A Review on Microdeletion Syndromes

Microdeletions involve sub-microscopic or minute loss of the genetic material. Microdeletions either arise spontaneously during pregnancy or get inherited. A microdeletion syndrome or a contiguous gene syndrome arises due to chromosomal deletions spanning several genes. The genes are too small to be detected under a microscope. Autosomal microdeletions involve microdeletions in the autosomes or non-sex chromosomes. Microdeletions also affect the sex chromosomal genes. Microdeletions range from deletion of a small region in a gene or several genes. Microdeletions in Y chromosome lead to missed genes. The condition is known as YCM or Y chromosome microdeletion. Although men with YCM do not exhibit symptoms, their fertility gets reduced with low sperm count. Specified partial deletions known as AzFc-gr/gr deletions cause infertility. Microdeletions known as X chromosome microdeletion affect both males and females.

The term haploinsufficiency describes microdeletion. In simple terms, haploinsufficiency means insufficiency of a single copy of a normal gene for producing protein, thereby affecting the function. Two situations arise in the case of haploinsufficiency. An individual, heterozygous for the gene mutation gets affected with deletion or microdeletion for a gene segment, a gene or a corresponding allele. Other situation arises when the individual is hemizygous for a particular locus. Deletion syndromes arise due to copy number losses. Submicroscopic differences (losses) in few sections of the DNA result into copy number variations. Microdeletions involve two types such as a terminal or interstitial deletions. Independent of a location of a gene, microdeletions occur anywhere such as Centromeric regions, telomeric regions or any other regions of the chromosomes. The deletions in the interstitial regions involve the regions between the centromere and the site of rearrangement. The microdeletions involving the chromosomal ends are known as terminal microdeletions. The inheritance of microdeletion syndromes follows autosomal or sex-linked inheritance. Few references site novel cases of telomeric microdeletions.

Two main classes of copy number variants (CNVs) include recurrent and non-recurrent copy number variants. Non-allelic homologous recombination (NAHR) gives way to recurrent copy number variants with breakpoints in the large duplicated sequences. Breakpoints in the unique sequences mark the non-recurrent CNVs.

Following examples include microdeletion syndromes:

1.     Prader-Willi syndrome:

This genetic disorder affects the muscles and the feeding abilities of children. It leads to obesity and diabetes accompanying intellectual impairment. It arises due to a loss of function mutation. A part of the 15^th chromosome of the father gets deleted leading to loss of the gene function. Hence, the genetic changes occur due to microdeletions. Prader-Willi syndrome involves a phenomenon known as genomic imprinting. The expression of genes involves a parent of origin-specific manner. Genes are known as snRNPs and necdin genes accompanying a few snoRNA genes get deleted. A part of the q arm of the 15^th chromosome consists of the above genes. Prader-Willi syndrome also includes cases with snoRNA-HBII-52 microdeletions.

Image 1: Gene mutations in Prader Willi syndrome

2.     Angelman’s syndrome

Nervous system impairment arises due to gene defects in Angelman’s syndrome. New mutations arise due to microdeletions. The patient’s mother exhibits a microdeletion on the 15^th chromosome. The patients or the proband inherit a mutated UBE3A gene on the 15^th chromosome. Angelman’s syndrome accompanies an inheritance of a loss of function mutation from the mother. However, very rare cases involve inheritance from the father.

Image 2: Gene mutations in Angelman's syndrome

3.     Wilm’s tumor:

11^th chromosome microdeletions increase the risk of Wilm’s tumor. The malignant tumor mainly affects the kidneys. Wilm’s syndrome involves alterations in the WT1 gene. Wilm’s tumor includes a group of disorders known as Wilm’s tumor Aniridia- Genitourinary malformations (WAGR). It involves intellectual disability and anxiety related problems.

