Yon et al. BMC Medical Genetics (2017) 18:30 DOI 10.1186/s12881-017-0394-7 RESEARCH ARTICLE Open Access A sibship with duplication of Xq28 inherited from the mother; genomic characterization and clinical outcomes Dong Keon Yon1, Ji Eun Park2, Seung Jun Kim3, Sung Han Shim2,4* and Kyu Young Chae1* Abstract Background: Loss-of-function mutations in methyl-CpG-binding protein 2 (MECP2; MIM *300005) results in the Rett syndrome, whereas gain-of-function mutations are associated with the MECP2 duplication syndrome. Methods: We did research on a family with two brothers showing Xq28 duplication syndrome using various molecular cytogenetic techniques such as multiplex ligation-dependent probe amplification and array-based genomic hybridization. Results: The duplicated region had several genes including MECP2 and interleukin-1 receptor associated kinase 1 (IRAK1; MIM *300283). MECP2 and IRAK1 were associated with the neurological phenotypes in dose-sensitive and dose-critical manner. The brothers demonstrated severe intellectual disability, autistic features, generalized hypotonia, recurrent infections, epilepsy, choreiform movements such as hand-wringing movement, and moderate increased spasticity with the lower limbs. The X-inactivation test showed a complete skewed X inactivation pattern of mother. In this reason, the mother had the same loci duplication but showed significantly little neurological manifestation compared to the two sons. Conclusions: MECP2/IRAK1 duplication at Xq28 is inherited as an X-linked recessive trait and male-specific disorder associated with severe intellectual disability. We tried to analyze the information of the relationship between neuropsychiatric phenotype and the extent of duplication at Xq28 by comparing with previous reports. Keywords: MECP2, IRAK1, Xq28 duplication, MECP2 duplication syndrome Background sense), microdeletions, and translocations. XLID caused by X-linked intellectual disability (XLID) is found in gain-of-function is via microduplication where causal genes approximately 5–10% of the intellectually disabled men [1]. are abnormally copied. A well-known XLID microduplica- XLID is divided into syndromic forms in which intellectual tion region is Xq28, in which there is duplication of X- disability is one of many symptoms, and non-syndromic linked genes such as methyl-CpG-binding protein 2 forms, in which intellectual disability is the only symptom. (MECP2; MIM *300005) a key gene involved in Rett syn- In a previous study, 102 genes were shown to be associated drome, a neurodevelopmental disorder that affects mostly with 81 out of 160 cases of XLID syndromes in over 50 girlsXq28duplicationsyndromeisanimportantaspectof families with non-syndromic XLID [1]. Most of the genetic XLID. Mutations in the MECP2 gene in Xq28 were first defects leading to XLID are loss-of-function mutations, in- reported in patients with Rett syndrome in 1999 [2] and cluding point mutations (frame shift, nonsense, and mis- other X-linked severe neurodevelopmental disorders. Par- ticularly, large deletions, single base mutations, or small * Correspondence: [email protected]; [email protected] frame shift mutations in MECP2 aremostlycommonlyas- 2 Genetics Laboratory, Fertility Center, CHA Gangnam Medical Center, School sociated with Rett syndrome [3, 4]. Classical Rett syndrome of Medicine, CHA University, 606-13 Yeoksam-dong, Gangnam-gu, Seoul 06135, Republic of Korea is typically characterized by a period of normal develop- 1Department of Pediatrics, CHA Bundang Medical Center, School of ment until 6 to 18 months of age. After this age, motor Medicine, CHA University, 351 Yatap-dong, Bundang-gu, Seongnam 463-712, and speak skills regress, followed by loss of useful hand Republic of Korea Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yon et al. BMC Medical Genetics (2017) 18:30 Page 2 of 9 skills; rather afflicted children exhibit repetitive hand mo- spasticity, neonatal or infantile hypotonia, poor speech tions, such as hand wringing. Additional symptoms of Rett development, recurrent respiratory infections, epilepsy, syndrome include acquired microcephaly, profound intel- and dysmorphic facial features such as large ears, mid-face lectual disability, epilepsy, ataxia, and autistic behaviors. hypoplasia, brachycephaly, and depressed nasal bridge [8]. There is a wide spectrum of disease severity for Rett syn- In this study we identified one family with two broth- drome