Papoulidis et al. Molecular Cytogenetics (2015) 8:71 DOI 10.1186/s13039-015-0175-y CASE REPORT Open Access Interstitial deletion at 11q14.2-11q22.1 may cause severe learning difficulties, mental retardation and mild heart defects in 13-year old male Ioannis Papoulidis1*, Vassilis Paspaliaris1, Elisavet Siomou1, Sandro Orru2, Roberta Murru2, Stavros Sifakis3, Petros Nikolaidis4, Antonios Garas5, Sotirios Sotiriou5, Loretta Thomaidis6 and Emmanouil Manolakos1,2 Abstract Interstitial deletions of the long arm of chromosome 11 are rare, and they could be assumed as non-recurrent chromosomal rearrangements due to high variability of the size and the breakpoints of the deleted region. The exact region of the deletion was difficult to be determined before the use of molecular cytogenetic techniques such as array comparative genomic hybridization (aCGH). Here, a 13-year old boy with severe learning difficulties, mental retardation and mild heart defects is described. Conventional G-band karyotyping was performed and it is found that the patient is a carrier of a de novo interstitial deletion on the long arm of chromosome 11, involving 11q14 and 11q22 breakpoints. Further investigation, using aCGH, specified the deleted region to 11q14.2-11q22.1. There was a difficulty in correlating the genotype with the phenotype of the patient due to lack of similar cases in literature. More studies should be done in order to understand the genetic background that underlies the phenotypic differences observed in similar cases. Background Moreover, before the introduction of molecular cyto- Terminal deletions of the long arm of chromosome genetic approaches, the resolution efficiency provided 11 have been numerously described, and they are as- by conventional karyotype analysis jointly with the sym- sociated with Jacobsen syndrome (OMIM 147791) metric 11q banding pattern [3, 4], limited the accuracy and characterized by thrombocytopenia, mental re- of identification of breakpoints and precise deleted gen- tardation, short stature, congenital heart defect, and omic regions. characteristic facial dysmorphism [1, 2]. On the con- trary, interstitial deletions of the long arm of chromo- some 11 are less common and often not fine-mapped, Case presentation due to the similarity between band patterns (11q14 The patient, a 13-year old boy, was the first and only and 11q22) when conventional karyotype is performed child of unrelated healthy Caucasian parents. He was [3, 4]. So far, approximately 30 cases of 11q intersti- born by cesarean section after a full term pregnancy. th tial deletions have been reported [3–24]. Nevertheless, Birth weight was 2,800 g (10 percentile), length th due to high variability of size and position of the 50 cm (50 percentile) and head circumference (HC) th deleted regions, phenotype-genotype correlations have 35.5 cm (50 percentile). Neonatal and infancy periods been hard to evaluate due to the wide range of pheno- were uneventful; nevertheless his motor development typic features, ranging from normal to severe conditions was delayed as he did not sit independently until the including developmental delay/mental retardation, fa- age of 15 months or walk unaided until the age of cial dysmorphisms and other medical implications. 22 months. At the age of 5, language delay was observed and laboratory investigation was performed, including audio- * Correspondence: [email protected] gram, biochemical and thyroid tests, which proved normal. 1Access to genome P.C., Clinical Laboratory Genetics, 33A Ethn. Antistaseos str, 55134 Thessaloniki, Greece He received speech therapy for a two-year period and his Full list of author information is available at the end of the article language difficulties resolved. He attended mainstream © 2015 Papoulidis et al. 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. Papoulidis et al. Molecular Cytogenetics (2015) 8:71 Page 2 of 7 primary school with extra educational support and finished procedures. The conventional cytogenetic analysis re- this level at the age of 12 years. At the age of 13 years he vealed a de novo interstitial deletion on the long arm was referred for full developmental assessment because he of chromosome 11, involving 11q14 and 11q22 break- was experiencing severe learning difficulties in secondary points (Fig. 1). school. Upon physical examination, he was characterized as To further investigate the specific finding, array-CGH quite a sociable child, with mild dysmorphic facial features was performed by