4.     William’s syndrome:

It arises due to a microdeletion in the 7^th chromosome. The genes such as CLIP2, GTF 21, GTF21RD1, LIMK1, and other genes help in the detection. Individuals show affected neurological and behavioral characteristics. The children with William’s syndrome require interaction, counseling, and motivation. The condition arises either sporadically or due to inheritance.

5.     Langer-Giedion syndrome:

This syndrome is a rare autosomal dominant one. It involves a microdeletion in chromosome 8. The missed regions include TRPS1 and EXT1 genes. It occurs sporadically. However, father to son and mother to daughter transmission is possible. These individuals exhibit physical and dental anomalies.

6.     Miller-Dieker syndrome:

Microdeletions involve small arm of the 17^th chromosome and accompany congenital malformations. Miller-Dieker syndrome follows an autosomal dominant inheritance. Microdeletions in the 17^th chromosome result into loss of multiple genes. The parent of the proband shows balanced translocations. These translocated genes become unbalanced while getting passed on from generation to generation. Hence, it results in either a loss of genes or gain of the extra material. Miller-Dieker syndrome is a contiguous gene syndrome. Submicroscopic deletion includes LIS 1 gene.

7.     Di-George syndrome:

It involves a deletion in a small segment of the 22^nd chromosome. Prevalence of the microdeletion involves the middle region of the 22^nd chromosome. Di-George syndrome is an autosomal dominant inheritance. The syndrome involves heterozygous microdeletions and TBX1 gene haploinsufficiency.

8.     Smith-Magenis Syndrome:

This type of microdeletion leads to a deletion in the short arm of the 15^th chromosome. Mainly the RAI1 gene of the 17^th chromosome gets affected. The patients with the condition show abnormalities in the jaw, eyes, nasal bridge and the teeth. Such an individual has a short stature and hearing problems.

9.     Rubinstein Taybi syndrome:

It involves physical and facial deformities such as short stature, broad thumbs, and toes. These individuals show susceptibility to cancer. The condition is an autosomal dominant one. A microdeletion in the 16^th chromosome involves CREBBP gene deletion. The gene CREBBP encodes for CREB binding protein that regulates the cell cycle and development.

10. Neurofibromatosis:

Two types of neurofibromatosis involve NF-1 and NF-2 respectively. NF-1 or Neurofibromatosis type 1 involves a mutation in a gene present on the 17^th chromosome. The gene encodes a protein known as neurofibromin, needed for normal functioning of human cell types. NF-1 is an autosomal dominant disorder. Neurofibromatosis type 2 is a genetic disorder involving NF-2 gene mutation on the 22^nd chromosome. It is also an autosomal dominant disorder.

11.Wolf-Hirschhorn syndrome:

It involves a partial deletion in the short arm of chromosome 4. Most of the cases exhibit de novo deletions. These patients exhibit craniofacial anomalies and intellectual disability.

12.Cri-du-chat syndrome:

It results in deletion in the short arm of the 5^th chromosome. The syndrome also arises due to microdeletions. Individuals with this condition have a high pitched voice resembling that of a cat.

Microdeletions in the mitochondrial DNA:

Few cases of infertility in males involved microdeletions in the mitochondrial DNA in the spermatozoa. In girls, a microdeletion in the cytochrome c oxidase (COX) subunit II in the mitochondrial DNA passes on exclusively from the mother, since the mtDNA inheritance follows maternal inheritance.

Detection of the microdeletion syndromes:

Various new methods help to detect microdeletions. Detection plays an important role in therapeutics. Following examples include detection tests:

1.     Prenatal diagnosis:

The invasive ways of the prenatal diagnosis involve a collection of fetal cells through amniocentesis or chorionic villus sampling. However, with the advancement in technology, the development of non-invasive techniques came into existence. There is an expansion in the global market for non-invasive prenatal techniques. NIPT or non-invasive prenatal testing helps in detecting aneuploidies, microdeletions and many other conditions. NIPT uses ultrasonography and serum screening. Unlike amniocentesis and chorionic villus sampling, NIPT uses cell-free DNA floating in the maternal plasma. These tests involve cell-free fetal DNA (cfDNA) screening along with different algorithms. The cfDNA test easily detects microdeletions.

