SELECTED STUDIES

Section Editor: Prof. Talaat I. Farag

Observations on Microdeletion Syndromes In Kuwait

Athari G. Al-Otaibi, Kamal K. Naguib, Sawsan J. Abulhasan,
Sadika A. Al-Awadi, Laila A. Bastaki, Makia J. Marafi

Introduction

Microdeletion syndrome is caused by a chromosomal deletion spanning several (contiguous) genes that is too small to be detected under the microscope using conventional cytogenetic methods. Depending on the size of the deletion, other techniques, such as FISH or other methods of DNA analysis can sometimes be employed to identify the deletion.

Objectives

Herein, we are reporting the experience of Kuwait Medical Genetics Centre (KMGC), FISH lab on microdeletion syndromes during a 12-year period from 1995 to 2007.

Material and Methods

The present study includes all cases referred to KMGC as Microdeletion syndromes during the 12-years period. All cases were investigated clinically, biochemically, cytogenically, and using FISH technique. The following results were obtained.

Results

• Of the 1627 cases referred to FISH lab, 705 (43.3%) cases were found to have microdeletion syndromes.

• Kuwaiti patients constituted 60% ,while non Kuwaiti constituted 27 % .

Only 21 % were found to have positive microdeletion , while 71 % had negative result . The distribution of the positive cases was as follows :

Positive cases

• Williams syndrome 31 %

• CATCH 22 21%

• Prader willi /Angelman 20%

• Retinoblastoma 0 %

• Liscencepaly 0 %

• Congenital heart 11 %

• Others 23 %

Discussion

• Prior to the 1960’s, only whole chromosomal aneuploidy was recognized as an aetiology for genetic syndromes. Microdeletions which are a major cause of mental retardation and human malformations, are not usually visible by routine chromosomal analysis. Preliminary data from microarray based (array-CGH) comparative genomic hybridization studies suggest that microduplications may also be important.

Many of children with known microdeletion syndromes, e.g. Williams syndrome, Velocardio facial syndrome, share a similar spectrum of abnormalities, e.g. Dysmorphic facial features, growth and developmental delay, and characteristic behaviour. Even though the differences between patients are enough to distinguish the conditions by clinical evaluation, there is a pattern emerges of features that are suggestive of a chromosomal disorder known as the 'chromosomal phenotype'.

Microdeletion syndromes are now recognized as a common aetiology for multiple syndromes. The mechanism underlying the deletion is thought to be unequal meiotic recombination, probably mediated by the highly homologous DNA sequences that flank the commonly deleted region. These homologous regions are known as low copy repeats or LCRs.

In the present study , more than one third of the cases (43.3 % ) referred to FISH lab as microdeletion syndromes. This high frequency does not reflect the actual magnitude of the problem, especially if we look to the percentage of the negative result.

The percentage of the negative result ranged from 70 % to100 % in some cases. This could be explained as clinical mis-evaluations of the different microdeletion syndromes. Accordingly ,we recommend to follow a minimum clinical criteria protocol for referring any patient suspected to have microdeletion syndrome. Microdeletion syndromes are few, although they are appear to be increasing.

Williams syndrome

The most frequent microdeletion detected is Williams syndrome (78 % ). The estimated incidence found was: 1 in 20,000 live births .

Located in chromosome 7q11.23.

FISH (72hr) culture showing Deletion 7q11.23 using (LSI Williams Elastin gene) probe.

46,XX Female with 7q11.23 deletion Karyotype

CATCH 22

• CATCH 22 is frequently diagnosed in Kuwait (35.7%) especially after following our protocol of screening any case with specific congenital heart .

Located in chromosome 22q11.2.

FISH (72hr) culture showing Deletion 22q11.2 using (LSI Digeorge) probe

46,XX Female with 22q11.2 deletion Karyotype

Discussion

Correlations between chromosomal rearrangements and clinical manifestations, or genotype/ phenotype correlations, can provide essential information for the discovery of the causes of developmental effects • However, progress towards the identification of these developmental genes has been slow.

The first step in the search for genotype/phenotype correlation is identifying the deletion size also called “the typically deleted region” (TDR) of the syndrome. It was found that each microdeletion syndrome has same-sized deletions in the majority of the patients. It was then suggested that there might be sequences at the breakpoints that are particularly prone to rearrangements.

The second step in identifying genes in these microdeletions syndromes is to compare deletions sizes from different patients with the same microdeletion syndrome in order to establish the shortest region of deletion overlap (SRDO). Although more tractable than the larger size of the typical deleted region, these SRDO’s commonly encompass multiple genes and identifying the disease genes is still a surprisingly difficult task. A third common strategy to identify the essential genes that are involved in a particular syndrome, is traditional positional-cloning in patients with unusual deletions or rare translocations.

Conclusion

Detailed description of the physical and behavioural phenotype of microdeletion syndromes, genotype/phenotype correlation and clinical and molecular examination of patients with rare translocations or deletions enable identification of developmental genes.

Further studies of the duplications flanking these microdeletions will provide more insight in the mechanism of their formation, and their possible effect on the genes within the microdeletion. The study of animal models has become a powerful tool to explore further the molecular and etiological basis of these microdeletion disorders.

Engineering small deletions and duplications can be used to find the gene responsible for a haplo-insufficient phenotype and to give insight into the embryological base of the disorder.

The results of these investigations are going to have a major impact on human genetics.

Athari G. Al-Otaibi, BSc (Kuwait). She joined the Kuwait Medical Genetics Centre in June 2004, and is now working as a Laboratory medical practitioner in the cytogenetics FISH lab. She attended the first and second Kuwait International Genetics Conferences in 2006 and 2008. Her email is: athari.79@hotmail.com.