Introduction

Have you ever wondered how a tiny change in our DNA can shape the way our bodies grow and develop? Our genes are like an instruction manual, and when a single page is altered, the results can be surprising. In Ellis-Van Creveld Syndrome, changes in two genes, EVC and EVC2, result in distinct differences in growth, especially in bones. 

Here, we’ll break down the science behind Ellis-Van Creveld Syndrome, exploring EVC and EVC2 genes, the effects of their mutations, and what this research means for the future of this genetic disorder. 

What is ellis-van creveld syndrome? 

Ellis-Van Creveld Syndrome (EVC) is a rare, autosomal recessive disorder. When a disease is recessive, the child must inherit two copies of the mutated gene from each parent, and autosomal means that this mutation is not located on a sex chromosome (X or Y). EVC is a skeletal dysplasia, mainly affecting bone growth and development. Patients clinically present with short stature, slowed growth, dental anomalies, polydactyly in the hands (extra fingers), as well as ectodermal and heart defects.¹ 

Importance of studying the genetic basis

There is a great importance in understanding the genetic basis of Ellis-Van Creveld Syndrome; knowing the exact mutations helps medical professionals establish an accurate diagnosis. This is especially helpful when clinical symptoms are unclear and inconclusive; in these cases, genetic testing can confirm whether a patient has EVC. Moreover, it supports genetic counselling, parents and families can make more informed decisions when they know whether the condition runs in the family and understand the effects of the genes involved.² With this information, they can make more informed decisions with greater confidence. In addition to diagnosis and counselling, uncovering molecular mechanisms opens the door for potential future therapeutics, offering hope for families affected by EVC.³ 

Overview of ellis-van creveld syndrome

Before going into the genetic basis of the disease, it is important to understand how common it is and how it affects patients. 

Epidemiology

Ellis-Van Creveld Syndrome is quite rare. Currently, about 250-300 cases have been reported. While it is estimated that around seven in every 10,000 people have this syndrome in isolated populations, these rates can be much higher. For example, in the Amish population, about 13% of the people carry the gene for EvC.¹

Symptoms

Symptoms of EVC may vary between patients. Polydactyly, meaning extra digits in the hands, is the most common, with 98% of patients presenting with extra fingers on both hands. Polydactyly in toes is less common but can still be present. Growth deficiency, both during pregnancy and after birth, is also very common for children affected by the condition. This results in short stature and shorter limbs. Bones may also develop more slowly, sometimes there can be fusions between bones of the hand and an underdeveloped rib cage. Another very common symptom is abnormalities in teeth, which can be highly varied. Most are growing in late stages as well as missing teeth (hypodontia). Underdeveloped (hypoplastic) nails with other deformations, such as discolourations, are among the common features too. Alongside these symptoms, heart problems from birth are frequent in individuals with EVC too.⁴

Mode of inheritance

To understand how EVC is inherited, it's good to understand a bit about genetics. All of us have two copies of each gene, one from each parent. Each gene has a specific sequence that determines its function. Sometimes changes occur in these sequences that can affect a gene’s function, these are called mutations.

 In the case of EVC, there are two mutations present in genes EVC and EVC2. The disease shows autosomal recessive inheritance, meaning that two copies of the mutated gene are needed for the disease to be present. This also means that both parents of the affected individual carry one copy of the mutated gene. Because two copies are needed, the disease tends to skip generations. This is the main reason why Ellis-Van Creveld Syndrome is so rare.⁵

Genetic basis of ellis-van creveld syndrome

Although there are several genes and mutations linked to Ellis-Van Creveld Syndrome, the most prominent mutations are in genes EVC and EVC2. 

Location, structure and function of EVC and EVC2 genes

Both EVC and EVC2 genes are located on chromosome 4, where they are adjacent to each other. This adjacency suggests that their activity is coordinated. It was also shown that there are no differences in the phenotypical manifestations of mutations in these two genes.⁶

The EVC gene encodes the protein called EVC, while the EVC2 gene encodes the protein limbin (or EVC2).¹ These proteins help transmit signals in what is known as the Hedgehog (Hh) signalling pathway. This pathway plays a crucial role in controlling growth and development, particularly in bones, teeth, nails, and other corresponding parts of the body.⁷ It influences how developing bones get their correct shape and length, how teeth form, and how skin and nails develop. When things go wrong in this pathway, such as the mutations in the EVC and EVC2 genes, the physical manifestation of this mishap is shorter bones, extra fingers, and missing teeth. 

