The interconnection of single-gene mutations and environmental exposures to produce complex disorders may represent one of the most significant obstacles in disease gene discovery. Polygenic background, numerous and infrequent variations, and gene-gene interplay affect are the main reasons why complex diseases occur. In personalized medicine, the solutions are based on the prediction of the identification of an individual's health status by a high-volume genetic analysis as well as bio-environmental factors. Whether it is a consideration of a normal or abnormal gene order, each should be taken into account in order to understand the basic complex requirements of health. Though it is quite challenging, the initial stage that involves the identification of common and unusual sources of genetic variation in individuals with higher disease likelihood is the foundational step. The role of multifactorial and unifactorial genetic variations in the etiology of HSCR was further examined in the literature as well. SNPs, on the other hand, are general genetic variants that at most times are detected in population with frequencies at 5% and above. Hypothetical risk is elevated by spontaneous varying in other genes and rare genetic variants on RET gene, which were shown to induce HSCR. Feature genetic factors influencing HSCR formation and development can be clarified by studying the common variations between HSCR and other disorders shown by GWAS research. Research from the HSCR could increase the likelihood of specific drugs for precision medicine, which will be customized to varieties of individual patient’s genome. Investigations of translational research, function, long-term studies, and the possibilities of gene-environment interactions, whole-genome sequencing, and a population oversample incorporate the broad aspects of future research topics.

Diseases are multifaceted, which fact is that each one of them, as a rule, is developed as a result of exposure to several environmental factors and single-gene mutations. In genes we differentiate rare and frequent variants as well as interacting genes. Also, we deal with complex inheritance patterns that can be either polygenic or monogenic. Air and natural resources include automobiles, household substances, pollution, chemicals, radiation, and health-compromising choices like food, alcohol, and smoking. The intricacy of a disease's development is explored by stress, socioeconomic status and health care access as well.

This multitude of facets of diagnosis, prevention and treatment of diseases demands a wide array of data on hereditary and environmental factors, as well. Health outcome is what is anticipated due to an individual's genetic profile and variations in environmental exposures, ultimately allowing for personalized medicine approaches to be formed [1]. Getting a hold over the type of genetic motifs, be it the most popular or otherwise, is one of the primary steps towards comprehending the various factors of the diseases. Several alleles from the different variants of the gene have a low probability in a person contracting a disease, but a rare variant can have a great significance in its development.

A significantly high level of detecting cases of common and uncommon gene can be salvaged with a type of approach that sets advanced genetic identification of patients with higher disease incidence based on collection of different variations. This strategy lowers the error rate and makes these models usable on real problems. Reviewing of not usual mutations unveils intricate details about molecular processes and mechanisms lying behind illnesses as well as provides us with valuable ideas about the most essential points of treatment. Simulations based on the modification of variants' mechanisms could probably be useful to millions of people classified as having a disease.

Hirschsprung disease (HSCR)

HSCR, its pathogenesis which is multifactorial i.e., multiple paths of both genetic and environmental factors, is just the fitting case to answer the question about the percentage distributing genetic defects for the complex disorders. Hypoganglionosis (HSCR) also known as Hirschsprung’s disease is a complex condition that causes the ganglion cells to be absent distally in the bowel which is responsible for the constipation, intestinal impaction and, externally the mold is the death [2]. This phenomenon has drawn the researchers most attention towards the attachment disorder as it is the key-stone of unlocking the mysteries of the genetic roots of illness.

Genetic Complexity in HSCR

• Polygenic Nature: HSCR refers to an example genetic disorder where a variety of genes in a person play a role in the disease's susceptibility to it. This trait is typical for most common complex diseases in which there is no "one-gene-to-the-disorder" rather, dozens of genes involved.
• Rare and Common Variants: In the wake of research on HSCR, both single and common gene mutations have been taken as contributors to its pathophysiology. Rare alterations, such as those in the RET gene, can have a clear-cut effect on the development of HSCR, while regular variants may have only a small increased risk but since there are much more of such differences among people their impact on the disease. as whole still can be significant.
• Gene-Gene Interactions: Furthermore, the disease indicates the influential role of gene-gene interactions, in case if one genetic variant produces different results along with variations at other genetic variants. For such reasons, these kinds of interactions might be argued to assortment the genetic landscape and become more essential for overall genetic risk to be understood.

