Abstract EN:

Chromosomal microarray analysis is commonly used in the field of neurodevelopmental phenotype. SNP array allows whole genome analysis to identify both copy number variants (CNVs) and ROHs. We screened a cohort of 5,050 patients with neurodevelopmental phenotype. In the first part, we focused on small CNVs with only one or two genes to characterize the genotype and the phenotype associated with several microdeletion syndromes. Our results allowed us to identify XPO1, USP34, BCL11A, EFNB2, NR4A2 genes involved in a neurodevelopmental phenotype and compound heterozygous variants in the INTU gene implicated in oral-facial-digital syndrome type VI. Then, we discussed how CNVs can modify the 3D organization of the genome by disrupting chromatin domains, resulting in Beckwith-Wiedmann syndrome in one case. In the second part, when SNP array revealed no genomic imbalances, we performed a region of homozygosity (ROH) analysis. These ROHs indicate ancestral homozygosity, uniparental disomy, or parental consanguinity depending on the size, the location and the chromosome(s) involved. In the context of several genetic disorders in children of consanguineous parents, the identification of the causal gene can be difficult given the great genetic and clinical heterogeneity. In these families, the mutated gene in the homozygous state is frequently found in a ROH. We performed a clinical interpretation of ROHs in 213 patients with a broad range of clinical indications including intellectual disability, developmental delay, multiple congenital anomalies, or autism spectrum disorder. We analyzed these regions in order to identify genes that could be implicated in recessive pathology concordant with patients’ phenotype. The analysis of ROH using the software "SNP array evaluation tool v3.0" found the mutated gene in 28/213 patients (13%). We further analyzed 30 multiplex families in which both affected and unaffected siblings were recruited. We studied common ROHs shared by affected patients, excluding ROH present in unaffected siblings. Based on key words describing our patients’ phenotype, we searched for OMIM genes implicated in recessive diseases concordant with the phenotype and selected candidate genes. ROHs analysis successfully lead to a diagnosis in 8/31 families (26%) in 15 patients. Finally, we performed whole exome sequencing in 8 selected multiplex families in which the ROH analysis was non-contributory and identified the causal gene in three out of eight families analyzed. We identified two novel pathogenic variants in ERBB3 reported to cause lethal congenital contractural syndrome 2 (MIM # 607598), one novel pathogenic variant in TNR associated with spastic quadriplegia and ID. The diagnosis of genetic and chromosomal disorder in a context of consanguinity, ROH analysis must be considered in order to sequence the gene of interest, or to target WES analysis. Our strategy improves the efficiency of genetic diagnosis in a more targeted and cost-effective way.