Neurogenetic Mysteries in Consanguineous Families with Trio Exome Sequencing
Neurogenetic diseases, often manifesting as severe disabilities or premature mortality, pose a substantial health and economic burden, especially in populations with a high prevalence of consanguineous marriages. In Turkey, where consanguinity rates reach 24%, autosomal recessive disorders frequently emerge, significantly impacting families and healthcare systems. The advent of trio exome sequencing (WES) offers transformative potential, as evidenced by an international collaborative study involving 190 Turkish families.
Understanding the Study's Approach
This research, spearheaded by experts from Turkey, the UK, and Canada, integrated deep phenotyping with WES to uncover the genetic underpinnings of pediatric neurogenetic conditions. Over 600 individuals, including patients, parents, and siblings, were recruited from three pediatric neurology centers. Unlike conventional diagnostic methods, this approach leveraged advanced bioinformatics platforms, enabling the identification of causative genetic variants across a spectrum of neurogenetic disorders.
Key Findings
High Diagnostic Yield: The study achieved a remarkable diagnostic success rate of 86%, identifying causative variants in 119 known and 27 novel genes. These findings underscore the efficacy of untargeted WES over traditional gene panels, which would have missed over half of the genetic diagnoses in this cohort.
Genetic Insights:
Homozygous Variants: Constituting 82% of detected mutations, homozygous variants highlighted the genetic landscape shaped by consanguinity. Notably, some genes, traditionally associated with dominant inheritance, exhibited recessive pathogenic mutations in this population.
Novel Gene Discoveries: Variants in 27 novel genes, many linked to intellectual disability and epilepsy, expanded the understanding of neurogenetic disease mechanisms.
Impact of Consanguinity: Despite expectations, the causative variants often did not align with the longest runs of homozygosity, complicating diagnosis in families with extensive consanguinity.
Pathway Insights: Gene ontology analyses pinpointed disrupted pathways, particularly those related to transcription, protein synthesis, and lipid metabolism. These insights pave the way for targeted therapeutic strategies.
Clinical Implications
Beyond providing diagnoses, the study delivered actionable outcomes for families. In 24 cases, genetic findings enabled targeted treatments, improving patient outcomes and offering hope for similar cases. Additionally, genetic counseling prevented further transmission in many families, illustrating the broader societal and economic benefits of comprehensive genomic approaches.
A Paradigm in Diagnostics
This study exemplifies the shift from pre-screening and gene panels to WES as the gold standard for diagnosing complex neurogenetic disorders. The ability to uncover rare and novel genetic mutations at comparable costs to targeted methods highlights its practicality and transformative potential, particularly in consanguineous populations.
Future Directions
While WES proved immensely effective, unsolved cases point to the need for whole-genome sequencing and transcriptomics to uncover intronic, structural, and epigenetic contributors. The integration of new technologies will likely enhance diagnostic rates, further unraveling the complexities of neurogenetic diseases.
Conclusion
This study not only advances our understanding of neurogenetic diseases in consanguineous populations but also sets a benchmark for global genomic research. By leveraging WES and international collaboration, it illuminates the path toward equitable, effective, and personalized genetic diagnostics.
References:
Hiz Kurul, S., Oktay, Y., Töpf, A., Szabó, N. Z., Güngör, S., Yaramis, A., ... & Horvath, R. (2022). High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases. Brain, 145(4), 1507-1518.
