Concomitant microduplications of MECP2 and ATRX in male patients with severe mental retardation

Abstract

the Japanese Mental Retardation Consortium 8Investigations of chromosomal rearrangements in patients with mental retardation (MR) are particularly informative in the search for genes involved in MR. Here we report a family with concomitant duplications of methyl CpG binding protein 2 (MECP2) at Xq28 and ATRX (the causative gene for X-linked alpha thalassemia/mental retardation) at Xq21.1 detected by array-comparative genomic hybridization. The alterations were observed in a 25-year-old man who inherited them from his mother, who showed a normal phenotype and completely skewed X-chromosome inactivation, and also in his cousin, a 32-year-old man. The proband and his cousin showed severe MR, muscular hypotonia, recurrent respiratory infections and various other features characteristic of MECP2 duplication syndrome. However, the proband also had cerebellar atrophy never reported before in MECP2 duplication syndrome, suggesting that his phenotypes were modified through the ATRX duplication in an additive or epistatic manner. Keywords: array CGH; ATRX; duplication; MECP2; X-linked mental retardation Duplication at Xq28 involving methyl CpG binding protein 2 (MECP2) has been detected at high frequency (1-2%) in males with unexplained X-linked mental retardation (XLMR). 1,2 MECP2 duplication syndrome is now recognized as a clinical entity showing severe MR, muscular hypotonia, absence of speech, a history of recurrent infection and mild dysmorphic features. 3 In the course of a program to screen possible patients with XLMR for copy-number aberrations by array-comparative genomic hybridization (aCGH) using a bacterial artificial chromosome (BAC)-based X-tiling array (MCG X-tiling array), 2,4 we detected an B0.4-Mb duplication at Xq28 involving MECP2 together with an B0.3-Mb duplication at Xq21.1 that included ATRX, the causative gene for ATR-X (X-linked alpha thalassemia/mental retardation) syndrome, in a 25-year-old man and his cousin, a 32-year-old man (Figure 1a).The proband (III-1, Figure 1b) was born at 41 weeks after an uneventful pregnancy as the first child of non-consanguineous healthy parents. At birth, his weight and occipital-frontal circumference (OFC) were 3280 g ( ± 0 s.d.) and 33.5 cm ( 0.3 s.d.), respectively. He was developmentally retarded: first smiling at 3 months, holding up his head at 5 months, rolling over at 7 months, sitting by himself at 12 months and crawling at 13 months. At 25 years, his height, weight and OFC were 160.8 cm (À1.7 s.d.), 50 kg (À1.2 s.d.) and 56.3 cm (À0.9 s.d.), respectively. The proband exhibited hypertelorism, microcephaly and synophrys (Figure 1c). At 28 years, magnetic resonance imaging (MRI) showed cerebral atrophy, cerebellar atrophy and a thin corpus callosum (Figure 1d). He could walk and communicate until he was 14 years old, but became unable to do either of this after developing epilepsy. At the age of 4 years and 10 months, his total Developmental Quotient was 22, calculated by using the Kyoto Scale of Psychological Development. A blood investigation showed tha...

Histone methylation: a dynamic mark in health, disease and inheritance

“…However, the activity of ATRX probably involves remodeling of heterochromatin structure through the helicase activity of this protein as some mutations in ATRX that cause ATRX syndrome have recently been shown to disrupt its ATP hydrolysis activity 128 . Interestingly, a recent study identified a patient with severe intellectual disability who carries duplication of both MeCP2 and ATRX, suggesting a possible functional link between these two proteins in regulating cognition 129 .…”

Duplication at Xq13.3–q21.1 with syndromic intellectual disability, a probable role for the ATRX gene

“…The concomitant microduplications of MECP2 and ATRX in male patients with severe ID in one family [Honda et al, ] were not quite different than those usually found in patients with MECP2 duplication, except that the proband was found to have cerebellar atrophy, with many of the clinical features common to both duplication syndromes. These patients did not show some characteristics associated with duplications of ATRX, such as short stature or mid‐face hypoplasia.…”

Microarray-based ultra-high resolution discovery of genomic deletion mutations

“…Such mutations are commonly distinguished from low-level gains/losses using a direct threshold of array data. However, the threshold value often differs greatly, ranging from a log 2 ratio of +/−0.4 for some studies [46,47] to as high as +/−1.0 for others [48,49]. The criteria we used to detect deletions were based on the aCGH patterns obtained from our mutant versus wild type hybridizations.…”