1q25

Chromosomes, intricate structures within the nuclei of our cells, contain the blueprint of life—DNA.  Each chromosome carries genes that encode instructions for building and maintaining our bodies, influencing everything from eye color to enzyme production. 

Chromosome testing helps unravel the complexities of genetic information, enabling clinicians and researchers to diagnose and understand a wide range of genetic conditions. 

As the carriers of genetic material, chromosomes play a pivotal role in heredity and disease susceptibility. The proper function of genes—units of heredity composed of DNA—ensures normal development and bodily functions. 

However, mutations occurring by alteration, deletion, or duplication of DNA segments have consequences ranging from benign to life-threatening. 

1q25 is a genomic locus harboring genes pivotal in various cellular functions, so understanding its molecular intricacies offers insights into disease mechanisms and progression.

What is 1q25?

1q25 Genomic Location and Significance

1q25, residing on the long arm of chromosome 1, is a genomic region comprising a cluster of genes that regulate essential cellular functions such as cell cycle progression, DNA repair, and apoptosis, as well as response to environmental stimuli.  [4.]

The significance of 1q25 lies not only in its involvement in normal cellular physiology but also in its implication in disease development and progression. Mutations, amplifications, or deletions within this region have been linked to a wide spectrum of disorders, including cancer, neurodegenerative diseases, and developmental abnormalities.

The genes located on chromosome segment 1q25 play crucial roles in various biological processes, including brain development, and are implicated in disease progression when altered.  [5.] 

1q23-25 Deletion Syndrome  [1.]

1q23-25 deletion syndrome is characterized by a complex set of malformations due to deletions within chromosome regions 1q23.3 to 1q25, affecting various genes critical for normal development. 

This syndrome presents with a spectrum of phenotypic abnormalities including intellectual disability, growth retardation, and distinctive craniofacial features.  The syndrome's complexity is further compounded by the involvement of multiple non-overlapping critical regions within the 1q23.3-q25 segment, each associated with different malformations. 

The deletion's variable expressivity and incomplete penetrance pose challenges in phenotype-genotype correlation, which researchers address using advanced mathematical models to associate specific traits with the loss of particular genes or regulatory elements. 

Key genes identified specifically within 1q25 include LHX4, associated with slowed and altered growth.   

Other genes on 1q25 have also been implicated in developmental abnormalities, including ASTN1.  [5.]

Despite the progress in mapping these deletions, the syndrome's genetic basis remains complex, influenced by the synergistic effects of multiple genes and the regulatory landscape within the deleted segments.

1q24q25 Deletion  [2.]

The 1q24q25 microdeletion syndrome is characterized by a distinct set of clinical features that make it a recognizable genetic disorder. Here are the key features and implications:

Prenatal Onset of Symptoms: individuals with this syndrome typically show signs prenatally, including growth deficiency and microcephaly, which continue postnatally.

Distinctive Physical Characteristics: affected individuals often have small hands and feet with brachydactyly, distinct facial features such as a short nose with a bulbous tip, small ears, and a tented upper lip, and other dysmorphic traits.

Severe Cognitive Impairments: there is a pronounced cognitive disability, often accompanied by significant developmental delays and speech impairments.

Skeletal Abnormalities: radiographs may show disharmonic bone maturation, markedly delayed bone age, and other skeletal anomalies.

Occasional Additional Features: some may exhibit cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures.

Genetic Background: the critical region for this deletion has been mapped to a 1.9 Mb segment on 1q24.3q25.1, which includes 13 genes. Among these, CENPL is crucial for kinetochore and mitotic functions, and its loss is linked to the growth deficiencies observed, similar to other forms of primordial dwarfism.

This syndrome shows a significant overlap with other conditions involving prenatal growth restriction and microcephaly, indicating a severe impact on development from the earliest stages.

Candidate Genes Located Within 1q25 and their Functions

ASTN1 (Astrotactin 1)  [3., 5.]

This gene is essential for glial-guided migration in the brain cortex and is linked to a range of cortical malformations such as lissencephaly and pachygyria. Deletions or mutations in ASTN1 can lead to significant neurological deficits.  

LHX4  [3., 6.]

The LHX4 gene is crucial for pituitary gland development and function.  LHX4 plays a significant role in early developmental stages: mutations in LHX4 have been linked to combined pituitary hormone deficiency (CPHD), characterized by varying deficiencies in hormones such as GH, TSH, and ACTH. 

These mutations can lead to severe developmental and functional abnormalities in the pituitary gland, including hypoplasia of the anterior pituitary and malformations such as a small sella turcica and chiari malformation. 

Furthermore, specific mutations impair the gene's ability to bind DNA and activate critical downstream genes, affecting pituitary hormone production. 

Despite the significant clinical impact of LHX4 mutations, the expression of symptoms can vary considerably, even among family members with the same mutation.

CENPL  [2., 3.]

Suggested to play a role in growth regulation.  The deletion of the CENPL gene results in critical consequences such as primordial short stature and severe microcephaly.  

CENPL is vital for the CENPH-CENPI-associated centromeric complex, playing an essential role in kinetochore function and mitotic fidelity.  Its loss disrupts cell division processes, leading to significant developmental anomalies.

CENPL is necessary for proper mitotic function, which ensures accurate chromosome segregation during cell division. The absence of functional CENPL disrupts this process, potentially leading to the developmental defects observed in affected individuals.

RASAL2, ANGPTL1, FAM20B, TOR3A, ABL2, SOAT1  [3.] 

These genes are included within the critical region of 1q25.2 and could potentially contribute to the phenotype, but their specific roles in the context of 1q25 deletion syndrome remain less defined.

PRG4  [3.]

Encodes Lubricin, involved in joint function; haploinsufficiency may be linked to skeletal abnormalities, although direct evidence linking it to clinodactyly of the 5th finger is not established.

Genetic testing can be done in many ways to identify individuals with specific chromosomal or SNP abnormalities.  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.

Laboratory Testing for 1q25

Laboratory testing for 1q25 abnormalities plays a crucial role in diagnosing genetic disorders and assessing disease risk.  There are many methods used for laboratory testing of 1q25.

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 1q25 abnormalities requires expertise and an understanding of genetic principles. A positive result indicating a deletion or duplication in the 1q25 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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