Interstitial microduplication at 2p11.2 in a patient with syndromic intellectual disability: 30-year follow-up

Jun et al. Molecular Cytogenetics 2014, 7:52 http://www.molecularcytogenetics.org/content/7/1/52 CASE REPORT Open Access Interstitial microduplication at 2p11.2 in a patient with syndromic intellectual disability: 30-year follow-up Kyung Ran Jun1, Reinhard Ullmann2, Saadullah Khan3, Lawrence C Layman4,5 and Hyung-Goo Kim4* Abstract Background: Copy number variations at 2p11.2 have been rare and to our knowledge, no abnormal phenotype with an interstitial 2p11.2 duplication has yet been reported. Here we report the first case with syndromic intellectual disability associated with microduplication at 2p11.2. Results: We revisited a white female subject with a chromosome translocation, t(8;10)(p23;q23)mat and a 10q telomeric deletion suspected by G-banding 30 years ago. This female with severe intellectual disability, no speech, facial dysmorphism, intractable epilepsy, recurrent infection, and skeletal abnormalities has been observed from the birth until her death. The karyotype analysis reconfirmed the previously reported chromosome translocation with a revision as 46,XX,t(8;10)(p23.3;q23.2)mat by adding more detail in chromosomal sub-bands. The array comparative genomic hybridization, however, did not detect the 10q terminal deletion originally reported, but instead, revealed a 390 kb duplication at 2p11.2; 46,XX,t(8;10)(p23.3;q23.2)mat.arr[hg 19] 2p11.2(85469151x2,8547435685864257x3,85868355x2). This duplication region was confirmed by real-time quantitative PCR and real-time reverse transcriptase quantitative PCR. Conclusions: We suggest three positional candidate genes for intellectual disability and recurrent infection based upon gene function and data from real-time reverse transcriptase quantitative PCR—VAMP8 and RNF181 for intellectual disability and CAPG for recurrent infection. Keywords: Array CGH, CAPG, Copy number variation, Duplication, Intellectual disability, Recurrent infection, RNF181, 2p11.2, VAMP8 Background A variety of terminal 2p duplications known as partial 2p trisomy are the unbalanced chromosomal rearrangements resulting from malsegregation of various balanced translocations [1-3]. Interpretation of the clinical phenotypes of carriers with these unbalanced translocations is complicated due to the co-existence of terminal monosomy and terminal trisomy. Different isolated duplications within the 2p region had been reported in more than 20 patients, but they vary in size and location, ranging from 2p12 to 2p25 [4-7]. These duplications are * Correspondence: 4 Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics and Gynecology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, Georgia Full list of author information is available at the end of the article associated with a syndromic phenotype including intellectual disability, growth and psychomotor retardation, delayed bone age, congenital heart abnormalities, pulmonary hypoplasia, hypoplastic kidney, genital anomaly, anencephaly, neural tube defects, finger and toe abnormalities, or dysmorphic facial features encompassing hypertelorism, prominent forehead, broad nasal bridge, low-set ear, and micrognathia [4-7]. Because the size and location of these 2p duplications may vary from individual to individual, comparison of overlapping regions for defining a minimal candidate region associated with a particular phenotype will be a useful strategy for identifying the causative gene as exemplified in the mapping of deletions [8,9]. Due to the limited resolution of banding and staining patterns of chromosomes in the pre-FISH (FISH-fluorescent in situ hybridization) and pre-CGH (CGH-comparative © 2014 Jun et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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. Jun et al. Molecular Cytogenetics 2014, 7:52 http://www.molecularcytogenetics.org/content/7/1/52 genomic hybridization) era, it is not uncommon to find misinterpretations of cytogenetic aberrations in the reported cases, which complicated attempts to assign a unique phenotype to a specific chromosome band. Here we revisited a case reported 30 years ago [10] and failed to confirm an ostensible 10q deletion. Instead, we identified a cryptic 2p11.2 microduplication by a microarray in the affected female subject. Some of her clinical features were developed years later in her life. To our knowledge, this is the first case with syndromic intellectual disability associated with an interstitial 2p11.2 duplication. Genotype/ phenotype relationships have been discussed. Results Clinical report in a 30 year time period The patient is a 30 year old white female with severe intellectual disability, a severe static encephalopathy, medically intractable epilepsy, and facial dysmorphism. She was first evaluated at the age of 10 months because of gastroenteritis and middle ear infection [10]. At that time, her height, weight and head circumference were in the 3rd percentile for chronological age. She is the first living child of healthy non-consanguineous marriage. The father was 42 years old and the mother with a previous spontaneous abortion was 26 years old at the birth of their daughter. Prenatal screening demonstrated normal alpha-fetoprotein levels for gestational age and a normal ultrasound, but studies indicated an Rh-sensitized status. The subject was a 2,700 g female at 35 weeks of gestation born by cesarean section. After at the age of one year, she was able to sit and look into the eyes of anyone who spoke to her with responding smiles. However, the direction of her gaze was difficult to determine because of her convergent strabismus. She did not show any autistic behavior as evidenced by her continual demands on her mother. At the age of two years, she started to babble words such as mama, water, etc. Her facial appearances from 3 years to 30 years of age are shown chronologically in Figures 1A-D. When she was evaluated at 10 months of age, her phenotype was as follows: hypotonia, long and narrow palpebral fissures, long eyelashes, prominent eyebrow, mild hypertelorism, broad nasal bridge, long philtrum, short neck, the trunk and extremities of normal proportion with hirsutism, redundant subcutaneous tissue on arms, legs, and the dorsum of hands and feet, bilateral simian crease, infantile external genitalia, and convergent strabismus [10]. She began walking at 5 years of age. At 9 years, she was diagnosed with epilepsy, reporting myoclonic seizures with atypical absences. The electroencephalograp (...truncated)