Variable Penetrance and Expressivity: 

The significant variability in HSCR is displayed in its varied penetrant and expressive features, manifesting in the fact that not all those with the risk genes will develop the disorder, as well as those with it still present with different severity levels. The disorder development phenomenon is unique among complex diseases and suggests that other genetic or environmental characteristics are at work.

Anatomical variant in Hirschsprung disease (arthritis ganglion cells in the bowel due to which intestine motility is slowed down and blockage occurs) as a disease further negatively affects the newborns [3]. Approximately 0.01% of newborns get affected. Moreover this disease is 130 times more likely to appear in men. The event aims to prepare competitors with a better knowledge of the use of online marketing strategies and how to effectively target and reach their custom segments.

The tendency to suffer from physical symptoms can be manifested in vomiting, belly dissention, chronic constipation, intestinal tract inflammation, diarrhoea and fail to grow children in late infancy. A length of the damaged intestine needed for the classification of the type of HSCR. This disease is associated with multigenic and hereditary links moreover with RTFI being crucial factor. Studies have provided evidence that the presence of the unique combination of EDNRB, GDNF, SOX10, and PHOX2B genes is a key to the formation of the Hirschsprung's

Disease-Nervous System during the formative stage. The disease under consideration is a mutated polygenic threshold model. The induction of different clinical phenotypes and prognoses are, in this case, a combined result of the genes cumulative impact. Genetic counselling should be considered an important tool into the hands of the mothers who carry the HSDC screenings, because it helps them find out the likelihood of the disease happening in other children and brothers.

Material and Methods

Through that route of identifying needed literature on the review of the topic I am going to emphasize, a systemic procedure is employed to achieving level of clarity. In addition to this systematic review and meta-analyses of studies published during the period of 2010 to 2023 were also taken into account. Seven databases like JumpMed, The Science Direct, The Cochrane Library, Web of Science, Google Scholar, Embase, and Scopus were searched along with the above stated. Only core journals were examined and academic papers studied, and the words used for search were relevant ones. There was no need to be confined with nation or language when printing books because there were books in English other than hers. Apart from other available sources of the Internet, also I focused on foreign medical university library as well as AIIMS report and they both proved to be the main sources of this paper.

Functions of Common and Rare Variants in the Genetic Basis of Complex Diseases

There are gene-gene and/or gene-environment interactions that occur in complicated illnesses which also have complicated genetic characteristics having several genetic variations and environmental factors involved. Such investigations have uncovered traits with diverse phenotypes which can partly be explained by the presence of more complex genetic pathways (Servetti et al., 2021) [4]. Another study equally well illustrated how results obtained by such studies might allow to more clearly understanding complex diseases by examining the genomic profiles through the molecular variations (Vandiedonck, 2018) [5]. The next-generation sequencing has also proven powerful, for it has now enabled the prediction of diseases based on the commonly mutated genes. This has helped deepen the knowledge about the genetic bases of human complex diseases (Müller et al., 2016) [6]. Improvements in technologies have immensely made the use of precision medicine that was genomic to be quite easy, especially when it comes to the sophisticated diseases.

For instance, the molecular research focused on gene disorders has examined how different genetic variants interact with one another and play a role in the cause and function of various diseases (Jackson, et al, 2018) [7]. There is evidence that rare variants are taking a specific position in the pattern of the complex disorders genetics that can be used to explain previously undefined connections. Hence, companies in this industry have earned particularly the spot-light (Momozawa & Mizukami, 2020) [8].

