THE GENETIC ROOTS OF RARE DEVELOPMENTAL DISORDERS

KAIMRC’s Medical Genomics Research Department is the only unit of its kind in Saudi Arabia, taking patients from initial genetic testing to a formal diagnostic report.

Policy-makers and researchers use ‘rare disease’ to describe a disorder that affects a small percentage of the population, but the term is slightly misleading—collectively, these disorders are estimated to affect roughly 5% of the world’s population. However, this collective figure comprises thousands of debilitating disorders and syndromes that are each very uncommon, some arising in fewer than one in a million newborns. Discovering the basis of these diseases not only offers the possibility of screening for them – and perhaps developing treatments – but also improves understanding of human development.

These conditions can often be traced to malfunctions in just a single gene, and Majid Alfadhel’s team at the Medical Genomics Research Department (MGRD) at KAIMRC is actively engaged in tracking down these causative mutations. “The conditions that most interest me are known as ‘inborn errors of metabolism’,” says Alfadhel, chairman of the MGRD referring to a category of genetic disorders that interfere with essential enzymatic pathways underlying the manufacture and digestion of fats, proteins and other biomolecules.

A subtle mutation in an enzyme can have far-reaching consequences. For example, it could lead to the accumulation of toxic chemical intermediates, or deficiencies in necessary cellular building

blocks, which could stunt normal development and lead to lifelong disabilities or even early death. To uncover such mutations, Alfadhel’s team works with patients and their families, using genome sequencing to identify potentially causative mutations that are subsequently validated through computational analysis and functional testing in the laboratory.

The MGRD is the only unit of its kind in Saudi Arabia, taking patients from initial genetic testing to a formal diagnostic report, and Alfadhel says that his team has achieved a roughly 50% success rate in finding causative mutations. In just two years, they have characterized 20 new genes and gene variants, and established formal diagnoses for six diseases. These achievements pave the way for developing molecular diagnostics that could help doctors recognize such syndromes earlier and could even suggest therapeutic interventions that might halt or slow disease progression.

Most rare genetic disorders are recessive, which means they only produce symptoms in children who have inherited mutations affecting both copies of a gene. To identify these, it is ideal to also perform genomic analysis of unaffected siblings and parents, because these can help researchers quickly home in on genes that are doubly mutated only in the patient. For example, in one study from February 2020, the MGRD team performed whole-genome sequencing on the full immediate family of a young boy with global developmental delay (GDD), axial hypotonia, and impaired neurological function, including extremely limited speech.1 This allowed them to identify a mutation that alters the amino acid sequence of an enzyme called UDP-glucose dehydrogenase (UGDH), which contributes to the production of certain complex carbohydrates.

Several studies in animal models have indicated that UGDH is essential for healthy development, with malfunctions having particularly severe consequences for the heart, brain and skeletal system, but this study was the first time that a mutation in this gene had been directly linked to human disease. Alfadhel and his colleagues predicted that the mutation they discovered destabilizes the UGDH enzyme and impedes its normal catalytic activity.

In a second study from September 2020, Alfadhel’s team uncovered the mutation underlying a syndrome affecting a brother and sister who exhibited mild intellectual disabilities, GDD, and distinctive dysmorphic features including a ‘triangular’ facial structure.2 The initial diagnosis was made by whole exome sequencing of the young girl—the subset of the genome comprising protein-coding genes—which led the investigators to a causative mutation in a gene called EMC10. They subsequently confirmed this mutation’s role through targeted genetic analysis of the parents and the girl’s affected brother.

EMC10 encodes one subunit of a complex that facilitates the folding of other proteins. Defects in other components of this complex are known to have far-reaching effects, producing a spectrum of neurological problems, but this was the first description of a clinical effect of mutations in EMC10.

“This gene plays a key role in developmental milestones, with the potential to cause neurodevelopmental disorders,” says Alfadhel. Unlike in the case of UGDH, this mutation did not affect the protein-coding region of the gene, but rather one of the regulatory elements involved in splicing. Splicing is the biochemical process that cells use to prepare newly-transcribed RNA molecules for translation, and defects here can lead to proteins that are truncated or contain jumbled sequence features.

Splicing abnormalities were also the culprit in a third study, where the MGRD team investigated four individuals from two different families affected by GDD3 that describes children born with clear deficits in motor function, social behaviour, speech, or other neurological functions. Whole-genome sequencing showed that all four patients had the same mutation in both copies of a gene called RAP1GDS1, an important signalling molecule that facilitates a wide range of cellular activities.

Alfadhel notes that this particular syndrome—which may now acquire his name, as its discoverer—highlights a potentially important developmental role for a broader class of signalling proteins. “Our observations add to the diverse and multi-symptomatic group of Mendelian disorders caused by variations in the RAP1GDS1 gene and related pathways,” he says.

The broader goal of the MGRD is to go beyond discovery, to translate their findings into meaningful changes in clinical practice and patient care. To this end, the department is building ties with other research centres, hospitals, and pharmaceutical companies to develop more sophisticated diagnostics and drugs based on their genetic findings.

But Alfadhel and his team are also looking into opportunities to further streamline their workflow and achieve an even higher diagnostic success rate. “We need to improve the genome databases and our ability to differentiate between pathogenic and benign variants, and minimize the variants of unknown significance,” he says, referring to mutations for which the functional impact is insufficiently clear to indicate a role in disease. More sophisticated computation could play a role here, and Alfadhel is keen to make use of artificial intelligence and other algorithmic tools that could enable faster and more accurate interpretation of complex genomic data from many individuals.

1. Alhamoudi, K.M., Bhat, J., Nashabat, M., Alharbi, M., Alyafee, Y., Asiri, A., Umair, M. & Alfadhel, M. A missense mutation in the UGDH gene is associated with developmental delay and axial hypotonia. Front. Pediatr.8, 71 (2020). 2. Umair, M., Ballow, M., Asiri, A., Alyafee, Y., al Tuwaijri, M., Alhamoudi, K.M., Aloraini, T., Abdelhakim, M., Althagafi, A.T., Kafkas, S. et al. EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability and speech delay. Clin. Genet. 98, 555–561 (2020). 3. Asiri, A., Aloyouni, E., Umair, M., Alyafee, Y., Al Tuwaijri, A., Alhamoudi, K.M., Almuzzaini, B., Al Baz, A., Alwadaani, D., Nashabat, M. et al. Mutated RAP1GDS1 causes a new syndrome of dysmorphic feature, intellectual disability & speech delay. Ann. Clin. Transl. Neurol. 7, 956–964 (2020).