Faulty Proteins and Failed Genes: Understanding the Biology Behind Congenital Diseases

Patients with congenital diseases often experience a range of uncomfortable symptoms. On one side of the world, a family with erythromelalgia, a painful condition which can cause redness and swelling of the skin, has difficulty walking. The condition affects their feet and the discomfort has lasted for weeks.

Elsewhere, two young patients with Jansen Type Metaphyseal Chondrodysplasia discuss a pain chart with their clinician. Their skeletal disorder, which less than twenty people have been diagnosed with worldwide, causes swollen joints, abnormal development, and a slight stature. Having expressed their level of pain, they then ask the clinician: “What does the smiling face mean?”

Research on congenital diseases has previously been lacking. However, according to The Economist, researchers studying genomics are gaining important insight into genetic mutations and what these reveal about humans on a biological level.

What is Genomics?

The National Human Genome Research Institute describes genomics as “the study of all of a person’s genes (the genome), including interactions of those genes with each other and with the person’s environment.”

In other words, genomics is the study of DNA – what makes you who you are. Approximately 3 million DNA base pairs make up your genome. A change in any pairs, gene, or cell can cause a congenital disease or disorder. By studying these changes or mutations, researchers are better positioned to provide people with these conditions with more knowledge.

Understanding Congenital Diseases

Dr. Mark Caulfield, the Chief Executive of Genomics England, shared that patients looking for a diagnosis through genomic testing can wait up to five years. In the case of the patients with Jansen Type Metaphyseal Chondrodysplasia, it took even longer. However, Caulfield also notes that testing has become faster as the field grows, with waits times averaging a few weeks to a few months.

Why is this important?

Many of those with genetic disorders may experience negative or uncomfortable symptoms. While many congenital diseases may be treated, some cannot be cured. However, genomic testing can pinpoint the exact gene mutations and defects. As such, clinicians can alter treatment to best suit patient needs.

Accurate diagnoses help patients stop invasive searches for answers. More so, it provides patients and their families support from others with the same diagnosis.

When four-year-old Jessica was experiencing delayed development, genetic sequencing discovered a misprint in her SLC2A1 gene that caused her cells to make too little of a specific protein. This meant that her brain was not receiving enough sugar to operate. Researchers suggested she try a low-carbohydrate diet. As a result, Jessica’s brain received more calories to promote higher function.

Six-year-old Mila was diagnosed with Batten Disease, an inherited nervous system disorder in which a build-up of lipopigments can cause seizures, vision loss, and a loss of motor skills. Through genomic sequencing, researchers discovered that her type of Batten Disease was due to an unhelpful protein. Neurologist Tim Yu produced an aso – milasen – specifically for Mila’s genome, which has provided relief from the symptoms. This gives a hopeful look into the future of genomic testing and the implications for congenital diseases.

Additionally, drug trials tailored around a target with a causal disease connection are two times more likely to develop a working drug.


Antisense oligonucleotides (asos) are a beneficial treatment solution for congenital diseases. When mutated genes are transmitted via messenger RNA, they create faulty proteins. Antisense drugs bind to messenger RNA. As a result, the faulty protein is not created.

Congenital diseases and disorders created by faulty proteins include:

  • Familial hypercholesterolemia – an inherited form of high cholesterol from LDLR, APOB, PCSK9, or LDLRAP1 genetic mutations.
  • Types of Duchenne Muscular Dystrophy – muscles cannot create dystrophin, which causes weakness, respiratory issues, and quadriplegia.
  • Spinal muscular atrophy – a mutation in the SMN1 gene causes muscle degeneration. There are four types of SMA, which are differentiated by the age of those who have it and their symptoms.

Antisense drugs can be tailored to each specific patient and congenital disease. Current drug trials in this realm exist for Huntington’s Disease, an adult-onset neurological condition which can cause personality changes, cognitive decline, and changes in motor skills. But researchers soon hope to find new solutions for sclerosteosis and van Buchem’s disease, Brown-Vialetto-Van Laere disease, and more beyond what is already available.

Biotech company Checkmate Pharmaceuticals can create an aso for patients within a year of discovering a faulty gene.

What’s Next?

Maze Therapeutics is researching genetic modifiers which may cause some congenital diseases to affect some people more quickly than others. The n-Lorem Foundation wants to be a key player in the development of asos.

There is still much research to be done in the realm of genomics and congenital diseases. But the strides made have taught researchers a lot about how human biology works, and how to approach future solutions.

Jessica Lynn

Jessica Lynn

Jessica Lynn has an educational background in writing and marketing. She firmly believes in the power of writing in amplifying voices, and looks forward to doing so for the rare disease community.

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