Academic journal article Genetic Counseling

Complex Chromosomal Rearrangements

Academic journal article Genetic Counseling

Complex Chromosomal Rearrangements

Article excerpt

Summary: Complex chromosomal rearrangements: Complex Chromosomal Rearrangements (CCRs) are constitutional structural rearrangements involving three or more chromosomes or having more than two breakpoints. CCRs preferentially occur during spermatogenesis and are transmitted in families through oogenesis. Recent investigation showed that CCRs are more complex and more common than initially appreciated. Here I present an overview of CCRs, including the important impact of CCRs in fertility, the mechanism of their development, the various meiotic errors that can occur and their consequences. The review also discusses the differential transmission of CCRs in males and females, the incidence of pregnancy outcomes of CCR carriers, genetic counseling and prenatal diagnosis.

Key Words: CCR, Cryptic chromosomal abnormalities, Prenatal diagnosis

INTRODUCTION

Complex Chromosomal Rearrangements (CCRs) are defined as structural chromosomal rearrangements with at least three breakpoints and exchange of genetic material between two or more chromosomes (43). Houge et al. (2003) defined that CCRs are constitutional structural rearrangements involving three or more chromosomes or having more than two breakpoints (25). CCRs includes complex interchromosomal and intrachromosomal rearrangements and can be very complicated, highlighted by reports of rearrangements involving up to 15 breakpoints (25). They may involve distal segments causing reciprocal translocations, interstitial segments causing insertions, inversions, deletions, duplications, or both distal and interstitial segments. CCRs can be familial or de novo, balanced or unbalanced and may be associated with a normal or an abnormal phenotype. If a chromosomal rearrangement is detected in a phenotypically normal individual this rearrangement is generally assumed to be truly balanced. These often represent familial cases. If however a chromosomal rearrangement is detected in a phenotypical abnormal individual then usually a submicroscopic imbalance or other genetic defect exist. These often represent de novo cases.

In the last few years, several groups have been investigating CCRs by taking advantage of recent advances in FISH and molecular methodologies (3, 22, 33, 34, 44, 48, 54, 57). These studies indicated that CCRs are more complex than initially appreciated. The study of CCRs becomes increasingly important for understanding the mechanism of their origin as well as the consequences of meiotic errors in prenatal diagnosis, spontaneous abortions and infertility.

This review address various important aspects of CCRs, such as (i) the complexity and behaviour of familial and de novo CCRs, (ii) their differential transmission and the excess of balanced CCR carriers in females than males, (iii) the meiotic segregation consequences and prediction of the outcomes of any CCR carriers, (iv) the effect of CCRs upon fertility, (v) the mechanism underlying the origin of CCRs and the unexpected level of complexity of CCR, (vi) the review aims to provide information on the incidence of various pregnancy outcomes in CCR carriers, (vii) the suggested genetic investigation and evaluation of pregnancy outcomes, and (viii) the estimated risk for malformations that are extremely important for genetic counseling and prenatal diagnosis.

CATEGORIZATION OF CCRS

During the last 25 years, scientists investigating CCRs have categorized them using a variety of criteria.

CATEGORIZATION BY THE WAY OF TRANSMISSION

Kleczkowska et al. (30) categorized CCRs by the method of transmission. The authors reviewed 38 cases and divided CCRs in familial and de novo rearrangements. Based on their transmission, the authors observed the following: 1 ) A high prevalence of maternal origin in familial CCRs. 2) A high occurrence of mental retardation in de novo CCRs. 3) A high reproductive failure in patients with CCRs. 4) No significant differences in the localization of the breakpoints between familial and de novo CCRs. …

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