Genetic Studies Provide New Light on Hirschsprung Disease

Absence of ganglion cells in the last part of intestine affects the peristaltic motility of the bowel and leads to serious condition of Hirschsprung’s disease (HSCR) which includes severe constipation or bowel obstruction. Involved many genes, during which study was made; RET being a key gene that contributes to the predisposition. Investigation thanks to the integrated contribution of the discoveries of the RET mutations' functional features clarified the genetic grounds of HSCR (Wang et al., 2019) [9]. In addition to that, several researchers evaluate the probability of HSCR susceptibility in connection with the most frequent polymorphisms in micro RNA molecules, which could possibly imply the functionality for regulatory RNAs in the onset of illness (Wu et al., 2020) [10]. Investigations on HSCR have homed in on the philippines of developing enteric nervous system primarily looking into the migration and differentiation of enteric neural crest cells. Modes that was designed from the human pluripotent stem cell were capable to exhibit how the develop dynamics of enteric nervous system happens, giving a new insights of HSCR (Lui & Ngan, 2022) [11].

There are two types of unusual genetic characteristics found in a population: special and hybrid genes. All these kind of differences expand genetic variety of people and are capable to be as well connected with a number of factors, including as their well-being against some of the illnesses. Usually, the common genetic variants, as the SNPs (single-point mutations), are alleles that frequently occur in the population and are rarely below 5% contrasted to the others [12]. They may after affect a man’s traits or his likelihood of getting sick, although they rarely have a visible output of how he grows up and is healthy. The most typical cases can be found, and genome-wide association studies (GWAS) are used to analyze their possible relation to features or diseases, searching the connections between them and different population’s sizes. The different individual common variations usually result in minor to moderate effects on the likely traits or illness risk of an individual. However, when they are combined among the entire population, they might have an outstanding effect on the population overall. Single-gene mutations in our DNA are becoming increasingly difficult to detect and analyze due to advances in whole-genome and exome sequencing technology [13].

Rare Genetic Variants in HSCR

RET Gene Mutations: The RES gene, the most recognized is the RET gene. It encodes a receptor tyrosine kinase that when mutated has been found to be associated with multiple NFCRs. The most common single gene defect leading to HSCR is a mutation in RET gene encoding for a protein located in RET tyrosine kinase receptor [14]. These mutations are mainly related to long-segment and familial disease forms. These mutations could cause the loss of RET protein function which plays a key role in neuron development and migration during the process of differentiation and migration of enteric neural crest cells.

• Other Rare Variants: The variants in RET, as well as that in EDNRB, GDNF, SOX10, and PHOX2B genes have been connected with HSCR. The genes are a point of intersection for pathways of critical importance to the development of enteric nervous system. For example, mutations in EDNRB, which encodes the endothelin receptor type B, have been implicated in both syndrome and non-syndrome forms of HSCR [15].

Common Genetic Variants in HSCR

• Common Variants in RET and Other Genes: Besides rare mutations, sporadic variants (polymorphisms) in not only RET and other HSCR-associated genes add together to genetic risk too. These variants, different from the rare mutations in general, may have a smaller influence upon the population but be more widespread [16].
• GWAS Findings: Genome-wide association studies (GWAS) displayed common variants linked to with HSCR. Such studies make possible to reveal the effects of shared hereditary factors that predispose to the illness, with a particular eye on the polygenic nature of HSCR in general [17].

Role of Common Variants: 

Zygosity promoters of HSCR together make an additive framework of the genetic risk of HSCR. Each variant has a relatively mild effect, and each variation individually might not be very influential; however, when the effects combine with other genetic or environmental factors, the risk of developing the disease is much greater [18].

 In day to day life, as you would envisage the global economy to expand and innovate, the need for workers to keep pace with the advancing technologies becomes more and more critical. The genetic mechanism underlying HSCR is complex, there are common and rare genetic variation types involved, which displays different genetic inheritance patterns [19]. In the initial research, mutations in the RET proto-oncogene in general and RET-related families in particular, where multiple congenital defects occur were found to be a main cause. The results of these point mutations are characterized by pathway disruption of receptor tyrosine kinases that are responsible for the activation of cells of ENCCs, inhibiting their migration and differentiation process.

