de novo interstitial deletions at the 11q23.3-q24.2 region
© Su et al. 2016
Received: 20 January 2016
Accepted: 17 April 2016
Published: 5 May 2016
Jacobsen syndrome (JBS) is a contiguous gene deletion syndrome involving 11q terminal deletion. Interstitial deletions at distal 11q are rare and their contributions to the clinical phenotype of JBS are unknown.
We presented the chromosome microarray (CMA) data and the clinical features of two individuals carrying a non-overlapping de novo deletion each at the 11q23.3-q24.2 region in an effort to analyze the correlation between region of deletion at 11q and phenotype. Both deletions are likely pathogenic for patient’s condition. The deletion at 11q23.3q24.1 is associated with short stature, relative microcephaly, failure to thrive, hypotonia and sleeping disorder. The deletion at 11q24.2 involves HEPACAM and our patient’s clinical presentation (relative macrocephaly, abnormal MRI, mild developmental delay and seizure) is not inconsistent with Megalencephalic leukoencephalopathy with subcortical cysts 2B.
Our finds support the notion that more than one critical region at 11q23.3-qter are responsible for the variable clinical presentation of JBS, thus JBS is a true contiguous gene deletion syndrome where multiple loci contributed to the clinical characteristics of JBS. Small interstitial deletions at 11q23.3-q24.2 and their associated unique features also suggest emerging novel genomic disorders.
The 11q terminal deletion, also known as Jacobsen syndrome (OMIM #147791), is a contiguous gene deletion syndrome involving the deletion of 11qter. Several hundred 11q terminal deletion patients had been described since it was first reported by Jacobsen in 1973 . The deletions observed in JBS patients range from 7 to 20 Mb in size and are almost always associated with 11q terminal deletions and the furthest breakpoint is located at 11q23.3. Typical features of JBS include developmental delay (DD)/intellectual disability (ID), dysmorphic facial features, platelet disorder and multiple congenital defects [1–6]. Interstitial deletions from 11q23 to 11qter are rare and their clinical significance is currently unknown. Some of previously reported 11q23-qter interstitial deletions were characterized by karyotyping analysis [7–9]. CMA analysis made it possible to better define the genotype–phenotype correlation. Since the first report of an 11q24.1q24.3 interstitial deletion characterized by CMA , eight cases with 11q23-qter interstitial deletion detected by CMA had been documented in literature (see Additional file 1: Table S1). The breakpoints of the 11q23-qter interstitial deletions are variable and deletions range from 2.89 to 12.8 Mb in size. Clinical presentations of affected individuals are also very heterogeneous, thus complicating the genotype–phenotype correlation analysis [4, 5, 10–14]. Patient with interstitial deletion at 11q23-qter region could share some of the JBS features such as hypotonia , macrocephaly [11, 14], microcephaly , trigonocephaly [4, 7, 9], some of dysmorphic facial features [4, 5, 7–14], limbs anomalies [7, 11, 13], congenital heart defect (CHD) [4, 5, 7, 9, 10, 12], but often did not exhibit the whole constellation of JBS [13, 14]. The most consistent feature among all patients with 11q23-qter interstitial deletion is DD/ID. Smallest overlapping regions helped to define some critical regions or candidate genes at the distal 11q region [4–11].
Here, we reported two individuals carrying non-overlapping interstitial deletions at 11q23.3-q24.2 region with different degrees of DD/ID and some dysmorphic features in an effort to further define genotype–phenotype correlation.
Patient 1 (P1) was a 5-year-old girl born to a 29-year-old woman at 41 weeks of gestational age. Pregnancy and delivery were uneventful. Her birth weight was 2.8 kg (~15thpercentile) and birth length around 48.2 cm (~15thpercentile). She had an apparently healthy twin brother and sister. At around 5–6 months of age she was noticed to have global delay including unable to roll over, delayed crawling, sitting and standing. She was at a 5-month developmental level at the age of one. She had a history of failure to thrive and hypotonia. She came to Genetics Clinic due to dysmorphic features and global developmental delay. At 5-years of age, her height was 101 cm (−2.11 SD), weight 14 kg (−2.58 SD) and head circumference 48.3 cm (7th percentile). She had overlapping toes, dysmorphic features including mild hypertelorism (inner canthal distance 27 mm, +1SD), prominent forehead, flat facial profile, broad nose, smooth philtrum with thin upper lip, upslanting palpebral fissures with epicanthal folds. Her brain MRI was normal. No other defect was noticed.
She had a history of sleeping disorder. Notably, her parents reported that she would vocalize around bedtime, often it is associated with body rocking and head banging. She would wake up and bang her head at midnight. She would sit Indian style on her bed and leaned forward until she banged her head on the mattress. This occurred in a fairly fast and rhythmic pattern. Often she would moan during such a movement and many times the moan escalated into very loud scream. She also had the rocking behavior during the daytime that she would move her back up against a hard surface and then rocked her lower back and buttocks on the floor. She was diagnosed as jactatio capitis nocturna and such behavior had improved but not resolved entirely.
