Rare diseases, as the name suggests, are found at a low frequency in any country or population set. Now, because the diseases occur at a low frequency, the opportunities to study them in detail are therefore scarce. Hence, the diagnosis of such disorders is not easy. Some symptoms like progressive blindness or the cat’s eye sign seen in retinoblastoma cases are very well known features of the syndrome and are a dead giveaway. What if there are symptoms that can be indicators of several different health issues? How is it possible to then zero in on a particular diagnosis, with a high degree of confidence?

This is one area, where genetic analyses can be of particular help. Genetic tests can provide insights into the molecular defects that cause rare disorders, such as birth defects evident in very young infants.

Let us take the case of a child who was referred to a prominent pediatrician and rare disease expert in Hyderabad. The child, let’s call her Trisha, showed signs of slow development at the age of 5 months. She had poor eye contact and persistent head nodding movements. Essentially, she had poor control over her neck muscles. Naturally, her parents were worried because by the age of 5-6 months, most babies develop a steady gaze and are also able to support their neck.

Trisha’s doctor asked her parents to get an MRI of her brain to understand if there are developmental issues. Additionally, she also asked them to provide Trisha’s blood sample to Strand Life Sciences, for genetic analysis.

Trisha’s brain MRI showed that she has a condition known as Joubert syndrome. Joubert syndrome is a developmental condition wherein the connections between the right and left halves of the brain are not formed properly. Joubert syndrome is a rare disorder with a frequency of incidence of 1/80,000 to 1/110,000 live births. However, the incidence of this syndrome can be as high as 1/5000 live births in societies with a high degree of consanguinity (marriage between blood relatives) and intermarriage, like some Arab societies. As it turns out, baby Trisha’s parents were cousins.

Genetic analysis revealed that Trisha’s genome did not have any copies of the NPHP1 gene. Normally, we all have two copies of most of the genes within us. Sometimes, we can get by on having one normal gene copy and one abnormal one. However, when both copies of any gene are either damaged (mutated) or are missing (deletions in chromosomes), then serious developmental defects can show up.

Normally, deletion mutations, wherein entire sections of a chromosome are missing, are hard to identify during genetic analysis, particularly when a technique called Next Generation Sequencing (NGS) is used. NGS is used as a standard laboratory technique in most genetic diagnostic labs. The process is akin to tearing up a book into fragments and then reading out specific bits of the book to piece the story back together. Several rounds of reading the specific bits are called ‘readouts’.

The analysis of the data that comes from such NGS readouts is where Strand’s custom-designed software makes all the difference. There are several software modules available for analysis of NGS readouts. However, most of them have the problem of not being able to detect deletions and insertions of abnormal gene segments. Strand NGS on the other hand, a software that has been built from scratch by bioinformaticians at Strand, has been designed to also pick up such anomalies.

In Trisha’s case, as seen in this figure, there were no readouts in the NPHP1 gene (area between two arrowheads), whereas the neighbouring genes were read correctly. The correct readouts are seen in green as two copy number variants.

absence of NPHP1 gene in Joubert syndrome

Screenshot of NGS Analysis showing deletion of the NPHP1 gene. The black bars show that the gene is missing in the child’s genome.

The genetic analysis confirmed the diagnosis of Joubert syndrome in this infant.

Her parents were counselled about lifestyle management strategies that can help them cope with their child’s slow development.

Strand offers several such tests for other developmental conditions including muscle defects and deficiencies of enzymes and other specific proteins.