Principles of Genetics Assignment 1 (Group 2) PDF

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C:\\Users\\hp\\AppData\\Local\\Microsoft\\Windows\\INetCache\\Content.Word\\PicsArt\_05-27-11.56.38.jpg {#cusershpappdatalocalmicrosoftwindowsinetcachecontent.wordpicsart_05-27-11.56.38.jpg.TOCHeading} ======================================================================================================= **College of health sciences** **Principles of genetics** **Assignment No\_1** [Group Members ] 1. Bezawit Fekede........................ UGR/2680/16 2. Fiker Abreham......................... UGR/1184/16 3. Kaku Tesfa.................................UGR/9775/16 4. Firdos Hussein...........................UGR/0574/16 5. Girum Merkebu........................UGR/5850/16 6. Bezawit Nigussu...................... UGR/0282/16 7. Elsabet Tsegaye........................UGR/9363/16 8. Bete Abrham..............................UGR/0738/16 9. Eden Bekele............................... UGR/7520/16 Submitted to: Prof. Mistire Wolde Submission date: 15/11/24 Table of Contents {#table-of-contents.TOCHeading} ================= [Introduction 1](#introduction) [What are Genetic disorders? 1](#what-are-genetic-disorders) [What are the causes of Genetic mutation? 2](#what-are-the-causes-of-genetic-mutation) [Classification of genetic disorders 2](#classification-of-genetic-disorders) [Tests for genetic disorders 4](#tests-for-genetic-disorders) [Treatment and Prevention of genetic disorders 4](#treatment-and-prevention-of-genetic-disorders) [Literature review on how mendelian principles are applicable to diagnose human disease 4](#literature-review-on-how-mendelian-principles-are-applicable-to-diagnose-human-disease) [The role of Mendelian inheritance in diagnosing genetic disease 4](#the-role-of-mendelian-inheritance-in-diagnosing-genetic-disease) [Monogenic disorders and Mendelian inheritance 5](#monogenic-disorders-and-mendelian-inheritance) [Mendel\'s Principles for genetic inheritance helped us identify genes for Mendelian disorders 5](#mendels-principles-for-genetic-inheritance-helped-us-identify-genes-for-mendelian-disorders) [Diagnosis of Genetic disease 6](#diagnosis-of-genetic-disease) [Genetic Testing 6](#genetic-testing) [How to apply Mendelian genetics to diagnose Diabetes Mellitus 7](#how-to-apply-mendelian-genetics-to-diagnose-diabetes-mellitus) [Application of Mendelian Genetics in diagnosing diabetes mellitus 8](#application-of-mendelian-genetics-in-diagnosing-diabetes-mellitus) [What is Diabetes? 8](#what-is-diabetes) [Mendel\'s law and MODY inheritance 10](#mendels-law-and-mody-inheritance) [Biochemical techniques to diagnose MODY 10](#biochemical-techniques-to-diagnose-mody) [Conclusion 13](#conclusion) [Ethical consideration of testing genes (diabetes mellitus) 13](#ethical-consideration-of-testing-genes-diabetes-mellitus) [Recommendations 14](#recommendations) [Reference 1](#reference) Introduction ============ Contemporary Genetics knowledge can all be traced back to one man and his experiments with peas. As we all have learned, the father of genetics; Gregor Mendel and his work were the foundation to modern day genetics. After his famous experiments with peas, he published his results at the verein meeting whose objective was to discover the laws of nature and to explain its creative forces using a material basis **(1).** Because his findings were not compatible with that time's scientific knowledge his experiments were not given much thought, and no one tried to repeat them **(1).** His work was finally recognized 16 years later after his death, and now earned him the title "Father of Genetics" His work focused on how traits are passed down, and concluded with three postulates which are the foundations for the laws of inheritance. 1. Unit factors in pairs 2. Dominance and Recessiveness **3**. Segregation These 3 postulated sum up what we call the Mendelian theory of inheritance. This theory is the basis to understanding how traits are passed down from parents to off-springs across all living things. Because of the lack of advanced microscopic tools scientists including Mendel were not able to see inside a cell making them blind ot the concept of chromosomes, genes and DNA. However, Mendel was the first person to deduce that there are certain factors which control the expression of trait which he called unit factors, giving the first hint of genes. From then on, many different scientists added on this concept until the latest milestone in the history of genetics, the Human Genome project was completed in 2003. which mapped the entire human genome, allowing scientists to identify all the genes in human DNA and explore their roles in the human body **(2).