Research directions
Genetic of autosomal recessive intellectual disability and developmental delay
Intellectual disability and developmental delay (ID/DD) constitute a highly heterogeneous group of disorders that affect 1-3% of European individuals and, due to their life-long consequences, have a major impact on families, healthcare systems and society. ID/DDs are the most common reasons for referrals to genetic services and their most severe forms are caused by single genetic defects. While autosomal dominant (AD) de novo mutations are the predominant cause of ID/DD in Western countries, autosomal recessive (AR) gene defects are the leading genetic cause of ID/DD in countries with frequent parental consanguinity, i.e., the marriage of close relatives, for religious, cultural and/or economic reasons. This inbreeding dramatically increases the length of homozygous regions in the genome of the offspring, and therefore may bring to homozygosity deleterious alleles of AR disorders. While the advent of high-throughput sequencing technologies allowed the identification of hundreds of causative genes, about half of patients remain without a diagnosis suggesting that numerous additional genes remain unknown.
To start filling this gap, we propose to study consanguineous families with multiple affected individuals from Pakistan, which has more than 220 million inhabitants and one of the highest inbred populations in the world. We are confident that the enrollment and sequencing of the affected individuals of families with ID/DD will lead to the discovery of novel causal genes.
Besides their scientific relevance, in as much as they provide a better understanding of the pathophysiological processes involved, thus opening avenues for therapeutic research, these discoveries are of utmost clinical importance not only to the specific families or geo-ethnic groups, but to patients worldwide since they improve diagnostic possibilities in every clinical setting.