Within the previous decades, studies in the sector of genetics have found out the non-coding regulatory elements and their function in the development of the pathologic symptoms regarding HSCR. Genome-wide investigations have shown the predominance of the known HSCR regulatory variants in the proximity to the genes of RET and SEMA3 that are associated with the condition, leading to disrupted gene expression as a result of this. There has been wide-ranging use of functional models in vitro and in vivo to display how the regulatory elements operate in the course of ENS development. Non-coding RNA (ncRNA) is also considered as one of the potential molecules that could be involved with HSCR. In particular in its investigation of the potential of miRNAs and lncRNAs in the various ENS developmental and functional aspects, sure evidence of their possible participation in the disease course arises. 

The interplay between the genetics and environment in POI has been revealed to possess a complicated genetic-environmental interaction such that it, to some extent, determines AD risk. The advancement of techniques in genomic technologies has shortened the process of identifying very rare genetic compositions and different types of structures of chromosomes that are also commonly found in HSCR. Moreover, a large part of the last couple of years has been dedicated to pigging out on pizza one too many times without fail which has inevitably resulted in something called a genetic architecture to form. Development of genomics, functional genomics, and bioinformatics gave a boost for the discovery of the important genes, regulatory astra and pathways that govern the HSCR phenotype.

Discoveries regarding the contribution of rare and common variants to HSCR

Hirschprung's disease (HSC) is a birth disorder of the ganglion cells in the upper part of the large intestine of the child. The genetics profile of HSCR is indeed complex with a mixture of both rare and common variants. Genetic infrequent variants, located at the frewer than 1% of a general population are the main risk factor of HSCR [20]. In most cases, it causes an obvious dysfunction. It is the most widely studied gene in the RET proto-oncogene that is the foundation of the retos syndrome. A manifestation of the mutation can lead to the introduction of the carriers. Also the cases of mutation in inflammatory EDNRB or connective EDN3 tissues might be impaired especially in syndrome cases or rarely may it also give rise to MEN. The common genetic variants in HSCR, taken alone, provide a modest increase in disease risk. However, their population frequency is high; therefore, it justifies their equally significant effect in disease development. Regarding HSCR, apart from the various genetic variants present, these are responsible for several functional aspects that deal with nervous system development and functioning. But these inclinations also surround fundamental mechanisms of HSCR's etiology similarly serve for genetic advising and shed light on possible therapeutic targets, making positive implications on the fight against this hard to manage condition [21].

Interplay between these variants and other potential risk factors

Hirschsprung's disease (HSCR) is as well a classic instance of a complicated condition where the genetic bases and the environmental parts cooperate to shape the risk of disease and its outcomes [22]. It reveals the multifactorial nature of the illness, highlighting the complexity of HSCR. It helps us understand, at least at a theoretical level, how such interplays could be at work in many other complex diseases likewise.

Genetic Variants and Their Interplay in HSCR

Mainly of disruptive in nature, the set of basic genes are implicated in the genes that are responsible for the function of the enteric nervous system. Among the various genes involved, RET proto-oncogene is the most significant, as rare RET variants are responsible for around half of the observed cases with susceptibility to Hirschsprung's disease [23]. Similarly, in the genes EDNRB, GDNF, SOX10, or PHOX2B are located coding rare variants that drive disease manifestation. Further, common variants reported through GWAS were also noticed to hammer the risk in a minuscule but in a very much influential manner.

The unusual joints of these combined rare and common variants also have much to say regarding the disease's depth ('phenotherapy'). For instance, the common variants only affect individually by a little but they can really enhance the risk of having the disorder when they are together with a rare or a very penetrant variant [24]. Gene–gene interaction, known as epistasis, can yield various clinical presentations of HSCR ranging from short-segment to long-segment disease in related to a particular combination of genetic variant that one person harbours.