** As genes are the blueprints of life the growing field of genetics since the early 1900s had countless applications in various fields such as medicine, agriculture and forensics. Even though our ancestors knew the influence of heredity, for example the use of cross pollination and pedigrees **(2)** they were blind to the actual mechanisms of heredity. But now as that knowledge is revealed we can manipulate the mechanism to better suit our needs. Among the vast and complex applications of genetics this research narrows down on human diseases. Of the many types of human diseases those related to genetics are called **Genetic disorders**. What are Genetic disorders? --------------------------- **Genetic disorders** are illnesses and conditions that are caused by mutations in genes or chromosomes. These disorders are usually hereditary which means they pass from one generation to another. The subset of disorders which are always inherited are called **Inherited diseases.** These disorders vary in their nature, type and symptoms. Usually, they present at birth but their symptoms may not appear until later in life. **(3)** What are the causes of Genetic mutation? ---------------------------------------- Genetic mutation is generally caused by changes in DNA specifically from changes in the four base pairs of DNAs (Adenine(A), Cytosine(C), Guanine(G), Thymine(T)) either through deletion, addition, or substitution. These changes can be caused by Natural and external factors. (3) 1. **Natural factors** in genes result from error during cell division. These errors can result in missing or adding extra chromosomes, improper attachment or breaking of chromosomes. 2. **External factors (Mutagens)** are environmental factors that could lead to genetic mutation. Such as chemical exposure, radiation exposure, smoking and even some viruses **(4)** Classification of genetic disorders ----------------------------------- Genetic disorders can be broadly divided in to three main categories **1**, **single gene disorders (unifactorial**): these genetic disorders are caused by mutations in a single gene, and the inheritance pattern is predictable because it follows mendelian genetics. The occurrence of a disease caused by a single gene mutation may occur in several main patterns or modes. These are grouped according to whether the trait is sex-specific (generally X-linked) or not (autosomal). **(4,5)** a. **Autosomal disorders** **Autosomal dominant single gene disorders** occur in individuals who contain a single mutant copy of the disease-associated gene. The affected individuals are heterozygous for the gene, which means that inheritance of only one copy from either an affected mother or an affected father is sufficient to cause a disease; hence the presence of a single nonmutant or "wild-type" copy of the gene is not enough to prevent the disease. Some examples **include**: Huntington's disease, [Myotonic dystrophy type 1](http://omim.org/entry/160900) Another common mode of inheritance is **autosomal recessive single gene disorder**, where two copies of the mutated gene are needed in order to have the disorder. They inherit one allele from the mother and one from the father, the risk of transmission of the disorder is 25%, while half of the unaffected offspring will be carriers for the gene. **Include**s: cystic fibrosis, sickle-cell anemia b. **X-linked disorders** **X-linked dominant inheritance** follows a pattern similar to autosomal dominant inheritance except that more females are affected than males, although such disorders are very rare. **X-linked recessive conditions** generally occur only in males, as second X-chromosome of females provides a normal allele, but males who inherit the recessive gene on their sole X-chromosome will be affected. Some examples **include**: [Rett\'s syndrome](http://omim.org/entry/312750), Hypophosphatemia rickets. Extremely rare **Y-linked single gene diseases** are always passed on from affected fathers to their sons. An example is: Y-linked Spermatogenic failure, Hypertrichosis of the Ears (Hairy Ears, Prof. Mistire's condition) **2, Chromosomal disorder**; Humans normally have 46 chromosomes arranged in pairs. 22 of these pairs are autosomes will the last pair is a sex chromosomes variation from this pattern causes chromosomal abnormalities. These abnormalities can be either: a. **Numerical abnormalities (aneuploidy)** Are caused by abnormal number of chromosomes. Is the most common chromosomal abnormality and caused by loss or gain of a chromosome. Some types of aneuploidy include: **Trisomy**: where the cell has 1 extra chromosome **Monosomy**: where the cell has 1 less chromosome **Euploidy**: loss of the whole set of chromosomes (mostly occurs in plants) Some disorders due to aneuploidy are: down syndrome, Klinefelter syndrome, Turner syndrome (6) b. **Structural abnormalities** this can happen in 4 ways: **Deletion**: where a portion of the