Neurodevelopmental disorders (NDDs) represent a complex web of genetic underpinnings,

particularly in ethnically diverse populations with high rates of consanguinity. Despite their

prevalence, the genetic causes of NDDs remain largely unexplored in many such populations. A

recent study aimed to address this gap by investigating the genomic landscape of a

well-phenotyped cohort of 576 neurodevelopmentally affected individuals from Bangladesh, of

whom 16% came from consanguineous families. This is the largest genomic diagnostic study

conducted on Bangladeshi children with NDDs.

Diagnostic Yield: Using Different Technologies

The study employed multiple advanced genomic techniques to uncover the genetic basis of

NDDs. These included chromosomal microarray (CMA), exome sequencing (ES), combined

CMA and ES, and long-read genome sequencing, each of which provided valuable insight into

different aspects of genetic variation. The integration of clinical multivariate data with genomic

variants enabled deeper stratification and analysis of the participants, revealing important

diagnostic information.

• CMA identified genetic causes in 17% (42/576) of cases.
• Exome sequencing showed a higher yield, diagnosing 29.92% (38/576).
• When CMA and ES were combined, the diagnostic rate increased to 37.13% (75/576).

Crucially, the study demonstrated a significant difference in diagnostic yield between children

from consanguineous and non-consanguineous families, with the former having a notably higher

success rate (p<0.01).

Horizon Intelligence: Powering Precision Genomics for Better Outcomes

GenomeArc's Horizon platform was instrumental in achieving these diagnostic insights. By

leveraging Horizon’s advanced AI and data integration capabilities, the study team could

streamline the interpretation of genetic variants, particularly in the context of complex

multivariate data. Horizon enabled the seamless combination of clinical phenotypes and

genomic results, allowing researchers to explore deeper associations between novel genetic

variants and neurodevelopmental outcomes. This precision-driven approach highlighted the

critical role of Horizon in identifying pathogenic variants in this ethnically diverse and

consanguineous population.

For instance, exome sequencing uncovered novel pathogenic variants in 36.19% (38/105) of

cases, implicating 35 unique genes—many of which had not been previously associated with

NDDs. Furthermore, long-read sequencing in unresolved cases revealed expanded FMR1

trinucleotide repeats, a known factor in seizure disorders.

G6PD Association to NDD: Surprising Unique Findings with Population-Specific

Relevance

One of the most striking results was the identification of recurrent X-linked variants in the G6PD

gene, found in 3.65% (12/329) of NDD participants. These variants were absent from large population control cohorts, including those with neurodevelopmental and neuropsychiatric

disorders of European descent. This suggests that G6PD may play a population-specific role in

NDD risk, likely influenced by ancient genetic drift. Such findings would not have been possible

without the deep phenotyping and high-resolution genomic analysis enabled by the GenomeArc

Horizon platform.

Conclusion: A Promising Step Forward in Genomic Medicine

This groundbreaking study sheds light on the genetic underpinnings of neurodevelopmental

disorders in a consanguinity-rich Bangladeshi population, with Horizon providing the necessary

infrastructure to achieve a high diagnostic yield. The study's findings underscore the importance

of population-specific genetic research and the power of advanced genomic platforms like

GenomeArc Horizon in driving precision medicine.

By revealing novel gene associations and offering better stratification of genetic risks in

consanguineous families, the study holds great promise for improving NDD diagnosis and

treatment in underrepresented populations. With Horizon’s robust capabilities, GenomeArc

continues to lead the way in the quest for more inclusive and accurate genomic diagnostics.