Disentangling the complex genetic architecture of neurodevelopmental disorders: the importance of reanalysis of unsolved cases in search for X-linked determinants.

Neurodevelopmental disorders (NDDs) comprise a wide spectrum of complex diseases that include autism spectrum disorders (ASD), intellectual disability (ID) and attention deficit hyperactivity disorder (ADHD). NDDs are frequent childhood disorders with a strong genetic component. Their prevalence is around 3% worldwide, with a higher incidence in males compared to females. The aim of this thesis was to focus on X-chromosome Copy Number Variants (CNVs) responsible for NDDs. We studied a rare CNV encompassing TMLHE (MIM 300777) and associated with autism spectrum disorder predisposition. We screened 441 NDD male patients, negative to array-CGH and exome sequencing analyses, for TMLHE gene deletion by PCR. We found three cases whose phenotype was variable from isolated ASD to severe neuropsychiatric disorder. Because TMHLE is involved in carnitine biosynthesis, a potential treatment for these cases might be available. We also studied a patient with a suspect of Alpha-thalassemia/mental retardation syndrome (MIM 301040) due to ATRX mutations. We proved that an intragenic deletion involving exons 3 and 4 of the gene was causative of the disease. Our work sustains the need to further investigate X-linked chromosome genes in male patients affected by NDD to uncover rare Mendelian forms of disease.