Patient 2 (P2) was a boy who came to hospital due to fever, mild developmental delay and seizure at the age of 10 months. He was a full term second child to a healthy parent who had a healthy 4-year-elder daughter. He was delivered via cesarean section without complication during pregnancy or delivery. His birth weight was 3.25 kg (25–50th percentile) and birth length was 50 cm (25–50th percentile). He had no significant medical history prior to presentation. No family history of seizure, autism, mental retardation or other neurologic impairments. He raised his head around 3–4 months of age, rolled over around 6–7 months of age, and pronounced first word at about 10 months of age. His developmental quotient (DQ) and the mental index (MI) suggested that he had mild development delay by the Denver Development Screening Test score (DQ = 51 and MI = 63). At the age of 10 months, his weight was 9.4 kg (30th percentile) and height 72.5 cm (25th percentile). He presented with a relative macrocephaly (circumference was 47.5 cm (+1.3SD)), mild hypertelorism, low nasal bridge, thin upper lip and strabismus. The magnetic resonance imaging (MRI) revealed the widening of the frontotemporal lobe, full bilateral ventricles and deep parietal sulci. He had normal electroencephalogram and electromyography. He was diagnosed with acute pharyngitis, secondary seizure, psychomotor retardation and mild development delay as well as cerebral hypogenesis.
Chromosomal microarray (CMA) analyses
DNA sample was extracted from peripheral blood lymphocytes using standard protocol, microarray was performed using Agilent 244 K array for patient 1 and the illumina HumanSNP cyto-12 array for patient 2.
Summary of clinical features of the eight patients with 11q23-qter interstitial deletions and our present cases
Deletion size (Mb)
Ranges from newborn to adult
Palpebral fissure anomalies
Developmental delay/intellectual disability
Social interaction difficulties
It is interesting to note that patient 1 exhibited the characteristic features of jactatio capitis nocturna, also known as rhythmic movement disorder (RMD). Most of RMD will spontaneously resolve by 4 years of age . Our patient’s condition had improved but not resolved entirely at age 5. The underlying cause of RMD is currently unknown, the deletion in P1 may provide a clue for investigating the molecular mechanism of RMD. 13 RefSeq genes including 10 OMIM genes (GRIK4, LRRC35, TECTA, SC5DL, SORL1, MIR100HG, MIR125B1, BLID, MIRLET7A2 and MIR100) are involved in the deletion. But it is unclear which gene or genes are likely responsible for the sleeping disorder. GRIK4 (OMIM #600282) encodes a protein that belongs to the glutamate-gated ionic channel family. Glutamate functions as the major excitatory neurotransmitter in the central nervous system through activation of ligand-gated ion channels and G protein-coupled membrane receptors. Takenouchi T et al. and Pickard BS et al. suggested that the haploinsufficiency of GRIK4 was related to DD, mental retardation, schizophrenia and bipolar disorder [16, 17]. The developmental delay present in our patient may be explained by the GRIK4 deletion.
The deletion interval in P2 encompassed 6 OMIM genes (ROBO3, ROBO4, HEPACAM, HEPN1, PKNOX2 and FEZ1). Sequence variants in HEPACAM (OMIM #611642) have been shown to cause Megalencephalic leukoencephalopathy with subcortical cysts 2A (an autosomal recessive form MLC2A, OMIM #613925) and 2B (an autosomal dominant form MLC2B, OMIM #613926), both of which are characterized with macrocephaly, abnormal MRI and variable degree of intellectual disability [18–20]. The clinical presentation of the autosomal form is milder, some features improve with age. Recently haploinsufficiency of HEPACAM was considered as a cause of two patients with heterozygous deletion at 11q23.3q24.2 interstitial deletion 11q24 and clinical features of MLC . P2 was presented with relative macrocephaly, abnormal MRI mild developmental delay and seizure, which is not inconsistent with MLC2B. The much smaller deletion detected in P2 overlap with the interstitial deletion in patient 2 of Yamamoto’s report. The smallest overlapping region between this two cases can exclude the involvement of FEZ1 (OMIM #604825) gene which plays a role in axonal outgrowth and has been proposed as a candidate gene for abnormal MRI by Tyson et al. .
In summary, we described two rare interstitial de novo deletions in JBS region. ID/DD is a shared feature with JBS, supporting the notion that Jacobsen syndrome is a true contiguous gene deletion syndrome and critical regions of ID/DD exist in different regions of 11q terminal. Our study further defined a smallest critical region associate with DD/ID. Each interstitial deletion also presented with its unique features and suggested distinct novel genomic imbalance disorder.
Written informed consent was obtained from the parents of the proband for publication of this Case Report and any accompanying images. The consent form was approved by the ethical committee of Guangxi Maternal and Child Health Hospital, China. A copy of the written consent is available for review by the editor of this journal.
We are grateful to the patients and families for participating in this study. We thank Dr. Sheng He for revised for this manuscript. This work was supported by grants from Guangxi Medical Plan Subject (Z2015238) and the project of science and technology of Guangxi Zhuang Autonomous Region (gui-ke-gong 14124004-1-8).
