Supplementary Material for: De novo Interstitial Triplication of <i>MECP2</i> in a Girl with Neurodevelopmental Disorder and Random X Chromosome Inactivation

Loss-of-function mutations of the <i>MECP2</i> gene are the cause of most cases of Rett syndrome in females, a progressive neurodevelopmental disorder characterized by severe mental retardation, global regression, hand stereotypies, and microcephaly. On the other hand, gain of dosage of this gene causes the <i>MECP2</i> duplication syndrome in males characterized by severe mental retardation, absence of speech development, infantile hypotonia, progressive spasticity, recurrent infections, and facial dysmorphism. Female carriers of a heterozygous duplication show a skewed X-inactivation pattern which is the most probable cause of the lack of clinical symptoms. In this paper, we describe a girl with a complex de novo copy number gain at Xq28 and non-skewed X-inactivation pattern that causes mental retardation and motor and language delay. This rearrangement implies triplication of the <i>MECP2</i> and <i>IRAK1</i> genes, but it does not span other proximal genes located in the common minimal region of patients affected by the <i>MECP2 </i>duplication syndrome. We conclude that the triplication leads to a severe phenotype due to random X-inactivation, while the preferential X chromosome inactivation in healthy carriers may be caused by a negative selection effect of the duplication on some proximal genes like <i>ARD1A</i> or <i>HCFC1</i>.