Speaker
Description
Background:
Consanguineous unions enhance the risk of homozygous loss-of-function (LoF) variants in the subsequent generations. Hence, highly endogamous populations like Pakistan provides an opportunity to identify naturally occurring human knockouts (hKOs) to further understand the complexity of human genome. We designed this study to identify novel recessive candidate genes underlying neurodevelopmental disorders (NDDs) and to better understand the involved pathobiology.
Methods:
We recruited cases with NDDs, performed clinical evaluation, exome sequencing (ES), reverse phenotyping, and disease modelling to understand disease pathomechanisms.
Results:
We performed ES in 271 unrelated consanguineous Pakistani families for genetic characterization. Our cohort predominantly showed Delayed developmental milestones (90%), speech anomalies (75%), cognitive impairment (70%) with the history of seizures (65%). Less common features included peripheral neuropathy, ataxia, muscle atrophy, and skeletal curvature anomalies. Concordant with the published reports, we achieved a genetic diagnosis (pathogenic/ likely pathogenic variants in a phenotype-matched OMIM gene) in 76 (28%) families. We identified hKOs for 34 genes from 34 families (12%), of which, we are currently pursuing DDIAS, RELCH, and YAF2 for detailed investigations to understand the underlying pathobiology. Further, we observed that 37 (13%) families have VUS in a phenotypically relevant known gene. Fifteen families (5%) carry missense VUS in a gene wherein we have preliminary evidence of candidacy based on relevant biological pathways, functions, and matching cases in the GeneMatcher. Cases from 100 (37%) families harboured VUSs in one or more uncharacterized genes, six remained inconclusive, while three are under process.
Conclusion:
Our cohort of hKOs will serve as a resource to understand the role of involved genes in health and disease. Further, our study will potentially aid in establishing a genotype to phenotype correlation and add to the list of genes critical for neurodevelopment and improve the rate of disease diagnosis.
| Author(s) | Ambrin Fatima1,2 Hammad Yousaf1, Lubaba Bintee Khalid1, Bilal Ahmed Mian1, Asmat Ali1, Zafar Ali3, Farhan Bahadar Ali4, Shahid M. Baig5, Mathias Toft6,7, Zafar Iqbal7 |
|---|---|
| Affiliation(s) | "1. Department of Biological and Biomedical Sciences, The Aga Khan University, Karachi, Pakistan. 2. Centre for regenerative medicine and stem cell research, The Aga Khan University, Pakistan 3. Centre for Biotechnology and Microbiology, University of Swat, Pakistan. 4. Peshawar Medical College, Peshawar, Pakistan. 5. Faculty of Life Sciences, Health Services Academy, Park Road, Islamabad 44000, Pakistan. 6. Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 7. Department of Neurology, Oslo University Hospital, Oslo, Norway." |
