Characteristics of 2P15-P16. 1 Microdeletion Syndrome: Review

Home , Angelman syndrome, KIAA1841, PAPOLG, PEX13

bs_bs_banner doi:10.1111/cga.12112 Congenital Anomalies 2015; 55, 125–132 125

INVITED REVIEW ARTICLE

Characteristics of 2p15-p16.1 microdeletion syndrome: Review and description of two additional patients

Keiko Shimojima1, Nobuhiko Okamoto2 and Toshiyuki Yamamoto1 1Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Tokyo, and 2Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan

ABSTRACT Many new microdeletion syndromes have microdeletions are variable and less distinctive. However, this vari- been characterized in the past decade, including 2p15-p16.1 ability provides an opportunity to study genotye-phenotype corre- microdeletion syndrome. More than 10 patients with this syn- lations and thereby understand the functions of the genes in the drome have been described. Recently, we encountered two addi- deletion region. Williams et al. (2010) analyzed genotype- tional patients with 2p15-p16.1 microdeletion syndrome. All phenotype correlations in patients with 2q37 deletions and nar- patients showed variable degrees of intellectual disability, with rowed the critical region for brachydactyly to the histone the autistic features characteristic of this syndrome. Seven out of deacetylase 4 gene (HDAC4) region. They then identified HDAC4 16 patients (44%) showed structural abnormalities in the brain, mutations in patients with similar clinical features but no. 2q37 which is also an important feature of this syndrome. The shortest deletions, thereby establishing that HDAC4 is responsible for region of microdeletion overlap among the patients includes two brachydactyly (Williams et al. 2010). Thus, the study of genotype- genes, USP34 and XPO1. Although these genes have some func- phenotype correlations is a powerful way to narrow the list of tional relevance to cancer, they have not been associated with potential candidate genes. neurological functions. Diagnosis of additional patients with In 2007, 2p15-p16.1 microdeletion syndrome was reported as an 2p15-p16.1 microdeletion syndrome and identification of patho- autism-related disorder (Rajcan-Separovic et al. 2007). Patients with genic mutations in this region will help identify the genes respon- 2p15-p16.1 microdeletions have distinctive clinical features associ- sible for the neurological features of the syndrome. ated with variable neurodevelopmental abnormalities. In addition to a patient previously diagnosed by us (Liang et al. 2009), we have Key Words: 2p15-p16.1 microdeletion syndrome, autistic features, identified two additional patients with 2p15-p16.1 microdeletions. intellectual disability, USP34, XPO1 Since the publication of the first study, over 10 patients with 2p15- p16.1 microdeletions have been described. However, the genes responsible for the clinical features of the syndrome have not been NEWLY IDENTIFIED RECURRENT established. Here, we report on additional patients and review the MICRODELETIONS characteristics of 2p15-p16.1microdeletion syndrome. Before the development of chromosomal microarray testing, only a small number of interstitial chromosomal deletions had been clini- cally recognized, including 22q11.2 deletion syndrome, Williams ADDITIONAL NEW PATIENTS syndrome, Smith-Magenis syndrome, Sotos syndrome, and Prader- The clinical features of two new patients and previously described Willi/Angelman syndrome (Emanuel and Shaikh 2001). Because patients are summarized in Table 1. patients with these syndromes show frequently distinct clinical features, clinical examinations can yield an initial diagnosis. The Patient 1 interstitial deletions associated with contiguous gene deletion syn- A 3-year-old boy was born at 39 weeks of gestation with a dromes are often mediated by surrounding low-copy repeats birthweight of 2360 g (3rd–10th centile), a length of 46 cm (3rd–10th (LCRs) located on both ends of the deletions (Stankiewicz and centile), and an occipitofrontal circumference (OFC) of 33 cm Lupski 2002). Therefore, most deletions mediated by LCRs share (25th–50th centile). His parents and elder sister are healthy. Imme- the same size and the same region. Consequently, patients with such diately after birth, he exhibited stridor due to laryngomalacia. He interstitial deletions exhibit common clinical features. After chro- had difficulty swallowing. He was able to sit alone at 9 months, mosomal microarray testing became widespread, numerous novel walk independently at 21 months, and jump at 3 years. However, he interstitial deletions were identified (Nevado et al. 2014), some of spoke no meaningful words. Brain magnetic resonance imaging which have genomic structures associated with LCRs. (MRI) examined at 12 months revealed corpus callosum agenesis Compared to LCR-mediated microdeletions, microdeletions (Fig. 1). He shows irritability and tactile hypersensitivity, suggest- mediated by random breakpoints are more difficult to diagnose, ing behavior abnormalities. At present, his weight is 13.7 kg (50th– because the clinical features of the patients carrying random 75th centile), his height is 95.9 cm (75th centile), and his OFC is 45 cm (<3rd centile), indicating microcephaly. He has small Correspondence: Toshiyuki Yamamoto, MD, PhD, Institute for Integrated palpebral fissures, telecanthus, and low-set ears (Fig. 2A). Medical Sciences, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ward, Tokyo 162-8666, Japan. Email: yamamoto.toshiyuki@ Patient 2 twmu.ac.jp An 18-year-old female patient was born at 41 weeks of gestation Received March 14, 2015; revised and accepted April 14, 2015. with a birthweight of 2310 g (3rd–10th centile). She has exhibited