2.     Next-generation sequencing and array CGH:

Screening of microdeletions also involves microarray and NGS technologies. These techniques detect small deletions. More and more advances are happening in the whole genome sequencing and exome sequencing techniques. Microarrays measure gain or loss of genes or portion of the genes throughout the genome. It involves detection of the copy number variants and single nucleotide polymorphisms. The whole genome sequencing analyses the entire genome including the introns, exons and other sequences. Exome sequencing involves the study of only the exons since introns are non-coding sequences.

3.     FISH:

The FISH technique involves detection of microdeletions and deletions less than five megabases. The technique identifies specific chromosomes, regions, genes and gene segments through hybridization. The fluorescently labeled probes attach to specific regions or DNA segments. The examination of the sample slides under a fluorescent microscope reveals striking results. The fluorescent lighting detects the presence of hybridized DNA through a fluorescent signal. The flashing of the fluorescent signal indicates the presence of the chromosomal material under study. No fluorescent signal indicates the absence of the material under study. The FISH technique detects microdeletions in the chromosomes, interphase nuclei, and the sperms. Metaphase FISH involves analyzing the chromosomes in the metaphase.

4.     Multiplex ligation-dependent probe amplification (MLPA):

This technique spans 50 different DNA sequences in one go. Thus, it is very helpful in detecting the copy number variations, microdeletions, microduplications, and sub-telomeric deletions and duplications. It also uses the PCR technique. MLPA is a variation of multiplex-PCR and allows amplification of multiple targets with only a primer pair.

References:
[1] Medical Genetics, Ian D Young
[2] Clinical Cytogenetics, An Issue of Clinics in Laboratory Medicine, Caroline Astbury
[3] Management of Genetic Syndromes, Suzanne B. Cassidy, Judith E. Allanson
[4] Molecular Cytogenetics: Protocols and Applications, Yao-Shan Fan

© Copyright, 2018 All Rights Reserved.

Dominance relationships

 A single allele becomes totally dominant over the other allele in the case of complete dominance. The phenotype of the heterozygote appears similar to the phenotype of the homozygous dominant. On the other hand, complete recessiveness requires two recessive alleles, meaning the recessive allele gets expressed only in the homozygotes. Hence, these two extremities get classified under a range of dominance relationships. Main topics covered under the dominance relationships include complete dominance, incomplete dominance, codominance, and the molecular explanations related to the same.

Complete dominance:

One allele has a powerful effect of masking the activity of the other allele. It is known as complete dominance. One allele dominates the other allele thereby masking its expression. The allele getting masked is known as a recessive allele. Hence, the phenotype of the heterozygote shows similarity with the phenotype of the dominant homozygote. Let us consider the example of complete dominance. Seed shape in peas helps in determining the dominant alleles present in the pea plant. Round peas have R allele, the dominant one. The wrinkled peas have r allele, the recessive one. Hence, the combination of alleles includes RR (having round peas), rr (wrinkled peas), and Rr (Round peas).

Incomplete dominance:

Incomplete dominance, also known as partial dominance, occurs when one allele lacks complete dominance over the other allele. It usually becomes partially dominant. Since there is an incomplete dominance, the heterozygote expresses a phenotype intermediate to that of the homozygotes having either of the alleles. Let us consider an example of incomplete dominance in chickens. The plumage or feather colors of the chickens vary. It is due to incomplete dominance. Consider a cross between the true breeding black strain and a true breeding white strain. The true breeding black strain is a homozygote and consists of C^BC^B alleles. The true breeding white strain is also a homozygote showing C^WC^W alleles. A cross between both of them gives rise to an F1 generation of birds having bluish-grey plumage. They are also known as Andalusian blues. They show a genotype of C^BC^W. The letter C symbolizes the color of the plumage and the letters W and B symbolize white and black colors respectively. Consider another cross between Andalusians. In this case, both the Andalusian blues have C^BC^W genotype. The F2 generation now shows 1:2:1 phenotypic ratio. The progeny involves one black, one white, and two Andalusian blue fowls.