chromosome is lost during cell division. **Duplication**: is the presence of a part of a chromosome in excess **Inversion**: involves breakage and reunion of a part of chromosome **Translocation:** transfer of a set of genes to a non-homologous chromosome. some disorders due to structural abnormalities include: Fragile X, Cri du chat **(6)** **3, Multifactorial genetic disorder (complex)**: are disorders that caused by gene mutations and other factors like diet, chemical exposure, alcohol use and others. Examples of this disorder can be common health problems such as heart diseases, diabetes and obesity. **(7)** **Diagnosis of genetic disorders** Diseases the follow mendelian pattern are called **Mendelian disorders,** and are commonly single gene disorders. And those who don't follow this pattern are called **Complex or non-mendelian disorders.** However, Mendel's laws are applicable for both. **(10)**. The sequencing of the human genome was a fundamental step in the process of understanding and diagnosis of genetic disorders. This helped to map and identify disease associated genes. This new large amount of data led to the creation of genetic databases such as The Online Mendelian Inheritance of Man (OMIM) which has recorded over 6000 Mendelian phenotypes. And led to creation of genome inspired fields such as **Bioinformatics,** which is a field of biology that analyzes genetic information to predict gene and protein function. **(11)** Researchers have also been using genetic model organisms such as mice to understand single gene diseases in humans because of the high level of similarity between their genomes. **(11)** Tests for genetic disorders --------------------------- Diagnosis of genetic disorders can involve combination of physical examination, family history, medical history, and genetic testing. Several different methods are currently used in genetic testing laboratories. Mainly there are three major types of genetic testing are available **Cytogenetic, Biochemical** and, **Molecular** testing In **cytogenetic** testing chromosomes are analyzed and studied if they undergone any structural changes while in molecular testing single or several genes are analyzed. **Biochemical testing** is a little bit different it uses body proteins for diagnosing. Tests that show changes in proteins or their function may indicate mutation in the DNA, which can cause genetic disorders. In this testing samples like blood, tissue and urine are analyzed. **(8,9)** Treatment and Prevention of genetic disorders --------------------------------------------- - Treatment of genetic disorders varies depending on the specific disorder and the severity of the symptoms. Some treatments may involve medication, surgery, or physical therapy. In some cases, genetic therapy may be used, which involve replacing or repairing the faulty gene responsible for the disorder. In addition to medical treatment individuals with genetic disorder may require supportive care and counseling to manage the emotional and psychological effects of the disorder. **(12)** - Preventing genetic disorder involve identifying and managing risk factors such as exposure to certain environmental toxins, maintaining a healthy lifestyle, and undergoing genetic counseling and testing.in some cases, prenatal genetic testing can help identify the risk of certain genetic syndromes, allowing for early intervention and treatment. **(12)** Literature review on how mendelian principles are applicable to diagnose human disease ====================================================================================== The role of Mendelian inheritance in diagnosing genetic disease --------------------------------------------------------------- A Growing body of researches underscores the application of Mendelian genetics in diagnosing genetic disorders. Mendelian studies of inheritance pattern in peace plant are solid foundation for our current understanding of how genetic disorders are inherited in a family (Heidi Chial, 2008). The human genome contains an estimated total of 20,000 - 25,000 genes that serves as blueprint for building all our proteins (International Human Genome Sequencing Consortium 2004). In single-gene disease a mutation in one of these genes is responsible for the disease. While in polymeric or complex disease more than one gene is participated in causing the disease aided by environmental factors. Although 1,822 of protein encoding genes in human are estimated to be associated with a monogenic disease, the identities of more than 1,500 of these group are unknown so that they are called orphan disorders, largely because many of the single-gene disease are rare and occur in small number of families (Antonarkis & Beckman, 2007). Some of the monogenic disorders are Cystic Fibrosis, Sickle Cell Disease, Neonatal Diabetes