11q22.3

Chromosome 11q22.3, located on the long arm of chromosome 11, contains genes essential for various bodily functions.  Genetic abnormalities here are linked to diverse disorders, including cancers and genetic syndromes.

What is 11q22.3?

To understand the significance of 11q22.3 in genetics and disease, it's essential to understand its basic characteristics, location on the chromosome, and the genes it encompasses. 

Definition and Chromosomal Location

11q22.3 is a specific region located on the long arm (q arm) of chromosome 11, at the 22.3 position.  Chromosomal locations like 11q22.3 are defined based on their unique banding patterns observed under a microscope. 

Each chromosome has a distinct set of light and dark bands, and these bands are numbered to help pinpoint specific regions.  

The 11q22.3 region refers to a precise area within these bands on chromosome 11, which contains genes of interest to genetic researchers and medical professionals.

The Genes Located at 11q22.3 and Their Functions  [1., 3., 4., 5.]

The ATM Gene

The ATM (ataxia-telangiectasia mutated) gene is located within this region, and mutations of this gene are associated with serious health implications.  

The ATM gene, part of the phosphatidylinositol-3 kinase (PI3K) family, encodes a 350 kDa nuclear serine/threonine kinase.  

The ATM protein is activated by chromosomal double-strand breaks from endogenous processes or external DNA-damaging agents like ionizing radiation.  The ATM protein is pivotal in maintaining genomic integrity by:

• Regulating cell-cycle checkpoints at G1/S and G2/M phases
• Activating DNA repair pathways
• Inducing apoptosis if damage is irreparable

Homozygous mutations in ATM lead to ataxia-telangiectasia, a disorder marked by neurological and immunological symptoms, radiosensitivity, and a high predisposition to lymphoid cancers. 

Epidemiological studies suggest a 0.5% to 1% carrier rate for ATM heterozygosity, associated with an increased risk of breast cancer and chronic lymphocytic leukemia (CLL).  

Approximately one-third of CLL patients have a non-functional ATM which results in compromised p53 damage response and impaired apoptosis following ionizing radiation exposure, which are critical factors in predicting treatment response and failure.

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The BIRC3 Gene 

BIRC3, or cellular IAP2, is part of the human inhibitors of apoptosis proteins (IAPs) family, recognized for their baculoviral IAP repeat (BIR) domains which facilitate protein-protein interactions. 

BIRC3 also features domains crucial for various cellular functions, such as the C-terminal ubiquitin-conjugating (UBC), caspase recruitment (CARD), and Ring zinc-finger (RING) domains.

This protein primarily acts as a survival and anti-apoptotic factor in cancer cells. For instance, its genetic inactivation is linked to poorer outcomes and reduced survival in chronic lymphocytic leukemia, as well as resistance to chemoimmunotherapy.  Conversely, BIRC3 expression increases in the progression of low-grade gliomas to high-grade, impacting prognosis significantly. 

The protein's function is intertwined with the non-canonical NF-kB pathway, with its inactivation affecting tumor cells dependent on this pathway for survival. BIRC3's roles in cellular mechanisms and its implications in cancer make it a target for the development of 'Smac mimetics,' a drug family designed to inhibit IAPs and promote apoptosis in cancer therapy.

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

11q22.3 in Health and Disease

11q22.3 Normal Physiological Roles

The genes located in the 11q22.3 region are involved in essential physiological processes. These genes contribute to crucial cellular functions such as cell division, growth, and apoptosis (programmed cell death). 

They play a role in maintaining the balance and stability of cellular activities, which is vital for normal development and functioning of the body. 

Deletion or Mutation of Chromosome arm 11q22-q23 in Disease  [1., 2.] 

Deletion of chromosome arm 11q22-q23, which includes the genes ATM and BIRC3, is commonly observed in chronic lymphocytic leukemia (CLL) and is linked to aggressive disease and reduced overall survival.  

ATM plays a key role in DNA repair and cell cycle regulation, with mutations in approximately 35% of CLL cases featuring 11q deletions.  BIRC3, an apoptosis inhibitor nearby, has a mutation rate of 4% in CLL.

One study included 60 de novo CLL cases with del(11q), identified by chromosome banding and further analyzed using deep sequencing for ATM and BIRC3 mutations, and interphase FISH for deletions. The cohort's mutation status for other relevant genes and survival data were also evaluated.

All patients showed ATM deletions, and 87.2% had BIRC3 deletions. Mutational analysis revealed ATM mutations in 31.7% and BIRC3 mutations in 5% of patients. Additional mutations included TP53 and SF3B1. 