Table 1 Clinical features of patients with microdeletions around 2p15-p16.1 . 2008 . 2009 et al . 20100 et al et al Prontera et al. 2011 Wohlleber et al. 2011 Hucthagowder et al. 2012 Piccione et al. 2012 Hancarova et al. 2013 Florisson et al. 2013 Fannemel et al. 2014 Jorgez et al. 2014 This study Total in patients with 2p15-p16.1 microdeletion syndrome§ Felix Rajcan-Separovic et al. 2007 de Leeuw Chabchoub et al. 2008 Liang P1 P2 P1 P2 P1 P2 P1 P2 #1 #2 #3 #4 #5 #6 #7 P1 P2 General Current age (years) 9 7 34 9449812020.3114132110411116144318 Gender F M M M F F F M F F F M F M F MMMMMMMMMFM/F= 12/10 IUGR + --NA++NA - - + NANA-NANA------++ 6/14 Mild to severe intellectual ++++++++++++++++- ++++++++ 20/20 disability Feeding problems +++NA NA +++- + NA NA + NANANA----+ NA NA + - 9/12 Short stature - ++ - + NA NA - - + - ++-----+ NA NA NA NA - + 8/15 Microcephaly +++ - ++++- + - ++++---+++NA NA ++ 16/19 Facial features Bitemporal narrowing +++NA - NA + --+ NA NA - +++NA NA NA NA NA + NA - + 10/13 Receding short forehead +++ --+ ---+ NA NA - - +/- NA NA NA NA NA NA NA NA - + 6/12 Strabismus + - + NA-----++- ++- - NA NA NA NA NA NA NA - + 7/15 Ptosis +++NA +++-----++++NA NA + NA + NA ++- 13/17 Telecanthus +++++++--+++++++NA NA + NA NA + NA ++ 18/18 Widened inner canthal +++NA + NA + --+ NA NA NA ++- NANANANANANANA + - 9/11 distance Short palpebral ﬁssures +++NA +++-- -NANA+ - - - NA NA NA NA NA NA ++- 7/13 Down slanting palpebral +++ + -NA-- - - + - + --+ NA NA ++NA NA NA ++ 11/17 ﬁssure Epicanthal folds +++NA + NA + --++++++-NANA++NA NA NA ++ 15/16

Broad/high nasal root +++ ++/- ++- ++ --++++NA NA NA NA NA NA NA ++ 13/15 al. et Shimojima K. Prominent nasal tip ++- + -NA+ --+ NA NA + --+ NA NA + NA NA NA NA - + 9/14 Long, straight eyelashes +++NA - + - - - NANANA + - + NA NA NA + NA NA NA NA - - 7/12 Long, thin eyebrows - + - NA- NA- - - NANANA + - + NA NA NA NA + NA NA NA - - 4/11 Large ears ++- + - ++------+ - NANANA + NA NA NA + - - 7/16 Smooth and long philtrum +++NA +++--NA++++++NA NA NA NA NA NA + - + 13/14 Smooth upper vermillion +++ + -NA+ --NA- - + --+ NA NA NA NA NA NA NA ++ 9/14 border Everted lower lip +++ + -NA+ --+ - ++- - - NA NA NA NA NA NA NA ++ 10/15 High narrow palate +++ + - ++--+ - ++- - NA NA NA + NA ++NA - + 13/18 Retrognathia - ++ - ++‡- --+ NA NA - - - + NA NA +‡ NANANANA ++ 9/15

Other physical features syndrome microdeletion 2p15-p16.1 Widened internipple +++NA - ++NA NA - NA NA + - - - NA NA NA NA NA NA NA + - 7/13 distance Extra nipple - + - NA - NA - NA NA - NA NA - - - + NA NA NA NA NA NA NA - - 2/12 Camptodactyly ++-- -+ -NANANA- + - ++-NANA+ NA +++- + 10/18 Metatarsus abductus ++--+† + -NANANA- - + - - NA NA NA NA NA NA NA NA - - 5/14 Spasticity legs ++--+ NA + NA NA + NA NA + - - NA NA NA NA NA NA NA NA - - 6/12 Other Optic nerve hypoplasia +++NA + --NANA------NANANANANANANA-- 4/15 Disturbed vision - ++NA NA + NA NA NA + NA NA + - - NA NA NA + NA NA NA NA - - 6/11 Hearing loss - + -NA---NANA--+ --++NA NA NA NA NA NA NA - - 4/15 Frequent upper respiratory + - + NA - - - NA NA + -----NANANANA++NA NA + - 6/16 infections Laryngomalasia - + - NA - NA - NA NA - NA NA - - - NA NA NA NA NA NA NA NA + - 2/11 Hydronephrosis +++NA - - - NA NA + ------NANANANA-NANA-- 4/16

05Jpns eaooySociety Teratology Japanese 2015 © Hypogonadism - + - NA - - - NA NA - ++----++++- ++- - 6/19 Attention deﬁcit behavior ++--+ NA + NA NA NA + NA- NANANANANA- NA + NA + - - 6/12 Structure brain ++NA NA - - - - - + - + - + NA- NANANA + NA NA NA + - 7/14 abnormalities

NA, not assessable; †Metatarsus adductovarus rather than Metatarsus abductus; ‡Micrognathia; NA and +/- are not included in the total counts. §The patient reported by Wohlleber et al. (2011) and #1, #2, and #7 reported by Jorgez et al. (2014), indicated column are shaded, excluded from total counts due to the genotype point of view. 127 128 K. Shimojima et al.