as determined by molecular diagnostics [5]. ers with Xq28 duplication syndrome and a mother who While loss-of-function mutations in MECP2 result in was a carrier with the same loci duplication. We charac- Rett syndrome gain-of-function mutations are associated terized the duplicated region of the brothers and the with MECP2 duplication syndrome. MECP2 duplications mother using various molecular and cytogenetic tech- were initially described in a female patient presenting niques and to present clinical features. with a speech variant symptom and was diagnosed mo- lecularly with atypical Rett syndrome [6]. MECP2 dupli- Methods cation syndrome and Rett syndrome share overlapping Patients clinical phenotypes include intellectual disability, motor A family including two sons aged 11 and 10 years old deficits, epilepsy, hypotonia, and progressive spasticity and their mother with Xq28 duplication was researched [7, 8]. Males with Xq28 duplication, including duplica- (Fig. 1a and Additional file 1: Figure S1). A duplication tions at the MECP2 locus spanning 0.3–4 Mb, have sub- of 411.478kb in Xq28 was identified in all three family sequently been reported by employing the multiplex members using the MLPA and array-CGH. ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridization (array- Patient 1 CGH) [7, 9–11]. Common phenotypes in males with Patient 1 was an 11-year-old boy who was born at 41 MECP2 duplication are severe to profound X-linked in- weeks’ gestation by spontaneous vaginal delivery. At tellectual disability, Rett syndromic features, progressive birth the boy weighed 2500 g, and there was no history Fig. 1 A pedigree of the family and the results of MLPA analysis. a A pedigree of the family. b Apparently normal GTG-banded X chromosomes of the patients. c MLPA result of the II-1 patient 1. MLPA analysis using the P015 MECP probemix showed duplications of the MECP2 and several other genes (rectangle) Yon et al. BMC Medical Genetics (2017) 18:30 Page 3 of 9 of brain damage (Table 1). The father passed away in car corresponded to those observed in children aged 30 and accident, and the mother was healthy and non- 20 months, respectively. Self-help and social levels were consanguineous. At birth, he was treated in the neonatal equivalent to that of a 24- and 18-month-old, respectively. intensive care unit over three weeks due to infantile cen- Language development was at the 14-months level. He was tral hypotonia with poor sucking. His feeding problems diagnosed with autistic spectrum disorder in accordance in infancy needed to be remedied via special feeding with the fifth edition of the Diagnostic and Statistical Man- techniques and improved gradually with age. His devel- ualofMentalDisorders(DSM-V)[13].Accordingtothe opmental delay became more obvious as time went by. mental developmental index of the Bayley Scales of Independent walking started at 36 months of age. He InfantDevelopmenttestII(BSIDII)[14],theequiva- was vulnerable to bacterial infections such as pneumonia lent age of the patient was 24 months, implying se- and gastroenteritis, requiring hospitalization about three vere intellectual disability. Mild dysmorphic features times a year. Currently, he cannot make eye contact and (brachycephaly, slightly upturned nares, and large and social-emotional reciprocity, nor form any meaningful low set ears) and generalized hypotonia were observed words. And he have excessive adherence to the pencil, (Fig. 2a-d). Upon neurological examination, he had hand stereotypes including hand shaking and hyper- significant weakness in the extremities; based on the reactivity to unusual interest. He can not live a social life Medical Research Council (MRC) for muscle strength without a carer. thepatientwasagrade3withregardstochoreiform At the time of study evaluation his height was 149 cm gait movements, such as hand wringing, and moder- (50–75th percentile), weight was 50 kg (75–90th percentile), ate to increased spasticity of the lower limbs. and occipito-frontal circumference was 53 cm (75–90th He presented with generalized tonic-clonic type seizures percentile). According to the Korean-Child Development at 10 years of age. In his interictal-electroencephalogram Review (K-CDR) [12], his gross and fine motor skills (EEG) there were epileptic sharp wave discharges from the Table 1 Clinical characteristics of the patients Patient Patient 1 Patient 2 Mother Age 11 years 10 years 38 years Gender