Introduction

The rare genetic condition known as CHARGE syndrome is defined by a series of birth defects, mainly caused by a mutation in the chromodomain helicase DNA-binding (CHD7) gene.¹ The most notable associated defects include coloboma, abnormal semicircular canals and choanal atresia, all of which are part of the diagnostic criteria. However, due to the CHD7 gene’s critical function in normal foetal development, patients can present variable structural and heart defects, or in rare cases, the immune system can be affected, depending on the nature of the CHD7 gene mutation. As a result, the type of genetic mutation in Charge syndrome is important to be determined and discussed during the process of genetic counselling.   

CHD7 mutation in CHARGE Syndrome

Genetic information, otherwise known as deoxyribonucleic acid (DNA), mainly exists in the form of chromatin, which is a looser form of the more commonly known chromosome.² The DNA double helix is wound around proteins called histones, which keep the DNA organised in the nucleus of the cells. If a segment of DNA is tightly wound around a histone, it is inaccessible to other proteins, and the genes are therefore “switched off” in that DNA region. The role of CHD proteins, such as CHD7, is to alter the chromatin structure, determine the accessibility of certain genes, and the production of the protein that those genes code for.³ 

CHD7 has been linked to various foetal developmental facial features – such as the nose, eyes and ears due to mainly being expressed (turned on) in the neural crest. This structure acts as the precursor of parts of the nervous system, skull and heart structures.^4,5 

Therefore, mutations in CHD7 that affect its normal function can result in defects in these tissues of patients with CHARGE syndrome.

De novo CHD7 mutation

The most common type of CHD7 mutation found in CHARGE syndrome patients is known as a de novo mutation.¹ In short, the mutations occur spontaneously in the sperm or egg cells of the parents.⁶ This means that in the case of CHARGE syndrome, the parents of the patient would not have a somatic mutation in the CHD7 gene if they undergo genetic testing, because the genetic change is found only in the reproductive cells.

In instances when CHARGE syndrome is suspected prenatally (such as during prenatal ultrasound scanning), it may be appropriate to test for de novo CHD7 mutations, particularly if the parents have tested negative for the somatic mutation.^7,8 

Certain heart and structural abnormalities of the skull are amongst some of the features detected by a sonography that can justify prenatal genetic testing, which involves taking a foetal DNA sample from the mother’s blood (foetal cell-free DNA) for whole genome sequencing (WGS). A comparison to the parents’ DNA would confirm a de novo CHD7 mutation.⁹

Inherited CHD7 mutations

In rare cases, CHD7 mutations can be inherited from the parents in an autosomal dominant manner.⁹ This means that the child would develop CHARGE syndrome if they inherit one copy of the mutated CHD7 gene. However, individuals who inherit CHD7 mutations are more likely to have increased variance in severity. This mainly depends on the nature of the mutation and if they have two mutated copies (inherited from each parent) or one mutated copy, which is more likely to be milder, as these heterozygous individuals will still have a functional copy of CHD7.⁹ 

Genetic counselling

Identifying the type of CHD7 gene mutation individuals with CHARGE syndrome have is an important basis of genetic counselling. It allows healthcare providers to have a tailored approach when educating families about the risks: how CHARGE syndrome can develop or be inherited, and the specific options available. It is also important to carry out genetic testing on the patient and on the parents, as it can shed light on the potential risks of having another child with CHARGE syndrome.⁹

For instance, when discussing risks of generational inheritance and the likelihood of having another child with CHARGE syndrome, both outcomes are far less likely in individuals with de novo mutations. Since neither parent carries the mutated CHD7 gene in de novo cases, the risk of having another child with CHARGE syndrome is only about 1-2%.⁹ This risk is mainly due to the likelihood of one of the parents having mosaicism in the egg or sperm precursor cells. Germline mosaicism is a rare phenomenon where an individual has at least two genomes in the cells of their gonads, one of which may contain a CHD7 gene mutation that is later passed onto the offspring.¹⁰

In the case of inherited CHARGE syndrome, because it is an autosomal dominant disorder, the child only develops the disease even if they inherit just one mutated CHD7 gene.⁹ As a result, the likelihood of the children acquiring CHARGE syndrome depends on the genotype of the parents. For instance, if one parent had two normal copies of the CHD7 gene and the other had one normal copy and one mutated copy (heterozygous), the likelihood of having a child with CHARGE syndrome is 50%. If both parents had one normal and one mutated CHD7 gene, then the likelihood would increase to 75%; this increases to 100% if both parents are carriers of one mutated CHD7 gene or one parent has two copies.⁹ 

Other topics expected to be discussed during genetic counselling are disease progression and severity, treatment options and what symptoms to expect. Disease severity mainly depends on whether the child has one or two mutated CHD7 genes, with the heterozygous types usually having milder symptoms and defects.¹¹ 

Counselling must be delivered with care and empathy. Families need to be well informed to make conscious decisions about their pregnancies and the treatments they need to consider for their child, making a tailored approach depending on the mutation type. It is also important to provide emotional support for families and provide continuous guidance throughout the process.

Summary

• CHARGE syndrome is a developmental disorder caused by CHD7 gene mutations 
• Symptoms mainly include coloboma, abnormal semicircular canals, choanal atresia and heart defects 
• De novo mutations are the most common causes of CHD7 gene mutations in CHARGE syndrome and occur spontaneously in the sperm or egg cell, and are not inherited from either parent 
• Inherited CHD7 gene mutations are passed down from parent to child in an autosomal dominant manner, meaning the child only requires one copy of the mutated gene to acquire CHARGE syndrome 
• Genetic testing is essential to deliver tailored genetic counselling, which is needed to appropriately inform patients on the risks, likely outcomes and what to expect when it comes to recurrence in future pregnancies and generations