Mellitus (NDM), Maturity-Onset Diabetes (MODY). While Hypertension, Schizophrenia, Asthma are few examples of complex disease. Even though now days studies are giving more attention to complex disease understanding the patterns of monogenic disease is key to understand how these complex diseases are inherited and how to diagnose them. Monogenic disorders and Mendelian inheritance --------------------------------------------- The basics law of inheritance is important in understanding patterns of disease transmission. The inheritance pattern of single-gene diseases are often refers to as Mendelian disorders since Gregor Mendel first observed the different pattern of gene segregation for selected traits in garden peas and was able to determine probabilities of recurrence of trait for subsequent generations. If a family is affected by disease, an accurate family history will be important to establish a genetic disease, particularly for common disease where behavior and environment play strong roles. **(12)** Recent advancements in studies have deepened our understanding of that the single-gene diseases are usually inherited in one of several patterns depending on the location of the gene and whether. One or two normal copes of genes are needed for the disease phenotype to manifest. Single-gene diseases run in families and can be dominant or recessive, and autosomal or sex-linked. Pedigree analyses of large families with many affected members are very useful for determining the inheritance pattern of single-gene diseases. The Mendel laws of inheritance are applicable to complex traits since the inheritance of each of the genes involved in the disease follow the Mendel's law. Thus, Mendel's theories remain instrumental in revealing casual mechanisms for both monogenic and complex disease. **(15)** Mendel\'s Principles for genetic inheritance helped us identify genes for Mendelian disorders --------------------------------------------------------------------------------------------- Early understanding of genetic underpinning of human disease studying their inheritance in families (pedigree analysis). This analysis together with knowledge of the location of genes on chromosomes helped in finding the dominant and recessive nature of allele of disease genes and difference in their inheritance pattern. **(13)** Further advancement in our understanding of molecular basis of genetic variants, as well as the technological capabilities to create genetic maps of chromosome, eventually led to the localization and identification of disease genes. Computational methods including linkage analysis use naturally occurring DNA variants as markers to trace inheritance patterns in families to identify the location of disease genes on the chromosome. The positional cloning phase of disease gene identification was very fruitful, since the genes responsible for most common Mendelian disorders were cloned during this period (Burke et al., 1987). Most Mendelian disease are caused primarily by a single high-penetrance mutation in a family. These mutations affect the coding or other functional regions of genes and have a low frequency within a population. (Online Mendelian Inheritance of Man (OMIM)). Diagnosis of Genetic disease ---------------------------- All disease have a genetic component. Mutation may be inherited or developed in response to environmental stresses such as viruses or toxins. The ultimate goal is to use this information to treat, cure, other of possible prevent the development of disease. **(14)** Genetic Testing --------------- Genetic testing is the use of a laboratory test to examine an individual's DNA for variations, typically performed in the context of medical care, ancestry studies or forensics. (4) In a medical setting, this testing can help identify genetic conditions determine of someone is carrier of genetic disorder and asses the risk of developing certain disease. In the context of diagnosing metabolic disorders like diabetes mellitus, genetic testing can help reveal specific gene mutations that increase the risk of developing the disorder or affect how it progress. Several different methods are currently used in genetic testing laboratories. The type of test will depend on the type of abnormality that is being measured. In general, three major types of genetic testing are available cytogenic, biochemical and molecular testing to detect abnormalities I\'m chromosome structure, protein function or DNA Sequencing, respectively. **(16)** **1, Cytogenetic Testing** Cytogenetics involves the examination of whole chromosomes for abnormalities. Chromosomes of a dividing human cell can be clearly analyzed under a microscope. White blood cells, specifically T lymphocytes, are the most readily accessible cells for cytogenetic analysis since they are easily collected from