Let us consider one more example of incomplete dominance. The Palomino horse has a golden yellowish brown body color with a white mane and a tale. Interbreeding of the Palominos gives rise to the progeny with a phenotypic ratio of 1:2:1. The F2 generation consists of two palominos, one cremellos, and one light chestnut.

Image: Incomplete dominance

Codominance:

The phenotype of the heterozygote resembles that of both the homozygotes in codominance. Codominance and Incomplete dominance are related to one another. Codominance is a form of modified dominance relationship. Example of codominance involves ABO blood groups. A glycoprotein known as the H antigen occurs on the surfaces of the blood cells. Three main alleles control the chemical modification of the glycoprotein. Two out of three alleles are codominant. They are known as IA and IB respectively. These alleles are dominant over the recessive “i” allele. Both IA and IB code for different enzymes. The one coded by IA adds an N-acetylgalactosamine to the H antigen. The one encoded by IB adds galactose. The recessive i allele does not modify anything.

In the ABO system of blood groups, there are four main phenotypes such as O, A, B, and AB. Individuals with A blood group express antigen A. Individuals with B blood groups express B antigen. Individuals with AB blood group express both the antigens. The individuals with O blood groups express none of the antigens. Out of the four types, the AB blood group individuals produce A and B antigens. Hence, it is an example of codominance.  Another example of codominance involves MN blood group system. Let us consider another example of codominance. Sickle cell anemia is a type of hemoglobinopathy. Three molecular types of hemoglobin include HbA/HbA, HbA/HbS, and HbS/HbS.

Molecular explanation

Both the homozygote phenotype so gets expressed in a heterozygote since it has both the alleles. It is a general explanation of codominance. However, incomplete dominance results in the expression of only one allele out of the two in a heterozygote. Hence, a homozygote consists of two doses of the gene product. Here we talk about haplosufficiency. Heterozygote showing normal dominance requires only half of the homozygous allele for expression of the phenotype. Dominance occurs due to the presence of a non-functional allele. Meaning, one allele loses its functions such as expressing a protein product or skips the process of transcription. It also occurs due to mutation altering the DNA sequence. Hence, the organism having a non-functional allele will show a particular phenotype. Example, albinism is an autosomal recessive disorder occurring due to the inefficient synthesis of the pigment melanin in the skin and the hair. Hence, such individuals show whitish-pink skin coloration. Let us consider the interaction between the alleles that make an allele recessive. The single allele produces a product or a phenotype identical to that of the homozygote (haplosufficiency). Hence, the functional allele becomes dominant to the non-functional one. In the case of an albino gene locus, the heterozygous individuals produce sufficient melanin in the skin. Hence, they exhibit normal pigmentation in the skin.

Consider another interaction involving haploinsufficiency. The phenotype expressed by the functional allele involves less severity when compared with that of a non-functional homozygote. Rarely may it also produce an insufficient gene product as compared to that of a non-functional homozygote. Sometimes, the non-functional allele may also produce defective protein products interfering with the normal protein functioning.

Dominant negative mutations mostly arise in the somatic cells. These mutations are harmful to the body. They provide scope for the mutant cells to proliferate and expand. Most of the dominant negative mutations a cancer cell or a mutant cell resistant to the natural cell death process known as apoptosis. Hence, the damaged DNA in these cells does not get repaired. Example, dominant negative mutations occur in the tumor suppressor gene such as p53. The p53 mutations occur in different types of cancer cells such as cells present in the breast, prostate, and the brain.

References:
[1] Principles Of Genetics 7/E, By Tamarin
[2]  Essential Genetics: A Genomics Perspective, Hartl, Elizabeth W. Jones

 © Copyright, 2018 All Rights Reserved.