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

Abstract

Loss-of-function mutations of the MECP2 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 MECP2 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 MECP2 and IRAK1 genes, but it does not span other proximal genes located in the common minimal region of patients affected by the MECP2 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 ARD1A or HCFC1.

A sibship with duplication of Xq28 inherited from the mother; genomic characterization and clinical outcomes

“…Mayo et al . specifically noted that the arrest-defective protein 1 homolog A ( ARD1A or NAA10 ; MIM *300013) and host cell factor C1 ( HCFC1 ; MIM *300019) as genes responsible for induced preferential XCI in females [33]. In our study the Mother had duplication in parts of NAA10 and HCFC1 , and thus the possibility of negative selection was considered.…”

Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation

“…ARD1A or HCFC1 ) may be responsible for complete skewing of X-inactivation in female carriers of an Xq28 duplication [29]. Consequently, smaller deletions would thus result in random X-inactivation.…”

Second‐trimester prenasal and prefrontal skin thickening—Association with MECP2 triplication syndrome

“…The MECP2 gene is located in the q28 region of the X chromosome and codes for the methyl CpG binding protein 2, which, by binding to methylated DNA, can activate or suppress transcription . In females, MECP2 loss‐of‐function mutations result in Rett syndrome.…”

“…The MECP2 gene, located on chromosome Xq28, codes for the methyl CpG binding protein 2, which plays a role in DNA transcription regulation . MECP2 duplication results in a well‐recognized syndrome in 100% of affected male children, characterized by recurrent respiratory infections and severe neurodevelopmental disabilities including severe mental retardation, seizures, absent or delayed speech, and infantile hypotonia progressing to spasticity.…”