blood and are capable of rapid division in cell culture. Cells from other tissues such as bone marrow (for leukemia), amniotic fluid (prenatal diagnosis), and other tissue biopsies can also be cultured for cytogenetic analysis. Following several days of cell culture, chromosomes are fixed, spread on microscope slides and then stained. The staining methods for routine analysis allow each of the chromosomes to be individually identified. The distinct bands of each chromosome revealed by staining allow for analysis of chromosome structure. **2, Biochemical Testing** The enormous numbers of biochemical reactions that routinely occur in cells require different types of proteins. Several classes of proteins exist to fulfill the multiple functions, such as enzymes, transporters, structural proteins, regulatory proteins, receptors, and hormones. A mutation in any type of protein can result in disease if the mutation ultimately results in failure of the protein to correctly function. Clinical testing for a biochemical disease utilizes techniques that examine the protein instead of the gene. Depending on the function, tests can be developed to directly measure protein activity (enzymes), level of metabolites (indirect measurement of protein activity), and the size or quantity of protein (structural proteins). These tests require a tissue sample in which the protein is present, typically blood, urine, amniotic fluid, or cerebrospinal fluid. Because proteins are more unstable than DNA and can degrade quickly, the sample must be collected and stored properly and shipped promptly according to the laboratory's specifications. **3, Molecular Testing** For small DNA mutations, direct DNA testing may be the most effective method, particularly if the function of the protein is not known and a biochemical test cannot be developed. A DNA test can be performed on any tissue sample and require very small amounts of sample. For some genetic diseases, many different mutations can occur in the same gene and result in the disease, making molecular testing challenging. There are many methods and technologies used to apply those genetic tests, the advancement of existing technologies and innovation of new technologies enable us to work and understanding this area of diagnosis. Next-generation sequencing (NGS), primary chain reaction (PCR), RNA sequencing, chromosomal Karyotype, Sanger sequencing are some examples of these technologies. How to apply Mendelian genetics to diagnose Diabetes Mellitus ------------------------------------------------------------- Diabetes, a disease of the endocrine system diagnosed by abnormally high blood glucose levels, is one of the most common and fastest growing diseases worldwide, projected to affect 693 million adults by 2045,1 a \>50% increase from 2017(Joanne B Cole). Diabetes is a chronic metabolic disorder characterized by high blood glucose levels that result from absolute or relative insulin deficiency, in the context of beta-cell dysfunction, insulin resistance, or both. Though it's classically divided into an early-onset autoimmune form (type 1 diabetes or T1D) and a late-onset non-autoimmune form (T2D), additional clinically recognizable subtypes exist, such as monogenic diabetes (e.g. Maturity-onset Diabetes of the Young \[MODY\] or neonatal diabetes), gestational diabetes, and possibly a late-onset autoimmune form (latent autoimmune diabetes in the adult or LADA). **(17)** Maturity-Onset Diabetes of Young (MODY) results from mutations in specific genes that are critical for pancreatic beta-cell function, including HNF1A, HNF4A, and GCK. These genes follow Mendelian principles, making it possible to predict and diagnose MODY based on genetic analysis and family history. Mendelian principles---such as segregation and independent assortment---provide a framework for understanding how MODY is inherited. **(18)** According to the principle of segregation, each individual inherits one allele from each parent, and because MODY is autosomal dominant, there is a 50% chance of passing the mutated gene to offspring. Recognizing this pattern helps clinicians and genetic counselors in identifying families at risk and enables a targeted approach to screening. **(19)** Mendelian, monogenic origin like MODY, rather than the more common polygenic Type 1 or Type 2 diabetes. By understanding these inheritance patterns, healthcare providers can conduct genetic testing to confirm the diagnosis. Application of Mendelian Genetics in diagnosing diabetes mellitus ================================================================= What is Diabetes? ----------------- Diabetes is a condition that happens when your blood sugar(glucose) is too high. It developed when your pancreas doesn\'t make enough insulin or any at all, or when your body isn\'t responding to the effects of