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Non Classical pattern of Inheritance

  1. Mitochondrial Inheritance:- Certain diseases display an atypical mode of inheritance because they result form mutations in mitochondrial DNA. Mutation of the mitochondrial genome (which are often deletions) can produce specific diseases. Abnormalities in these disorders are typically seen in one or more specific organs, the brain, eye and skeletal muscle. Because mitochondria are inherited exclusively from the mother, these conditions are passed from mother to offsprings, without regard to sex of the latter (thus differing from X-linked recessive inheritance). Sperm head is devoid of mitochondria so disease is not transmitted through paternal route.
    E.g. -        Kearns sayre syndrome
    Leber optic neuropathy
    Myoclonic epilepsy
    Mitochondrial disease affect both male and female but transmission is exclusively by affected female (Exclusive maternal transmission) Q
  2. Triplet repeat mutations:-
    E.g.  Fragile x syndromeQ                    
    Huntington choreaQ
    Myotonic muscular dystrophyQ           
    Friedrich’s ataxiQ  
    Spino-cerebellar ataxia Q

    Anticipation phenomenon: - is a phenomenon in which the severity of genetic condition appear to be more severe and or arise at an earlier age with subsequent generations.

II. Genomic imprinting 


Phenotypic expression depend upon parental origin of mutant gene.


People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or “turned on,” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting.

In genes that undergo genomic imprinting, the parent of origin is often marked, or “stamped,” on the gene during the formation of egg and sperm cells. This stamping process, called methylation


Autosomal recessive inheritance
. Parents carry the gene but do not suffer from disease. The offspring of a normal parent carrier parent have a 50% chance of being carriers (Generation II). When two carriers marry, the disease shows itself with no sex bias with a 25% chance in the next generation (Generation III).


imprinting defects including Beckwith-Wiedemann syndrome, Silver-Russell Syndrome, Angelman Syndrome and Prader-Willi Syndrome.


Prader-Willi syndrome is the first human disorder attributed to genomic imprinting. In such disorders, genes are expressed differentially based on the parent of origin. An imprinting center has been identified within 15q11-13; gene expression may be regulated by DNA methylation at cytosine bases.5 Prader-Willi syndrome results from the loss of imprinted genomic material within the paternal 15q11.2-13 locus. The loss of maternal genomic material at the 15q11.2-13 locus results in Angelman syndrome.6


Uniparental disomy

  1. Normally, we inherit one copy of each chromosome pair from our biological mother, and the other copy of the chromosome pair from our biological father.
  2. Uniparental disomy refers to the situation in which two copies of a chromosome come from the same parent, instead of one copy coming from the mother and one copy coming from the father.
  3. Angelman syndrome and Prader-Willi syndrome are examples of disorders caused by uniparental disomy.

Angelman syndrome (Happy puppet child)

  1. People with Angelman syndrome (AS) have an unusual facial appearance, short stature, severe mental retardation with a lack of speech, stiff arm movements, and a spastic, uncoordinated walk.
  2. They may have seizures and often have inappropriate outbursts of laughter. Angelman syndrome results when a baby inherits both copies of a section of chromosome #15 from the father (rather than one from the mother and one from the father).
  3. That is parental disomy

Prader-Willi syndrome (PWS) [H3O: Hypotonia, hypogonadism, hyperphagia, obesity]

  1. Prader-Willi syndrome (PWS), on the other hand, results when a baby inherits both copies of a section of chromosome #15 from the mother and that is maternal disomy.
  2. Uniparental maternal disomy for chromosome 15 is thought to cause Prader-Willi syndrome because there is absence of needed paternally contributed genes in the critical PWS region (del 15q11-q13).
  3. The paternal contribution is hypothesized to be necessary because the homologous maternally derived genes are inactivated or imprinted (perhaps by methylation).  Between 2 to 4 years of age, the child becomes obsessed with food and is unable to control their appetite.
  4. The overeating often results in rapid weight gain and obesity. Individuals with PWS have short
  5. stature, small hands and feet, and mental retardation. 

