Pediatirc/ Genetics (3)

X-linked recessive inheritance

Over 400 disorders have been described in which an abnormal recessive gene is carried on the X chromosome

1. males are affected

2. occasionally a female carrier shows mild signs of the disease (manifesting carrier)
3. each son of a female carrier has a 1 in 2 (50%) risk of being affected

4. each daughter of a female carrier has a 1 in 2 (50%) risk of being a carrier

5. daughters of affected males will all be carriers
6. sons of affected males will not be affected, since a man passes a Y chromosome to his son

SUMMARY

1. males are affected; females can be carriers but are usually healthy or have mild disease

2. family history may be negative - new mutations and gonadal mosaicism

3. identifying female carriers is important to be able to provide genetic counselling

X-linked dominant inheritance

in which female carriers typically manifest abnormal findings. An affected man will have only affected daughters and unaffected sons, and half of the offspring of an affected woman will be affected .

Some X-linked dominant conditions are lethal in males. An example is incontinentia pigmenti.

Chromosomal abnormalities

Chromosomal abnormalities are either numerical or structural. They occur in approximately 10% of spermatozoa and 25% of mature oocytes and are a very common cause of early spontaneous miscarriage

The estimated incidence of chromosomal abnormalities in live-born infants is about 1 in 150 and these usually, but not always, cause multiple congenital anomalies and learning difficulties. Acquired chromosomal changes play a significant role in carcinogenesis and tumour progression.

Down's syndrome (trisomy 21)

This is the most common autosomal trisomy and the most common genetic cause of severe learning difficulties. The incidence in live-born infants is about 1 in 650.

Cytogenetics

The extra chromosome 21 may result from non-disjunction, translocation or
mosaicism

Non-disjunction (94%)

most cases result from an error at meiosis
the pair of chromosome 21s fails to separate, so that one gamete has two chromosome 21s and one has none
fertilisation of the gamete with two chromosome 21s gives rise to a zygote with trisomy 21
parental chromosomes do not need to be examined.

Translocation (5%)

When the extra chromosome 21 is joined onto another chromosome (usually chromosome 14, but occasionally chromosome 15, 22 or 21), this is known as an unbalanced Robertsonian translocation. An affected child has 46 chromosomes, but three copies of chromosome 21 material. In this situation, parental chromosomal analysis is essential since one of the parents carries a balanced translocation in 25% of cases. Translocation carriers have 45 chromosomes, one of which consists of the two joined chromosomes

the risk of recurrence is 10-15% if the mother is the translocation carrier and about 2.5% if the father is the carrier
if a parent carries the rare 21:21 translocation, all the offspring will have Down's syndrome
if neither parent carries a translocation (75% of cases), the risk of recurrence is <1%.

Mosaicism (1%)

In mosaicism some of the cells are normal and some have trisomy 21. This usually arises after the formation of the zygote, by non-disjunction at mitosis. The phenotype may be milder in mosaicism.