insulin properly. **(22)** There are several types of diabetes. The most common these are: Type1 diabetes, Type2 diabetes, Prediabetes, Gastational diabetes, Latent autoimmune in adults (LADA), Maturity-Onset Diabetes (MODY). About 80% of the case is type 2 Diabetes with inheritance range from 30 to 70%. Type 1 Diabetes being the most sever type. According to genetic analysis diabetes can be monogenic or polygenic. **Monogenic diabetes** rare type of diabetes caused by a single gene mutation and this diabetes most often affect young people. MODY (maturity onset diabetes of the young) can be mentioned as an example for the monogenic diabetes. It's caused by mutation in autosomal dominant genes that disrupt the secretion of insulin. Examples of these genes are HNF1A, HNF4A, and GCK. Another example of monogenic diabetes is Neonatal diabetes. And it occurs due to mutation in genes affecting pancreatic beta cell function. The other diabetes type is **polygenic type**. This diabetes caused not by a single gene but multiple genes contribute a small effect besides the environmental factor. Type 1 diabetes is a polygenic one that influenced by multiple genes specially those related to immune function. Type 2 diabetes also factored by many genes those contribute to body's insulin resistance and beta cell dysfunction. Mendelian inheritance pattern can be applied to have a clear understanding on transmission of particular type of diabetes especially monogenic ones. While polygenic type of diabetes doesn't strictly follow Mendelian inheritance pattern. But it is s till important to understand the interaction of multiple genes and environmental influences. Mendelian genetics also plays a critical role in predicting the inheritance of diabetes within families. Because monogenic diabetes follows an autosomal dominant pattern, a child of a parent with MODY has a 50% chance of inheriting the mutation. In case of our research we will focus on monogenic type specifically MODY. **Maturity-Onset Diabetes (MODY)** happens due to inheritance genetic mutation that affect how your body makes and use insulin. **(23)** MODY is caused by a single gene mutation that leads to a defect in beta cell insulin secretion in response to glucose stimulation. There are now at least 14 different known MODY mutations. They include GCK, HNF1A, HNF4A, HNF1B, INS, NEURO1, PDX1, PAX4, ABCC8, KCNJ11, KLF11, CEL, BLK, and APPL1. The different genes vary with respect to the age of onset, response to treatment, and the presence of extra-pancreatic manifestations. The most common gene mutations are the following: **1**, Gene mutation in the hepatocyte nuclear factor 1 alpha (HNF1A) accounts for 30% to 60% of MODY. **2**, Gene mutation in the hepatocyte nuclear factor 4 alpha (HNF4A) accounts for 5% to 10% of MODY cases. **3**, Gene mutations in glucokinase (GCK) account for 30% to 60% of the cases of MODY. Gene mutation in hepatocyte nuclear factor 1 beta (HNF1B) accounts for less than 5% of the cases of MODY.MODY can be caused by a mutation in one of several genes. HNF1A-MODY, GCK-MODY, HNF4A-MODY, and RCAD, are caused by mutations in the HNF1A, GCK, HNF4A, and HNF1B gene, respectively. All of these genes provide instructions for making proteins involved in the production of insulin to control blood glucose levels in the body. In particular, the proteins are important in specialized cells in the pancreas called beta cells, which secrete insulin. The proteins produced from the HNF1A, HNF4A, and HNF1B genes all act as transcription factors, which means they control the activity of other genes. In particular, these proteins regulate genes that direct the development and function of beta cells. HNF1A, HNF4A, or HNF1B gene mutations result in production of an altered transcription factor that is unable to function normally. These changes alter gene activity in cells, impairing normal beta cell development and function. As a result, beta cells are less able than normal to produce insulin in response to glucose in the blood, which means the body cannot control blood glucose. Elevated blood glucose results in the signs and symptoms of MODY. Some of these MODY-related genes play roles in the development of other body systems, in addition to beta cells. Disrupted development of these systems underlies additional signs and symptoms in particular forms of MODY. For example, the HNF1B gene is involved in kidney development, which helps explain the kidney abnormalities in people with RCAD. The protein produced from the GCK gene acts as a sensor that recognizes when the amount of glucose in the blood rises. In response, the protein helps stimulate the release of insulin from beta cells so glucose can be taken up and used by cells for energy. This protein also helps determine when excess glucose should be taken into liver cells and