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Genetics and infertility: a genetic consultation

letto 7772 volte | autore: Sebastiana Pappalardo, biologa (vai al curriculum)


The genetic compromise of reproductive functionality due to the presence of chromosomal abnormalities presents itself clinically with symptoms that vary from sterility to infertility.

Genetic risk factors of the probability of diseases in men are represented by structural and numeric chromosomal aberrations in the autosomes or sexual chromosomes and can result in alterations of reproductive functionality with clinical manifestations that vary according to the type of abnormality, practically disturbing the male and female gametogenesis without necessarily causing phenotypic effect on the individual carrier: they manifest with either sterility or total or partial infertility.  Many cases can clinically manifest with abortivity, sometimes as “serious” as not to allow implantation, and hence the formation of the embryo goes unnoticed.  Pairing errors, that is the coupling of  homologous chromosomes, are more frequent in oocytes than in spermatocytes, but the damage of oogenesis and the reduction of  the number of oocytes is nevertheless compatible with reproduction on the other hand spermatogenesis is futher compromised in that the exact pairing of the homologous zones of the XY pair, seemingly, directly controls  the initial processes of meiosis, with a consequent block in the gametogenesis and consequent arrest in the maturation of the spermatides. Doubts may arise to the gynaecologist who sees a couple with infertility problems, so after he performed all the investigations possible, he may request genetic examination and a genetic consultation in order to evaluate possible abnormalities.

Incidences on genetic abnormalities in infertility

  • in men: 15% (chromosomal + genetic)
  • in women: 10% (chromosomal + genetic)

Incidences of infertility associate with chromosomal abnormalities

  • 6%, 75% of which regards the sex chromosomes and 25% of the autonomous incidences of genetic abnormalities
  • About 9% in men and 4% in women
  • The frequency of chromosomal abnormalities in infertile individuals is five times greater than that found in fertile individuals (22% compared to 4,5%) in which 75% are found in women and 25% in men
  • In infertile men the percentage of chromosomal abnormality is inversely proportionate to the concentration of spermatozoa in the seminal liquid (oligospermia)
  • In infertile women the frequency of chromosomal abnormalities is estimated at about 5%, half of which regards the sex chromosomes and the other half autonomous

What tests should you request?
In 2001 a commission of experts, researchers and Italian clinics styled, the guidelines to genetic diagnoses of the infertile couple.  These guidelines forecast the requests made after analyses made in the presence of specific conditions, and should be followed only after a year of unprotected sexual relations aimed at  conception without results.

Investigations: chromosomal investigations
Types of analyses: karyotype of peripheral blood
Suggestions: in the presence of  azoospermia,  severe oligoazoospermia, idiomatic infertility in men, in the presence of: primitive amenorrhoea, oligomenorrhoea, polycystic ovaries (PCOS), early menopause, ultrasound  query of the reproductive system, poor ovarian response (poor responder), idiomatic infertility

genetic investigation : type of molecular analysis – PCR – of peripheral blood for: clinical situations of azoospermia in men with deferent agenesis, in the woman whose partner is a cystic fibrosis carrier, in men with cryptorchidism, renal agenesis, hypogonadism hypogonadodtropo (HH), in women in the case of primary hypergonadotropic amenorrhoea, hypogonadism hypogonadotropo (HH) in the case of early menopause, oligoamenorrhoea with the progressive increase of the gonadotropines, poor response to ovarian stimulation, in the case of  azoospermia, and serious non obstructive idiopathic oligospermia.  Spermatic concentration <1mil/ml
pathology : cystic fibrosis, Kalmann syndrome – KAL1, fragile X syndrome, micro deletions of the Y
suggestions: hormonal treatment results in fertility in these subjects, this way allowing for the transmission of the defect to the offspring, this abnormality is transmitted to male offspring who inherit the deletion, sometimes spermatic aneuploid is associated with the risk of having children with Turner syndrome

Genetic consultation in infertility  
Consultation is required for :
- potential abnormalities of the chromosomes (cytogenetic)
- potential abnormalities of the genes (molecular genetic)

(1) Chromosomal alteration of the female sexual genes
These alterations interfere with the genetic control of differentiation of the germinal cells

alteration: monosomia
chromosomal picture : 45,X
pathology/prevalence/consequences: Turner syndrome, affects 1:8000 born, in general manifests with absence of ovarian function
alteration: triosomia
chromosomal picture  47,XXX
pathology/prevalence/consequences: triple X syndrome, affects 1:1000 born, does not result in infertility but decreases fertility.

alteration: mosaichism    
chromosomal picture: 45,X/46,XX,45X/47;XXX
pathology/prevalence/consequences: infertility of varying degrees

