure. Single gene disorders/Mendelian disorders follows Mendelian pattern of inheritance whereas Multifactorial inheritance are disorders where apart from genetic factors, environmental factors also play a very important role. Non-Mendelian disorders are disorders that do not follow typical Mendelian pattern of inheritance for example Trinucleotide repeat disorders, Gonadal imprinting .

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What are Chromosomal Disorders?

Disorders where either the structure or the number of chromosomes is affected. Chromosomes are large chunk of genetic materials (Total no of chromosomes in human – 46). Chromosome can either be missing, duplicated, or altered in some form. E.g., Down syndrome: Trisomy 21 (3 copies of Chr. 21 instead of 2) and Turner syndrome: 45, XO (Female with single X chromosome)

Single gene disorders/Mendelian disorders 

These disorders follow typical Mendelian pattern of inheritance. It includes:

  • Autosomal dominant (Sex chromosomes are not involved, somatic chromosomes are involved)
  • Autosomal recessive 
  • X-linked recessive
  • X-linked dominant 
  • Y-linked conditions: Very rare

Non-Mendelian disorders

  • Trinucleotide repeat disorders 
  • Mitochondrial disorders/Mitochondrial pattern of inheritance
  • Genomic imprinting
  • Gonadal mosaicism 

Multifactorial disorders 

Disorders where apart from genetic factors, host related factors and environmental factors also plays a very important role. E.g., Cleft lip, cleft palate, Neural tube defects, Diabetes, Hypertension.

What are the Mendelian Disorders?

Single gene disorders which follow typical Mendelian pattern of inheritance :

Autosomal Dominant Disorders 

Autosomal dominant disorders are those disorders that manifest even if one of the alleles of a gene is affected (both the alleles need not to be affected). In dominant disorders either of the parents is also affected by the same disorder (at least 1 parent is affected). Examples of autosomal dominant disorders :   

  • Hereditary spherocytosis, Hypercholesterolemia 
  • Ehlers Danlos syndrome 
  • Achondroplasia
  • Von Willebrand disease 
  • Pseudohypoparathyroidism 
  • Dystrophia Myotonica (Myotonic dystrophies)
  • Osteogenesis imperfecta (most types are autosomal dominant)
  • Marfan syndrome -Clinical presentation of marfan syndrome is tall stature, arm span increased, arachnodactyly 
  • Intermittent porphyria 
  • Noonan syndrome
  • Adenomatous polyposis coli (pre-cancerous condition for carcinoma colon) 
  • Neurocutaneous conditions – Neurofibromatosis and Tuberous sclerosis (runs in families)

What are Autosomal recessive disorders? 

Disorders that manifest only if both the copies/alleles of a gene are affected If both the parents are carrier than only the children will manifest this disease. Wilson disease is caused by ATP 7B gene that is going to manifest only if both the copies/alleles of this gene are abnormal. In this the Parents are usually the carrier. If one of the parents is affected then all the babies will be carriers of that disorder even if the other parent is normal. Examples of autosomal recessive disorder:

  • Albinism, Alkaptonuria
  • β-Thalassemia - If both the parents have thalassemia trait then each baby have 25% risk of being affected
  • Cystic fibrosis, Congenital adrenal hyperplasia 
  • Deafness (Congenital Sensorineural deafness)
  • Emphysema caused by α1 antitrypsin deficiency
  • Gaucher disease, Galactosemia 
  • Homocystinuria (classical variety) 
  • Mucopolysaccharidosis – Autosomal recessive inheritance
  • Most of the metabolic disorders have autosomal recessive inheritance

What are X-linked recessive disorders?

These are sex chromosome (X) linked recessive disorders. Predisposition: Males are more commonly affected 

Males              Females

46, XY               46, XX     

Since males have single X chromosome, and if that chromosome is abnormal then also disease is going to manifest as there is no other normal copy of X chromosome. Female have 2 X chromosomes, even if 1 X chromosome is affected, there is another normal copy of same gene on another X chromosome. Females are usually not affected in X-linked recessive disorder. All daughters of an affected male are going to be carriers. Father to son transmission is not seen as son receives Y chromosome from father and X chromosome from mother. Father to son transmission rules out X-linked inheritance

Examples of X-linked recessive disorders:

  • G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency : in this RBCs can get hemolyzed very easily so in this condition we should Avoid notorious drugs which precipitates hemolysis 
  • Duchenne muscular dystrophy (DMD)
  • Color blindness- it is more common in males
  • Fabry disease (Lysosomal storage disorder)
  • Chronic granulomatous disease  (CGD - Immunodeficiency condition)
  • Hemophilia A and B
  • Hunter disease (Type 2 MPS)
  • Agammaglobulinemia/Bruton’s disease 
  • Albinism 
  • Lesch Nyhan syndrome- It is Self-mutilation disease in which there is uric acid accumulates in body
  • History: If Child is affected and there is history that mother’s brothers is also affected with same disorder 

When can Females Manifest X-linked Recessive Disorders?

In Female there are  2 X chromosomes, even if 1 X chromosome is affected, there is another normal copy of same gene on another X chromosome. If Female manifest X-linked recessive disorder if they have single X chromosome i.e., 45, XO then it can point towards Turner syndrome which is  45, XO. Normally, in females one of the X chromosomes get randomly inactivated and other remains active So, if X chromosome carrying abnormal allele remains active and normal one gets inactivated then the female can manifest the disease.

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What are the X-linked dominant disorder?