stored. Mutations in the GCK gene limit the protein\'s ability to sense a rise in blood glucose, so levels remain elevated. Mendel\'s law and MODY inheritance ---------------------------------- Maturity-Onset Diabetes of the Young (MODY) is a form of diabetes that follows an autosomal dominant inheritance pattern, meaning that a single copy of the mutated gene can cause the disease. MODY is a monogenic disorder, which means it's caused by a mutation in a single gene, consistent with Mendelian inheritance. From Mendel's law of dominant and recessive allele, dominant allele is expressed in phenotype both in homozygous and heterozygous condition. MODY is autosomal dominant so if the person has at least one allele of mutated allele of the gene then it will become affected. From Mendel's law of segregation, each parent contributes one of the two possible allele. Here the MODY inheritance in a family history is shown Fig (1)  Fig (1) Biochemical techniques to diagnose MODY --------------------------------------- Diagnosing MODY accurately is crucial because its management differs from type 1 and type 2 diabetes. Biochemical techniques and genetic testing are the primary tools used for MODY diagnosis. Here are some key biochemical approaches: 1. **Blood test** A blood sugar test is the first step toward diagnosing MODY. If your results indicate you have diabetes which means your glucose level is higher than normal, your doctor may order additional tests to determine if you have MODY or another type of diabetes, such as type 1 or type 2. Since MODY is caused by a genetic mutation, a genetic test can also help to diagnose it. The testing will determine the exact type of MOD **(26)** The expected values for normal fasting blood glucose concentration are between 70 mg/dL (3.9 mmol/L) and 100 mg/dL (5.6 mmol/L). When fasting blood glucose is between 100 to 125 mg/dL (5.6 to 6.9 mmol/L) changes in lifestyle and monitoring glycaemia are recommended. Patients with MODY2 are typically asymptomatic and may have stable mild fasting hyperglycaemia (100 to 145 mg per dL \[5.55 to 8.05 mmol per L\]) for years **(27)** 2. **C-Peptide** C-peptide is a small linear peptide, which is susceptible to enzyme proteolytic cleavage, consequently, quickly centrifuging and freezing sample is usually required. The measurement of C-peptide is used to assess endogenous insulin production in diabetic and non-diabetic individuals, despite treatment with insulin. Several methods of C-peptide measurement have been proposed. Venous blood C-peptide levels can be measured in the random, fasting or stimulated state. Fasting and random non-fasting C-peptide are simple, quick to perform, and correlate with diabetes type. The 24-h urinary C-peptide (24 h UCP) sample collection is non-invasive and stable for 72 h in boric acid but is time-consuming and requires good patient compliance. Urinary C-peptide/ creatinine ratio (UCPCR) is a reproducible measure that correlates well with 24-h UCP in non-diabetic subjects. Second-void fasting UCPCR was suggested as the optimum approach for the assessment of baseline endogenous C-peptide production using a spot urine test. One important feature distinguishing type 1 diabetes from MODY is long-term evolution of residual pancreatic function. In type 1 diabetes, complete insulin deficiency ensues in most patients after 5 years of evolution. In MODY, since there is no direct destruction of beta-cells, residual endocrine pancreatic function may be observed after several years of evolution, therefore, detectable serum C-peptide outside the honeymoon period may indicate a diagnosis of MODY. This can be especially useful in transcription factor MODY, which presents frequently as a differential diagnosis to type 1 diabetes. In contrast, in type 2 diabetes, obesity-related insulin resistance may result in elevated levels of insulin and C-peptide. **(28)** A normal result is between 0.3 to 3.3 Nano grams per millilitre (ng/mL), or 0.2 to 1.0 Nano moles per litre (nmol/L). Patients with MODY result are 1.78 (1.24 - 2.88) ng/mL. **(29)** Where sufficient resources are available, testing all children with negative antibodies and detectable C‐peptide will be a highly sensitive systematic approach to diagnosing MODY in pediatric clinics, identifying 99% of cases. In patients diagnosed under the age of 30 years, testing patients with negative antibodies and detectable C‐peptide identifies MODY in one in five patients tested. If necessary, specificity can be improved by testing only those patients with a parent affected with diabetes, and/or those with less severe hyperglycemia at diagnosis. MODY patients have a milder presentation with lower HbA1c and lower incidence of ketoacidosis and osmotic symptoms. Having negative antibodies, detectable C‐peptide, a parent affected and/or an HbA1c \