Exploration génomique de la déficience intellectuelle

Intellectual disability (ID) regroups greatly heterogeneous conditions that are characterized by early-onset cognitive impairment. ID affects about 1-3% of Western populations; but its prevalence is much higher in deprived regions of the world where socio-demographic factors like poor healthcare, lack of resources and parental consanguinity prevail. Non-genetic factors are involved in the etiology of ID; approximately 25% of ID cases are of genetic origin. Traditionally, the molecular basis of ID have been assessed through cytogenetic analyses, genetic mapping and candidate gene approaches. These classical genetic tools are still put to the test in the study of complex diseases like ID.  Until recently, X-linked ID cases were the main focus of studies on ID with more than hundred ID genes identified only on the X chromosome. Compound heterozygous mutations are identified in autosomal forms of ID, in the context of non-consanguineous unions. However, the occurrence of such mutations is rare in outbred populations, so that dominant de novo mutations are most common in unrelated individuals. Homozygous mutations are expected in consanguineous unions or in populations marked by a founder effect. In fact, the molecular bases of autosomic recessive ID have been almost exclusively studied in populations with high consanguinity rates. ID remains unsolved in more than 60% of patients. In the absence of environmental factors associated with ID in these individuals, it is possible to consider that unidentified genetic factors are involved in these unexplained ID cases. In this research project, we used next generation sequencing technologies to highlight the genetic causes of ID in twenty families were an autosomal recessive mode of inheritance is expected. We prioritized the use of whole-exome sequencing, namely all coding exons in the genome of this individual. In our analyses, we filtered out variants that were too common in control individuals to describe a rare condition like ID. We focussed our attention on rare autosomic recessive varaiants (homozygous and compound heterozygous), these mutations were confirmed by Sanger re-sequencing to segregate with an autosomal recessive mode of inheritance in the family. We identified mutations in candidate genes for ID in some of the family analysed, we validated the functional impact of the mutations in these genes to confirm their involvement in the pathophysiology of ID in the family studied. We explained the molecular basis of ID in eight of the families studied. We identified the second case of Warsaw-Breakage-Syndrome, a rare genetic disorder characterised by dysfunction of the RNA helicase DDX11. We showed that disruption in TBC1D7, a functional subunit of the TSC1-TSC2 protein complex, cause ID and megalencephaly. We demonstrated that ASNS, the Asparagine Synthetase gene, is defective in patients with congenital microcephaly and progressive encephalopathy. We showed that the gene coding for the mitochondrial protein MAGMAS is involved in the pathophysiology of a condition characterised by developmental delay and severe skeletal dysplasia. We identified a truncating mutation in SPTBN2, encoding for the spinocerebellar ataxia 5 proteins, in a family with ID and spinocerellar ataxia. We also identified a mutation in a gene involved in the biosynthetic pathway of glycosylphosphatidylinositol anchors; the mutation in PIGN may cause the epilepsy and hypotonia features observed in the affected individuals of that family. Finally, we identified a loss of function mutation in CLPB, coding for a mitochondrial chaperone, in individuals with severe encephalopathy, hypereklexia and 3-methylglutaconic aciduria. The diagnostic potential of next generation sequencing technologies is undeniable. These technologies will revolutionize the world of molecular genetics; they will help deciphering the molecular basis of complex diseases like ID.

Keyphrases: DDX11, TBC1D7, ASNS, MAGMAS, PIGN, SPTBN2, CLPB, Intellectual deficiency, Exome sequencing