Pedigree chart of autosomal dominant trait (vertical pattern)

Sex linked recessive inheritance. Females carry the gene but do not usually suffer from disease. There is a 50% chance of a male child being affected and a 50% chance that female would be a carrier. A history of afflict on in the maternal uncle may be available (oblique inheritance)Q

Sex linked dominant inheritance. Females suffering from the disease pass it on to offspring either sex while males suffering from it can transmit disease only their daughters. 

III. Important Syndromes


A. Down’s Syndrome

Down’s Syndrome or Trisomy or Mangolism


Down syndrome is the most common and best known chromosomal disorder in humans.

Incidence 1 case in 800 Live Births.




  1. Non dysjunction – 95%           
  2. Translocation -4%           
  3. Mosacism – 1%

Nondysjunction thus implies the failure of homologus chromosome to separate during the meiotic division.

In trisomy 21 extra chromosome in > 75% cases of maternal origin and incidence of Down syndrome increases with advancing maternal age.


Maternal age Chances of down syndrome
25yr 1/1200
30yr 1/900
40yr 1/100
45yr 1/25


Translocation are Robertsonian, generally between the long arm of 21 and another acrocentirc chromosomes like 14 or 22.


Recurrence in translocation type of Down syndrome depends upon


- Sex of the parent carrying the translocation


- Involved chromosome in translocation


- Independent of maternal age, frequency is higher in younger mother.


Clinical Features

  • Skull – Brachycephaly, microcephaly, sloping forehead, a flat occiput, large fontanels with late closure,   absent frontal and sphenoid sinuses.
  • Eyes - Upward slanting palpebral fissure, bilatenal epicanthic fold, Brush field spots in Iris, Q refractive errors (50%), strabismus (44%), Nystagmus (20%), Congenital cataract (3%)Q
  • Nose  - Hypoplastic nasal bone and flat nasal bridge. Q
  • Mouth and Teeth - Open Mouth with tendency of tongue protrusion, a fissured and furrowed tongue. crowded small malformed teeth, abnormal pattern of eruption.
  • EAR - The ears are small with over folded helix, low set ear.
  • Neck - Short, broad, increase neck fold thickness, Atlantoaxial instability.
  • Chest  - The internipple distance is decreased
  • Abdomen - Diastasis recti and umbilical hernia
  • Congenital Heart disease - Occur in 40-50% of Down syndrome. Endocardial cushion defect is commonest. Q They are the  most common cause of death in first 2 years of life
  • GI System (12%) - Doudenal atresia or stenosis, Hirschsprung disease, TE fistula, imperforated anus and omphalocele are observed.
    The prevalence rate of celiac disease in Down syndrome is 5-15% 

Genitourinary Tract


Renal malformation, Hypo spadias, micropenis, and cryptorchidism.


Endocrine system

  1. Hypothyroidism (16-20%) of young adultQ
  2. Diabetes and decreased fertility. 

Central Neruous System

  1. Moderate to severe mental retardation occur with an intelligence quotient (IQ) of 20- 85 approximately
  2. 50% Hypotonia improve with age. Articulatory problem are present, Sleep apnea can occur.
    Seizure disorder (5-10%). Infantile spasm are most common seizure observed in infancy where as tonic clonic are most common in older children. 

Hematologic System


The relative risk of leukemia 20-30 times that of individual with out down syndrome.


Approximately 1 in 100 patient develop leukemia

  1. Neonatal lukemoid reaction (pseudo leukemia) are common.
  2. Transient myleoproliferative disorder (TMD) present in Infant with Down syndrome (10%) spontaneous. regress with in first 3 month of life. Q
  3. Leukemia in children with Down syndrome is usually ALL although a higher than normal incidence to AML also reported Acute mega karyoblastic leukemia (AML) FABM7 is strongly associated with down syndrome. 