It is More commonly seen in females. Female karyotype is  46, XX. This disease manifest only if one of the alleles is abnormal/affected. So, if one X chromosome is affected and other X chromosome is normal – Disease is still going to manifest. Male karyotype is 46,XY, If the only X chromosome in males is affected then this condition becomes lethal and they succumb in utero. All daughters of an affected male have the disease but all sons are normal Father to son transmission is not seen. Father to son transmission in pedigree rules out X-linked inheritanc.e 

Examples of X-linked dominant disorders:

  • Charcot Marie tooth disease – Peripheral neuropathy, Pes Cavus 
  • Alport syndrome (controversial)
  • Rett syndrome
  • Rickets: X-linked Hypophosphatemic rickets


Diagrammatic representation that shows the inheritance of various genetic trait through different generations in a family

Drawing of a Pedigree

Drawing of a pedigree
Drawing of a pedigree symbols
Drawing of a Pedigree

Mode of inheritance:

Mode of inheritance

For 1st  generation: female is affected, all her children are affected. For 2nd generation -Male is affected but his children are not affected but Female is affected and all her children are affected. So its Interpretation is Mitochondrial inheritance 

 Mode of inheritance:

Mode of inheritanc

Male is affected but parents are unaffected that is  Recessive pedigree Father’s father is affected. There is no father to son transmission so Interpretation is X-linked recessive inheritance.X-linked recessive inheritance runs more commonly in males e.g., Hemophilia, Duchene muscular dystrophy

Non-Mendelian Disorders         

Trinucleotide repeat disorder

These disorders are due to increase in the number of trinucleotides repeats above a certain threshold . More the number of repeats, more the severity of disease .

“Anticipation” phenomenon: In this the disease manifestations worsen or appear at an earlier age in subsequent generations. It occurs because of increase in nucleotide number with each generation.


Name of disorderRepeats
Huntington diseaseCAG
Myotonic dystrophyCTG
Fragile X syndromeCGG

Fragile X Syndrome 

Gene involved in fragile x syndrome is  FMR-1ntal retardation) gene which is present  on X chromosome :

Genetic basisNo. of CGG repeats
Normal population5-55
Carriers55-200 (premutation)
Fragile X syndrome>200 repeats

In premutation stage there are no clinical features seen . In females, it is associated with premature ovarian failure 10% of female may have intellectual disability/low IQ. It is more common in males.

  • Clinical features 
    • Long face
    • Large ears
    • Large mandible/Prominent jaw
    • High arched palate
    • Hyperextensible joints
    • Mitral valve prolapse
    • Macroorchidism/large testes: Seen in adolescent age group
    • Intellectual disability (developmental delay, mental retardation)

Mitochondrial disorders

All children of an affected female have the disease . In all cells of body, there is nucleus containing nuclear DNA and mitochondria containing mitochondrial DNA present in cytoplasm.

When sperm penetrates ovum, only head of sperm enters the ovum. Head of sperm contains DNA material from father, Rest entire part of cell is formed from mother.When zygote forms entire ovum goes from mother and only head of sperm comes from father i.e., all mitochondrial DNA material/nuclear material comes from mother in the baby.

Heteroplasmy: Presence of both wild type (Normal) and mutated mitochondrial DNA in same individual 

Threshold effect: The minimum percentage of mitochondrial DNA required for the manifestation of disease


  • Kearns Sayre syndrome
  • Leber’s hereditary optic neuropathy
  • MELAS (Mitochondrial Encephalo-myopathy, Lactic acidosis, Stroke like episodes)
  • MERRF (Myoclonic epilepsy, Ragged red fibre)
  • NARP (Neuropathy, Ataxia, Retinitis pigmentosa)
  • CPEO (Chronic progressive external ophthalmoplegia)
  • Pearson syndrome: Bone marrow involvement, pancytopenia, pancreatic involvement

What is Genomic Imprinting?

It is due to parent specific inactivation of certain genes. Genomic imprinting refers to alteration in DNA without any change in nucleotide sequence. It occurs due to epigenetic phenomenon. Epigenetic changes are Alteration in DNA without any change in nucleotide sequence. There is differential gene expression depending on the parent of origin Epigenetic change usually responsible is methylation of DNA.

Prader Willi syndrome – It is due to paternal gene silencing or imprinting

Angelman syndrome – It is due to maternal copy of the gene silencing or imprinting 


Prader Willi syndrome

Angelman syndrome

  • Paternal copy of gene
    • Deleted or
    • Silenced or
  • Maternal disomy 
    • Two copies of maternal allele have formed, no copy from father
  • Maternal copy of gene
    • Deleted or
    • Silenced or
  • Paternal disomy
    • Both copies from father instead of mother
  • Gene involved – UBE3A gene on Chromosome 15
  • Gene involved – UBE3A gene on Chromosome 15
  • Clinical features
    • Obesity 
    • Short stature
    • Intellectual disability
    • Hypotonia
    • Hypogonadism (delayed puberty)
    • Typical dysmorphism 
      • Almond shaped eyes
      • Tapering fingers/digits
  • Also known as Happy puppet syndrome: Children have happy demeanor 
  • Clinical features: ANGELMAN
    • Ataxia
    • Not intelligent/Intellectual disability
    • GTCS
    • Excessive Laughter (Episodes of laughter similar to gelastic seizures in hypothalamic hamartoma)
    • Maternal gene Not there

What is Gonadal mosaicism? 

It is a condition that occurs due to mutation that happens after zygote formation somatic cells are unaffected but gonadal cells/germ cells are affected. If Somatic cells are unaffected so  Individual remains asymptomatic whereas gonadal cells affected so multiple children can be affected.

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