Environmental Influences on HSCR

The genes are the backbone of HSCR, though non-genetic factors build the very brick of its development. In utero factors, which include maternal nutrition, health, and toxic exposure, can affect fetal neural crest cell development to some extent. It could be a potentially risk factor to embryo development. Prenatal conditions including prematurity and low birth weight are risk factors for the condition whereby HSCR diagnosis is increased than in normal births, which may play a hand in any existing mutation vulnerabilities [25]. Possible additional risk might be underlying genetic propensity to HSCR as a consequence of postnatal drug or environmental toxin or through their combination. However, further studies are needed to confirm this phenomenon.

Modifier Genes in HSCR

Modifier genes are the ones not categorically leading to disease but affecting their criticality or the level of severity. They can make the transmission of complex processes involving thorough analysis of clinical presentations of the same patients with the same causative mutations facilitated. A modifier gene may influence HSCR phenotype by lengthening or aggravating an aganglionic segment, or by manifesting in more acute symptoms [26]. Among individuals with a pathogenic mutation for this syndrome we can find some cases without disease manifestations that imply the presence of modifier genes for the protective effect. While the interaction of several genes that potentiate other genes at work might lift the risk and severity of HSCR way far from what could be expected from each gene's effect alone.

How the findings from this study can be applied to understand other complex diseases?

The analysis of Hirschsprung disease serves as a model for examining the multi-genic and environmental interaction role in the development of complicated diseases [27]. Through studies that pick out some specific genetic models (both common and rare) and their interaction with environmental influences and modifier genes, researchers broaden horizons and unveil applicability to a wide range of disease conditions.

Application to Other Complex Diseases

Polygenic Risk: The phenomenon of polygenic exposure, shown by HSCR through multiple common variants being the reason for event, can be understood and applied similar diseases to be cured too like diabetes, cardiovascular diseases, and psychiatric disorders. The effect of all the common alleles in a combination that if small still can aggregate to cause disease may improve risk prediction models and offer insights into the mechanisms of the disease [28].

Gene-Environment Interactions: The exploration of HSCR underlines the significance of environmental factors as the pathogenesis already occurs even in the presence of robust genetic predispositions. This leads to the idea which is compatible to each other. It is supposed that the majority of diseases belong to the category of complex ones, whose appearance is influenced completely or partially by heredity and environment. In this sense, for example, questioning upbringing and environmental factors that may drive ailments such as cancer or asthma can also be treated similarly as research conducted in HSCR area [29].

Modifier Genes: The concept of modifier genes in HSCR, which influence the severity or presence of the disease, can be applied to other conditions where there is notable phenotypic variability. Understanding how these genes operate could provide insights into the variable expressivity and incomplete penetrance observed in many genetic disorders [30].

Therapeutic Interventions: Insights from HSCR regarding the pathways and genes involved in disease pathogenesis can guide the development of targeted therapies. Similarly, identifying key pathways and genes in other diseases can facilitate the development of precision medicine approaches tailored to the genetic makeup of individual patients [31].

Potential implications for genetic testing, counselling, or treatment strategies for HSCR

Level of colonic functional paralysis is found in Hirschsprung's disease (HSCR). It occurs due to absence of ganglion cells in its distal segment, leading to the blockage of colon or obstruction. Genetic testing and counselling, together with treatment therapies have significant role in the efficacy and outcome management of HSCR. Genetic testing can find mutations in certain genes such as RET, EDNRB, GDNF, and SOX10, helping the doctor to provide accurate diagnosis and possible future assessment of the disease across the family [32]. This is highly significant in so far as it means that the consideration of pregnancy and genetic counselling is concerned.

Getting the views of genetics behind a patient’s HSCR may help in the identification and management of treatments, because a patient with a replicated mutation may have a body that can react adversely to surgical interventions or come with another subsequent condition. Genetic counselling is one of the key human aspects of the inheritance education, which helps to analyze pattern of inheritance, risks and further complications of HSCR and gives guidance and information to families for sure and safer decisions regarding testing, treatment and reproductive planning [33].