The study found no significant associations between ATM mutations and clinical parameters, but a trend towards shorter survival was noted in patients with ATM mutations compared to those without.

ATM and BIRC3 deletions are prevalent in CLL with del(11q), with significant mutation frequencies, especially for ATM.  The presence of ATM mutations is potentially more impactful on prognosis than BIRC3 mutations, indicating their critical role in the disease's progression.  [2.] 

The study authors note that further research is needed to identify other genetic factors influencing CLL in patients with del(11q).

Mutations in Chromosome 11q22.3 and Ataxia-Telangiectasia  [5.] 

Ataxia-telangiectasia (A-T), also known as Louis-Bar syndrome, is a rare autosomal recessive disorder characterized by progressive neurological decline, skin changes, and immune deficiency.  The key aspects of A-T include:

Genetics: A-T is caused by mutations in the ATM gene located on chromosome 11q22-23, which is crucial for DNA repair, cell cycle control, and response to cellular damage.

Symptoms: features include progressive cerebellar ataxia, cutaneous telangiectasias, high cancer risk, radiosensitivity, immune deficiencies, and elevated alpha-fetoprotein levels.

Incidence: varies widely, with about 1% of the U.S. population carrying ATM gene mutations.

‍Pathophysiology: ATM mutations lead to defective DNA repair, abnormal cell proliferation, and increased malignancy risk. Impaired immune response is due to defective immunoglobulin production and lymphoid cell survival.

Clinical Management: involves multidisciplinary care focusing on symptom management, monitoring for malignancies, and treating recurrent infections.  No cure exists, but supportive treatments like physical therapy and immunoglobulins are used.

Prognosis: prognosis is highly variable; classical forms may only survive into early adulthood, while milder or atypical forms can have a longer life expectancy.

This disorder necessitates a comprehensive approach for diagnosis involving clinical evaluation, neuroimaging, and genetic testing, and emphasizes the importance of an interprofessional team in managing the diverse complications associated with A-T.

Laboratory Testing for 11q22.3

Laboratory testing for 11q22.3 abnormalities plays a crucial role in diagnosing genetic disorders and assessing disease risk.  There are many methods used for laboratory testing of 11q22.3.

Overview of Testing Methods

Genetic testing involves various methodologies to analyze DNA and chromosomes for medical and research purposes. Here are the primary types:

Polymerase Chain Reaction (PCR): this technique amplifies small DNA samples to detect or measure specific genes or regions. It's widely used for identifying genetic variants associated with diseases.

DNA Sequencing:

Sanger Sequencing: once the standard for clinical DNA sequencing, this method involves marking DNA nucleotides with fluorescent dyes to read sequences. It's precise but limited to short DNA sections and one sample at a time.

Next-Generation Sequencing (NGS): this includes whole exome and whole genome sequencing, capable of analyzing millions of DNA fragments simultaneously. It's used for comprehensive genetic screening to identify mutations across all protein-coding regions (exome) or the entire genetic makeup (genome).

Cytogenetics:

Karyotyping: this traditional method examines the number and structure of chromosomes under a microscope, identifying abnormalities like extra chromosomes or translocations that can lead to diseases such as Down syndrome or chronic myelogenous leukemia.

Fluorescence In Situ Hybridization (FISH): FISH uses fluorescent probes to illuminate specific gene segments on chromosomes, useful for identifying gene amplifications or deletions.

Microarrays: this technology assesses DNA for duplications, deletions, or large identical DNA stretches using fluorescently labeled DNA samples hybridized on a chip, providing detailed chromosomal information.

Gene Expression Profiling: this test measures which genes are active in cells, using RNA from a tissue sample to determine gene activity. It's particularly used in cancer to guide treatment decisions based on the genes expressed by a tumor.

Each of these technologies plays a crucial role in diagnosing genetic disorders, guiding treatment decisions, and advancing our understanding of genetic diseases.

Sample Types

Samples typically include blood, saliva, or tissue samples containing DNA.  Sample collection can be as simple as performing a cheek swab or collecting saliva.

Interpretation of Test Results

Interpreting test results for 11q22.3 abnormalities requires expertise and an understanding of genetic principles. A positive result indicating a deletion or duplication in the 11q22.3 region may suggest an increased risk of certain genetic disorders or predisposition to specific health conditions. 

However, the clinical significance of these findings can vary depending on factors such as the size and location of the genetic alteration, as well as the presence of other genetic or environmental factors. 

Genetic counseling is often recommended to help patients and their families understand the implications of test results and make informed decisions regarding healthcare management and treatment options.

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