hybridizing the sample against a male such as almond shaped eyes, hypertelorism, anteverted nos- human reference commercial DNA sample (Promega bio- trils, and gothic palate. His weight at the time was 49 kg tech) using an array-CGH platform that includes 60000 (40th percentile), height 160 cm (60th percentile) and HC oligonucleotides distributed across the entire genome 54 cm (25th percentile). Upon neurological examination, he (Agilent Technologies). The statistical test used as param- showed mild motor delay with severe clumsiness but with- eter to estimate the number of copies was ADAM-2 out focal neurological signs. Ophthalmologic examination (provided by the DNA analytics software, Agilent Techn) was normal. Heart auscultation revealed a mild systolic with a window of 0.5 Mb, A=6. Only those copy number murmur. changes that affected at least 5 consecutive probes Upon developmental evaluation, he was found to with identically oriented change were considered as function at the mental level of a 10-year old. His cog- Copy Number Variations (CNV). As a consequence, nitive abilities, according to the Wechsler Intelligence for the majority of the genome, the average genomic Scale for Children test (WISC III), were assessed as powerofresolutionofthisanalysiswas200kilobases. borderline, as his full-scale score was 75 with verbal Array-CGH analyses detected an interstitial deletion score 75 and performance score 80. spanning region 11q14.2-11q22.1, genomic coordinates Extensive laboratory investigation followed, including chr11: 85,702,633-97,854,695 (Genomic coordinates brain magnetic resonance imaging (MRI), electroenceph- are listed according to genomic build GRCh37/hg19). alogram, kidney-liver- spleen ultrasound, bone age, bio- No additional pathogenetic Copy Number Variations chemical tests, blood and urine amino acids, organic acids, (CNVs) were detected and thus the molecular karyotype very low fatty acids, thyroid function, ACTH, FSH, LH, was: arr 11q14.2q22.1 (85702633–97854695)x1 (Fig. 2). DHEA-S, prolactin, estradiol e2, progesterone, testosterone, The specific deletion contains approximately 12,15 Mb of 17a-OH progesterone and IGF-1, all proved normal. Heart genomic material and includes 30 OMIM listed genes ultrasound showed mild mitral valve prolapsed. (Table 1 and Fig. 3). Material and methods Discussion Metaphase chromosomes were obtained from phytohem- Here we report a patient with a de novo 12.15 Mb intersti- agglutinin (PHA)-stimulated peripheral blood lymphocytes tial deletion of chromosome 11 long arm, spanning from and high resolution (thymidine treatment) G-banding nt85702633 to nt97854695, exhibiting developmental delay, karyotype analysis was performed, using standard borderline mental retardation, severe speech delay, and Fig. 1 G-banding karyotype of the patient. It is illustrated the interstitial deletion on the long arm of chromosome 11 Papoulidis et al. Molecular Cytogenetics (2015) 8:71 Page 3 of 7 Fig. 2 Ideogram of the deleted region as it is detected using array CGH. The interstitial deletion is at 11q14.2-11q22.1 some dysmorphic features. The genotype of the patient was genome that might compensate for the deleted copies of compared to 19 previously described patients carrying over- these genes. lapping interstitial deletions of chromosome 11 long arm Goumy et al. [6] described three cases of 11q14.3- (Fig. 4). Cases with uncertain or not accurately defined q22.1 deletion transmitted in three-generation kindred. breakpoints were not considered [4, 5, 13, 24]. The proband, a normal girl without dysmorphic features, Regarding these 19 cases, only six studies [9–12, 25, 26] was tested during mother’s pregnancy by genetic amnio- were conducted using molecular cytogenetic techniques, centesis because of a positive Down syndrome maternal such as a-CGH analysis with BAC clones or high-density serum screening test at 15 weeks gestation. The deletion oligonucleotide probes. In the remaining cases, conven- was identified in the mother, who had toe camptodactyly tional karyotype analysis and/or fluorescence in situ and ophthalmologic disorders, and in the phenotipically hybridization analysis was performed in order to de- normal grandfather. The minimal deletion size, mapped fine the position and size of the deletions. Table 2 by combining CGH analysis and FISH with BAC clones summarizes the genotypes and phenotypic features of was 8.5 Mb from RP11-372E19 to RP11-775E2. This region the present case and of the 19 cases with overlapping