Psychosocial support is provided to families when they receive the diagnosis during which time and the process of informed consent. Genetic counsellor is the staff member that will be guiding families in understanding genetic counselling complexities, such as possible results and limitations. Surgical approaches as well as reparative medicine, and pharmacogenomics medical breakthroughs will be the focal points of future treatments. Exploration of new methods of surgeon-to-patient genetics may provide with more personalized and therefore comprehending surgical techniques to ease the complication rate and better the outcomes [34].

The possibility of genetic diagnosis in early ages may also make it possible to implement earlier interventions, which could consequently improve the survival rate of infants that have HSCR. The major role of genetic testing in the newborn period for the population of increased risk is emphasized. Meanwhile, as we shed more light on the underlying genetics of HSCR and uncover the complexity involved, our scope for designing smart medications which will be impactful will also increase. Thus, we will begin to hope for our patients with HSCR.

imitations of the current study

Although the HSCR study has some limitations, including genetic heterogeneity, underestimating a role of environmental factors, focusing on some populations and gene phenotype variability, I still consider it as a highly informative and useful one. HSCR can be classified as a genetic heterogeneity which includes different mutations in the genes all of which cause the similar clinical picture. The complete study may not capture all the genetic variations connected with the HSCR; hence, there is a possibility of overlooking the subtler variations, whether less common or novel in nature. Apart from that, the research might not capture the whole extent of what the inherited component of HSCR could mean for the gravity of the disease, which is vital in understanding the seriousness of the illness and crafting custom treatment plans [35].

Areas for Future Research

The studies on HSCR in the future should comprise a survey of the wide population group to reveal the genetic variations from that spectrum that are linked to the disease. Whole-genome sequencing may reveal existing rare and novel mutations, which may be the covariate factors in diseases complexity. Knowing the impact of interactions of environmental and genetic factors is the essential pillar to understand what further steps would be taken in preventing the condition through health policies and safety instructions. The functional studies must be centred on the approach of the mutations and their influences at the level of cellular processes as well as developmental processes resulting to the absence of ganglion cells in the intestine. Protracted trials give us the chance to learn the fate of various therapies and see how genetic factors can impact the outcome for the duration of the treatment. Translational science is an inevitable step to eliminate the data-physician confrontation, hence, yielding genetic tests guiding diagnosis, therapy, and family planning [36]. The genetic aspects of multi-factorial diseases should not be neglected because of importance for personalized medicine, preventive precautions, and widening the disease knowledge.

Hetvi Shah's et al., study investigates if the rare and the common variants of the genes, Hirschsprung's disease (HSCR) can serve as a model to understand complex diseases. The finding states that the disease of HSCR has a genetic composition where multiple genes interact to show disease susceptibility. For instance, occasional mutations in the RET gene tend to be allelomorphic with regard to syndrome development, but common variants appear to be having a lesser but not negligible impact. The research paper underlines how the effects of gene-gene interactions are a key to the development of HSCR, rather than of one variant itself, which can be altered by another variant’s presence. The heterogeneity of the expression and the penetrance of HSCR are also addressed; there is individual variability of HSCR in those who are carriers of the predisposing genetic factors, while some who have a lower HSCR risk may not develop the condition, and those who do may exhibit different severity levels. It also accentuates the possibilities offered by findings gained from stem cell research and other sophisticated tools that could subsequently expose HSCR to other factors that are debatably involved in its faulty development and results into defects in various parts of the body. These results give us the broader framework of learning complex diseases where HSCR insights can be used as basis for genetic testing, counselling and treatment. 

Ethics approval and consent to participate

No any animal or human were used during this experimental study.

Consent for publication

The research work embodied in this article is original review work of me and my team. It is neither published nor being considered for publication elsewhere. 

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Not applicable.

Competing interests

The author declares that they have no competing interests.

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Authors’ Contributions

All authors have read and approved the final