Structural alterations:

alteration : deletion of the (Xq); and (Xp)
chromosomal picture :
pathology/ prevalence/ consequences

alteration: isochromosome Xq
chromosomal picture:

alteration: auto immune  X translocation
chromosomal picture:
pathology/prevalence/consequences: the integrity of the  X chromosome is indispensable for the normal development of the gonads - hypogonadism

alteration: chromosomal order
chromosomal picture: 46,XY
pathology/prevalence/consequence: Morris syndrome, gonadic disgenesis, hermaphroditism

(2) chromosomal alteration of the male sex chromosomes
These alterations disturb the genetic control of differentiation of the germinal cells

alteration: trisomia 
chromosomal picture: 47,XYY
pathology/prevalence/consequence: double Y syndrome, affects 1:1000 born, hypogonadism, generally fertile

Structural alterations:

alteration: deletion, inversion, auto immune Y translocation , isochromosome
pathology/prevalence/consequences: the severity varies according to the affected zone

(3) structural chromosomal alterations of the autosomes and their incidences

alteration: Robertsonian translocation
%/chromosomal aberrations/consequences : 15% of all chromosomal aberrations cause  foetal monosomia and trisomia

alteration: reciprocal translocation
%/chromosomal aberrations/consequences: 9% of all chromosomal aberrations cause foetal mmonosomia and trisomia

alteration: inversions
%/chromosomal aberrations/consequences: 5%  of all chromosomal aberrations cause pairing defects

alteration: over numbered markers
%/chromosomal aberrations/consequences: 4% of all chromosomal aberrations, pairing defects, meiosis disturbances

The damage they cause is mechanical for the interference of the normal pairing process and disjunction of those corresponding with meiosis with consequent damage of the gametes and lowering of fertility.  Robertsonian translocation constitutes the most important aberration group for their frequency and in their role in both retarded and early abortivity.  Investigations of the karyotype of the couple can show the presence of a balanced structural aberration, which does not show phenotypical  effects, but through the processes of meiosis and fertilisation causes the constitution of an abnormal karyotype in the product of conception.

(A)  Male genetic alteration
Mutations of the single gene

alteration: microdeletion of the Y chromosome
description: deletion of the eucromatic distal part of the distal part of the long arm of the chromosome which maps the DAZ gene (loci AZF a, b, c) for the control of spermatogenesis
consequences/prevalence: azoospermia, 10% prevalence of the micro-deletion in infertile patients

alteration: cystic fibrosis
description: recessive autoimmune disease where the gene is located in chromosome 7 where it maps a gene for the protein CFTR, present in about 500 mutations 
consequences/prevalence : azoospermia, incidences of mutations in the population : 1:2500 affected, 1:25 asymptomatic carrier

alteration: Kalmann Syndrome
description: an X-Linked gene is involved which encodes for the protein Anosmine, which is fundamental for the migration of GnRH neurones and the olfactory nerves to the hypothalamus
consequences/prevalence: affects 1:10000 men

(B) Female genetic alteration

alteration: fragile X syndrome
description: X-Linked syndrome caused by the expansion of the triplet CGG of the FMR1 gene on chromosome Xq27.3. (permutation is caused by the presence of 50-200 repetitions of the triplet CGG)
consequences/prevalence: causes mental retardation in male children, 1:1200 males born

alteration: cystic fibrosis
description: like that in men

alteration: Kalmann syndrome
description: like that in men but a lot less frequent (because it is X-linked)

Medically assisted procreation (MAP) and the risk of transmission of genetic alteration
In the case of artificial insemination there is enough experience to exclude the increase in transmission of abnormalities.  There is however less experience with in vitro fertilisation.  According to studies conducted till now, there is evidence of a significant increase in abnormalities in births from MAP, however the techniques of assisted fertilisation, in particular ICSI can render the transmission of genetic pathologies possible, especially of male origin since they surpass natural selection.  The identification of genetic factors in an infertile couple is therefore more frequently necessary  in order to refine the techniques that make fertilisation possible in a couple who would, naturally, be infertile.

Target cells to investigate

cells: gonadic cells – polar globule
pro: absence of protocol problems
contro: creates notable interpretation problems of the results because : the information that is obtained is only about the female gamete and a lot of it is fake

cells: embryonic cells – blastomere
pro: information on the genetic inheritance of the offspring, easier interpretation, higher number of cells available, a good source of DNA for genetic pathologies
contro: protocol problems

Disclaimer: the information provided on this site is designed to support, not replace, the relationship that exists between a patient/site visitor and his/her existing physician.

giovedì 20 marzo 2008

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