  1. Short and broad hands                                                  
  2. Clinodactyly of fifth figures.
  3. Single flexion crease (simian crease)                                    
  4. Hyper extensible finger joint.
  5. Increased space between the great toe and second toe (Sandak gap).  
  6. Acquired hip dislocation. 

Dermato glyphics

  1. Distal axial triradius in the palm
  2. Transverse palmar creases.
  3. Ulnar loops 

Pre mature aging  Decreased skin tone, early graying or loss of hair, Hypogonadism, cataract, hearing loss, age related increase in Hypothyroidism, seizure, neoplasm, degenerative vascular diseases, increased risk of senile dementia of Alzheimer type are observed Q


Perinatal Screening

Indication Advanced maternal age ,H/O Child with Down Syndrome, Translocation carrier.


Screening Test

  1. Maternal Serum Marker
    1. AFP (alfa fetoprotein)   Decrease
    2. UE 3 (unconjugated estriol)  Decrease
    3. HCG (Human chorionic gonado trophics)  Increase
    4. PAPP-A ( pregnancy associated plasma protein) Decrease
    5. Inhibin  Increase
    6. Neutrophil Alkaline Phophatase  Increase    
  2. Amnio centesis
    1. Usually carried out between 14-18 wk of pregnancy. 
  3. Chorionic villus Sanpling
    1. Usually carried out between 10th and 12th week of pregnancy.
    2. CVS offers the opportunity for 1st
Trimester diagnosis when elective pregnancy termination carries lowest risk of maternal morbidity. 
  1. USG (11-20 wk)
    Ultra sonographic findings associated with fetal Down syndrome.
    1. Intra uterine growth retardation
    2. Mild cerebral Ventriculomegaly.
    3. Choroid plexus cysts.
    4. Increased nuchal fold thickness
    5. Hypoplastic nasal bone / absent nasal bone. Q
    6. Cystic Hygromas
    7. Echo genic intracardiac foci
    8. Congenital Heart defects
    9. Increased intestinal echogenicity
    10. Doudenal atresia (double bubble sign )
    11. Renal pelvis dilation
    12. Shortened humerus and femurQ
    13. Incurving (clinodactyly) and Hypoplasia of fifth finger
    14. Two vessel umbillical cord. 

Screening first trimester


Maternal serum markers

  1. PAPPA
  2. Beta hCG

Fetal markers


Nuchal fold thickness > 4mm



(Percentage indicate accuracy of prediction)


 Recurrence Risk


- When standard trisomy 21 (due to non dysjunction ) is diagnosed. There is no need to under take karyotyping of the parents Recurrence risk in this setting depends upon the maternal age


Type of Down syndrome


Trisomy 21 (non dysjunction) 
Chance of recurrence


* 1 in 100 if mother < 40


* If mother > 40, twice usual chance for her age.


- Translocation Down syndrome does not depend on the maternal age but it is related to sex of the parent carrying the translocation and involved chromosome in translocation.


If both parents are normal in translocation type of Down syndrome, the risk of Down syndrome in subsequent pregnancy is 2-3%


Type of Translocation Parents carrying the translocation Chance of recurrence
14/21 Mother/Father 10%/2.5%
22/21 Mother/Father 10%/2.5%
21/21 Mother/Father 100%

B. Trisomy 13 (Patau syndrome)

  1. Aplasia cutis congenitaQ
  2. HoloprosencephalyQ
  3. Microphthalmia
  4. Cleft lip/palate
  6. Polycystic kidneys
  7. Polydactyly

C. Trisomy 18 (Edward’s syndrome)

  1. Low birth weight
  2. Microcephaly
  3. Micrognathia
  4. Overlapping of fingersQ
  5. Abnormal dermatoglyphics
  6. Nail hypoplasia
  7. HypertoniaQ
  8. Prominent occiput Q
  9. Rocker bottom feet

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