Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy

Abstract

Duplications in Xq28 involving MECP2 have been described in patients with severe mental retardation, infantile hypotonia, progressive spasticity, and recurrent infections. However, it is not yet clear to what extent these and accompanying symptoms may vary. In addition, the frequency of Xq28 duplications including MECP2 has yet to be determined in patients with unexplained X-linked mental retardation and (fe)males with severe encephalopathy. In this study, we used multiplex ligation-dependent probe amplification to screen Xq28 including MECP2 for deletions and duplications in these patient cohorts. In the group of 283 patients with X-linked mental retardation, we identified three Xq28 duplications including MECP2, which suggests that approximately 1% of unexplained X-linked mental retardation may be caused by MECP2 duplications. In addition, we found three additional MECP2 duplications in 134 male patients with mental retardation and severe, mostly progressive, neurological symptoms, indicating that the mutation frequency could be as high as 2% in this group of patients. In 329 female patients, no Xq28 duplications were detected. In total, we assessed 13 male patients with a MECP2 duplication from six unrelated families. Moderate to severe mental retardation and childhood hypotonia was noted in all patients. The majority of the patients also presented with absent speech, seizures, and progressive spasticity as well as ataxia or an ataxic gait and cerebral atrophy, two previously unreported symptoms. We propose to implement DNA copy number testing for MECP2 in the current diagnostic testing in all males with moderate to severe mental retardation accompanied by (progressive) neurological symptoms.

Figure 1

Schematic overview of the duplication mapping in the six affected families. (a–f) Pedigrees of the six affected families. (g) Detailed overview of the genomic region on the X chromosome surrounding MECP2. Genes tested by MLPA analysis are shown at the top. Black lines indicate the duplicated region and the dotted lines indicate the break point region between the last duplicated MLPA probe and the first probe with a normal copy number.

Figure 2

Photographs of five patients with a MECP2 duplication. (a) Patient II-1 from family D at the age of 8 years. (b) Patient II-1 and (c) patient II-2 of family E at the age of 11 and 8 years, respectively. (d) Patient III-7 and (e) patient III-9 of family A at the age of 14 and 7 years, respectively. Note high forehead, small nose, deep-set eyes, large ears, eversion of lower lip and/or prominent chin in several patients.