Open AccessThis 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.
- Mattina T, Perrotta CS, Grossfeld P. Jacobsen syndrome. Orphanet J Rare Dis. 2009;4:9.View ArticlePubMedPubMed CentralGoogle Scholar
- Grossfeld PD, Mattina T, Lai Z, et al. The 11q terminal deletion disorder: a prospective study of 110 cases. Am J Med Genet A. 2004;129A(1):51–61.View ArticlePubMedGoogle Scholar
- Penny LA, Dell Aquila M, Jones MC, et al. Clinical and molecular characterization of patients with distal 11q deletions. Am J Hum Genet. 1995;56(3):676–83.PubMedPubMed CentralGoogle Scholar
- Guerin A, Stavropoulos DJ, Diab Y, et al. Interstitial deletion of 11q-implicating the KIRREL3 gene in the neurocognitive delay associated with Jacobsen syndrome. Am J Med Genet A. 2012;158A(10):2551–6.View ArticlePubMedGoogle Scholar
- Ji T, Wu Y, Wang H, Wang J, Jiang Y. Diagnosis and fine mapping of a deletion in distal 11q in two Chinese patients with developmental delay. J Hum Genet. 2010;55(8):486–9.View ArticlePubMedGoogle Scholar
- Fryns JP, Kleczkowska A, Buttiens M, Marien P, van den Berghe H. Distal 11q monosomy. The typical 11q monosomy syndrome is due to deletion of subband 11q24.1. Clin Genet. 1986;30:255–60.View ArticlePubMedGoogle Scholar
- Sirota L, Shabtai F, Landman I, et al. New anomalies found in the 11 q- syndrome. Clin Genet. 1984;26:569–73.View ArticlePubMedGoogle Scholar
- Ono J, Hasegawa T, Sugama S, et al. Partial deletion of the long arm of chromosome 11: ten Japanese children. Clin Genet. 1996;50:474–8.View ArticlePubMedGoogle Scholar
- Pivnick EK, Velagaleti GV, Wilroy RS, et al. Jacobsen syndrome: report of a patient with severe eye anomalies, growth hormone deficiency, and hypothyroidism associated with deletion 11 (q23q25) and review of 52 cases. J Med Genet. 1996;33(9):772–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Wenger SL, Grossfeld PD, Siu BL, et al. Molecular characterization of an 11q interstitial deletion in a patient with the clinical features of Jacobsen syndrome. Am J Med Genet A. 2006;140(7):704–8.View ArticlePubMedGoogle Scholar
- Tyson C, Qiao Y, Harvard C, Liu X, et al. Submicroscopic deletions of 11q24-25 in individuals without Jacobsen syndrome: re-examination of the critical region by high-resolution array-CGH. Mol Cytogenet. 2008;1:23.View ArticlePubMedPubMed CentralGoogle Scholar
- Van Zutven LJ, van Bever Y, Van Nieuwland CC, et al. Interstitial 11q deletion derived from a maternal ins(4;11)(p14;q24.2q25): a patient report and review. Am J Med Genet A. 2009;149A(7):1468–75.View ArticlePubMedGoogle Scholar
- So J, Stockley T, Stavropoulos DJ. Periventricular nodular heterotopia and transverse limb reduction defect in a woman with interstitial 11q24 deletion in the Jacobsen syndrome region. Am J Med Genet A. 2014;164A(2):511–5.View ArticlePubMedGoogle Scholar
- Yamamoto T, Shimada S, Shimojima K, et al. Leukoencephalopathy associated with 11q24 deletion involving the gene encoding hepatic and glial cell adhesion molecule in two patients. Eur J Med Genet. 2015 Sep;58(9):492–6.Google Scholar
- Khan A, Auger RR, Kushida CA, et al. Rhythmic movement disorder. Sleep Med. 2008 Mar;9(3):329–30.Google Scholar
- Takenouchi T, Hashida N, Torii C, et al. 1p34.3 deletion involving GRIK3: Further clinical implication of GRIK family glutamate receptors in thepathogenesis of developmental delay. Am J Med Genet A. 2014;164A(2):456–60.View ArticlePubMedGoogle Scholar
- Pickard BS, Malloy MP, Christoforou A, et al. Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. Mol Psychiatry. 2006;11(9):847–57.View ArticlePubMedGoogle Scholar
- Lopez-Hernandez T, Ridder MC, Montolio M, Capdevila-Nortes X, et al. Mutant glialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. Am J Hum Genet. 2011;88:422–32.View ArticlePubMedPubMed CentralGoogle Scholar
- Lopez-Hernandez T, Sirisi S, Capdevila-Nortes X, Montolio M, et al. Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts. Hum Molec Genet. 2011;20:3266–77.View ArticlePubMedGoogle Scholar
- Arnedo T, Lopez-Hernandez T, Jeworutzki E, Capdevila-Nortes X, Sirisi S, Pusch M, Estevez R. Functional analyses of mutations in HEPACAM causing megalencephalic leukoencephalopathy. Hum Mutat. 2014;35(10):1175–8.View ArticlePubMedGoogle Scholar