Uniparental Disomy

In normal individuals, the chromosomes get inherited from both the parents. However, in certain conditions, both the chromosomes get inherited from a single parent. The other parent fails in contributing the chromosome to the zygote. This condition is known as uniparental disomy. It results in an abnormal phenotype. The chromosomes inherited through uniparental inheritance include maternally derived or paternally derived chromosomes. The disorders associated with the uniparental disomy get detected through the uniparental disomy studies. The basic subtypes of uniparental disomy include isodisomy and heterodisomy. Many mechanisms lead to uniparental disomy.  They include trisomic rescue, gamete complementation, chromosomal translocations, and others. Nondisjunction gives rise to a condition known as monosomy, leading to the formation of a diploid cell line. Sometimes, centromere misdivision also leads to an Isochromosome (a chromosome with identical long arms). These conditions include uniparental disomy. Non-disjunction in meiosis-II also creates isodisomy. Sometimes, only a portion of a genomic region gets affected. It also results in the birth of a child with no disabilities. But, it certainly affects the growth of the child and the placental health.

Most of the cases do not involve phenotypic anomalies. However, genotypic changes due to the events favoring uniparental disomy (in Meiosis-II) result in the manifestation of rare recessive disorders. The phenotypic consequences could be of two types. The first one includes the presence of duplicated autosomal recessive alleles. We know that the autosomal recessive disorder mostly manifests due to the presence of two copies of mutant alleles. For example, cystic fibrosis is an example of autosomal recessive disorder with the presence of two mutant alleles. It is an example of maternal uniparental disomy-7. The offspring receives two copies of the seventh chromosome of the mother. Thus, it follows maternal uniparental disomy. Another important contributor includes genomic imprinting. It is a kind of modification to the genomic expression. The differential modification mainly arises due to the uniparental chromosome contribution. The other parent would not contribute anything to a particular chromosome pair. It involves a reversible phenomenon. Thus, the imprint gets established during the gamete formation. The imprint gets maintained throughout the embryogenesis. Next, the imprint gets erased in the germline. Imprinting is an example of the epigenetic phenomenon, and also requires chromatin modification to some extent. An example includes X-chromosome inactivation.

                        Image: Uniparental diagnosis (Pedigree analysis and electrophoresis)

Prader-Willi syndrome and Angelman’s syndrome:

Inheritance of the 15^th chromosome pair only from the father results in a condition known as Angelman’s syndrome. Mother cells do not contribute the 15^th pair of the chromosome to the baby. The Prader-Willi syndrome arises due to the inheritance of the 15^th chromosome pair from the mother. In some cases, the offspring inherits the genes normally. However, the genes inherited from any one of the parents remain silent or unexpressed. For example, in Prader-Willi syndrome, only the paternal copies of genes get expressed.

Detection of uniparental disomy:

DNA polymorphism studies majorly help in detecting the uniparental disomy. They include single nucleotide polymorphism so (SNPs), variable numbers of short sequence repeats (SSRs), a variable number of longer repeats (VNTRs), and retrotransposons. The detection of single nucleotide polymorphism and includes allelic frequencies and heterozygote frequencies. The SSRs are also known as microsatellites. They exist in more than two alleles per locus. VNTRs exhibit very high polymorphisms. It involves many alleles. Retrotransposons show diallelic systems. Examples include Alu elements and LINES.

Consider a case in which the father shows heterozygosity for two alleles say “L” and “M” respectively. The mother possesses different alleles to say “Q” and “P” respectively. However, the offspring inherited the “L” and “M” alleles. Thus, the offspring inherited both the alleles only from the father. Hence, it is an example of uniparental disomy.

Trisomic rescue:

Trisomic rescue leads to the loss of a chromosome from an initial trisomy. Initially, the fertilized ovum consists of 47 chromosomes. However, later on, during the process of cell division, the cell loses one chromosome. Thus, the trisomic state gets converted into a disomic state. However, it carries errors. Two types of errors based on the phases of the cell cycle include the meiotic and mitotic errors. The meiotic error leads to the trisomic state. The mitotic error leads to the removal of the extra chromosome. The extra chromosome gets removed through nondisjunction or anaphase lag. If the removal of the extra chromosome occurs due to nondisjunction, the consequence proves to be lethal. It results in the disomic or the tetrasomic condition. However, if the extra chromosome gets removed due to the anaphase lag, it results in a trisomic or a disomic state. But, the disomic state often accompanies mosaicism. Incidences of uniparental disomy due to trisomic rescue include 4%.

Gamete complementation:

It occurs due to cytogenetic errors. Mainly, the errors occur during meiosis. Gamete complementation occurs due to nullisomy and disomy. Coincidently, they correct each other during the fertilization and look like the normal ones. Gamete complementation studies involved experiments on mice.

Chromosomal translocation:

A segment of chromosome gets shifted to some other place. It could be either another chromosome or the same chromosome. Translocations also lead to uniparental disomy. Translocations leading to uniparental disomy mostly occur in the acrocentric chromosome. Robertsonion type of translocations mainly leads to uniparental disomy.

They include the familial type of Robertsonion translocations. First, the paternal and the maternal gametes fuse and give rise to a zygote having trisomy. Later on, it undergoes trisomic rescue and loses one extra chromosome. Thus, it leads to uniparental disomy. Other types of mechanisms leading to uniparental disomy include monosomic rescue, somatic recombination, and tumors.

References:

[1] Genomic Imprinting and Uniparental Disomy in Medicine, Eric Engel, Stylianos E. Antonarakis.

[2] Uniparental Disomy (UPD) in Clinical Genetics: A Guide for Clinicians and Patients, By Thomas Liehr.

[3] The Principles of Clinical Cytogenetics, edited by Steven L. Gersen, Martha B. Keagle.

[4] Emery's Elements of Medical Genetics E-Book: With Student Consult Online Access, by Peter D Turnpenny, Sian Ellard.

[5] Medical Genetics E-Book: With Student Consult Online Access, Lynn B. Jorde, John C. Carey, Michael J. Bamshad.

[6] Thompson & Thompson Genetics in Medicine E-Book: With Student Consult Online, by Robert L. Nussbaum, Roderick R. McInnes, Huntington F Willard.

Copyright, 2019, Study Genetics Online. All Rights Reserved.

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

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