Pathogenic mutations

Various types of mutations have been identified in both EVC and EVC2 genes. 

• Missense mutations: Missense mutations happen when only one nucleotide in the DNA sequence is changed. This causes the amino acid (the individual molecules that make up proteins) to be different from the original, affecting the function of the protein.¹⁰ The level of functional change depends on the specific amino acid change
• Nonsense mutations: A nonsense mutation is where the change in nucleotide causes a “stop” signal before all of the protein is encoded. This results in a shortened protein that can’t function properly.¹⁰ In 2007, researchers assessed 65 EVC patients and identified that the majority of the mutations in Evc and Evc2 resulted in a premature termination of the protein⁹ 
• Splice-site mutations: Splice-site mutations change where the raw transcript (pre-mRNA) is cut and stitched together. In the case of wrong splice sites, important information can be left out, or the wrong bits might be incorporated. This can, in turn, produce abnormal and dysfunctional proteins.¹⁰ In the case of EVC, two splice site mutations in EVC have been identified and reported to cause exon skipping, altering how the protein is built
• Deletions: In the case of certain mutations, nucleotides can be deleted. This means loss of information and can result in critical parts of the protein being missing^9,10 
• Insertions/ Duplications: This happens when extra nucleotides are added to the gene. This often shifts the “reading frame”, meaning wrong translation of the gene into the protein.¹⁰ A 15-basepair duplication of exon 14 of the EVC gene has been identified⁶ 

Effects of mutations on protein function and signalling pathways

There could be several outcomes of these mutations, which can differ between patients: 

• EVC and EVC2 proteins might be fully absent, or if present, completely dysfunctional¹¹ 
• EVC and EVC2 proteins might not be able to localise in their correct region (the cell membranes of cilia). This could prevent them from interacting with other proteins. This can disrupt the Hedgehog (Hh) signalling pathway responsible for growth and development¹¹
• As a result of the disrupted Hh pathway, bone growth is affected¹¹ 
• In some rarer cases, mutations may result in a dominant negative effect, meaning that abnormal proteins produced from faulty genes can interfere with the functioning of normal proteins, contributing to varying symptom severity between patients¹²

Mechanism of disease development

With Ellis-Van Creveld Syndrome, understanding the underlying disease mechanisms involves examining the molecular disruptions, particularly the Hedgehog (Hg) pathway. Disruption of the Hedgehog Signalling Pathway

Hedgehog pathway is an essential signalling pathway inside our cells, telling them when and how to grow, divide, and take on specific roles. Under normal conditions, EVC and EVC2 proteins reside in the membrane of the primary cillium. They relay signals to other proteins within the cell as part of the pathway.

 Figure 1 illustrates the signalling mechanism. Upon the binding of Hh ligands to the cell membrane protein, another protein called Smo is released and can interact with EVC and EVC2 proteins. Following this, complete disassociation of inhibitory complex Sfu/Gli3 is promoted, leading to now free Gli3FL, which can go into the nucleus and bind to DNA, turning on the gene expression. As a result, this pathway directs the development of bones, such as their lengthening, separation of fingers and toes, and formation of ectodermal tissues such as nails, teeth, and skin.¹¹

In Ellis-Van Creveld Syndrome, mutations in the EVC and EVC2 genes disrupt this process, leading to absent, altered, or misplaced proteins, which prevent proper propagation of the Hh signals and cause abnormal bone growth and ectodermal development.

Summary 

Ellis-Van Creveld Syndrome is a rare genetic disorder caused by mutations in the EVC and EVC2 genes, which have a crucial function in relaying signals within the cell as a part of the Hedgehog signalling pathway. This pathway guides information on bone, teeth, and nail growth and development. Disruption of it leads to the hallmark clinical features: short stature, extra fingers, teeth and nail defects, and heart conditions. Understanding the genetic basis of EVCallows for a more accurate diagnosis helps understand inheritance risks, and provides more effective genetic counselling for those affected and their families.