Fig. 1 Brain magnetic resonance imaging (MRI) of patient 1. Parallel dispositions of the lateral ventricles are noted in the T1-weighted axial image (left). Com- plete loss of the corpus callosum is shown in the T2-weighted sagittal image (right).

Fig. 2 Distinctive features of the patients. (A) Patient 1 at 3 years has small palpebral fissures, a flat nasal bridge, telecanthus, and low set ears. (B) Patient 2 at 18 years has a small mandible. Written informed consent to use this photograph was obtained from the family of patient 1. developmental delay since early infancy; she was able to turn over 2012). In patient 1, we identified a 238-kb microdeletion in 2p15, at 9 months and sit at 11 months. She started to walk unsupported indicating arr 2p15(61 495 220-61 733 075) × 1. Chromosomal at 2 years and 7 months. Brain MRI showed no abnormalities. At microarray testing using the same platform was performed using present, her weight is 44 kg (3rd–10th centile), her height is 147 cm DNA from the parents, and the deletion identified in patient 1 was (<3rd centile), and her OFC is 52.8 cm (<3rd centile), indicating short not detected in either parent, indicating a de novo origin. Patient 2 stature and microcephaly. We also noted the distinctive feature of a had a 3.5-Mb interstitial deletion in 2p14-p15, described as arr small mandible (Fig. 2B). She exhibits severe developmental delay 2p15p14(61 618 699-65 142 743) × 1. Because the parents of this and speaks no meaningful words. Her unbalanced diet and strong patient declined to be genotyped, it is unknown whether the deletion resistance to changing her daily life pattern indicate autistic is of de novo origin. The presence of the deletions was not con- features. firmed in the described patients (such as by quantitative polymerase chain reaction [PCR]). The deletion regions in both patients are summarized in Table 2 and depicted on the genome map together CHROMOSOMAL MICROARRAY TESTING with those of previously reported patients (Fig. 3). All of the FOR 2P15-P16.1 MICRODELETIONS genomic positions refer to build19 in this study. This study was performed after receiving approval from the ethics committee at Tokyo Women’s Medical University. After obtaining GENOTYPE-PHENOTYPE CORRELATION written informed consent from both patients’ families, blood samples were obtained from the patients and from the parents of The 2p15-p16.1 microdeletion was first reported in 2007 by patient 1. Genomic DNA extracted from blood samples was used Rajcan-Separovic et al. (2007). They described two patients with for further studies. Genomic copy number aberrations were exam- 2p15-p16.1 microdeletions. The patients shared common features ined using an Agilent Hmn array 60 K (Agilent Technologies, with moderate to severe intellectual disability, autistic features, Santa Clara, CA, USA) as described previously (Shimojima et al. microcephaly, structural brain anomalies including cortical

Table 2 Deletion regions in patients with 2p15-p16.1 original cases reported by Rajcan-Separovic et al. (2007) (Fig. 3). microdeletion syndrome Indeed, the patients described by Wohlleber et al. (2011) did not show any distinctive facial features of 2p15-p16.1 microdeletion Published Deletion region† syndrome. These findings establish a borderline at the 62.5-Mb Researchers year Start End region, which divides the reported patients into separate categories (Fig. 3). Patients in the first category have deletions closer to the Rajcan-Separavic 2007 P1 56,143,087 61,660,124 telomeric region, near the chromosome band boundary between et al. 2p16.1 and 2p15. These patients exhibit a typical combination of P2 57,307,217 61,660,124 clinical features, including mild to severe developmental delay, Chabchoub et al. 2007 61,389,240 61,660,124 growth delay in association with microcephaly, distinctive features, de Leeuw et al. 2008 57,913,898 61,488,792 and brain anomalies. On the other hand, patients with deletions closer to the Liang et al. 2008 59,241,620 62,385,716 centromeric regions, not including the chromosome band boundary Félix et al. 2010 59,139,200 62,488,871 between 2p16.1 and 2p15, do not exhibit the characteristics Prontera et al. 2010 56,853,162 60,380,981 described above. Rather, as Jorgez et al. (2014) have suggested, Wohlleber et al. 2011 P1 63,903,236 66,130,003 patients whose chromosomal deletion encompasses the orthodenticle homeobox 1 gene (OTX1) region exhibit genitouri- P2 62,687,128 65,523,986 nary defects with variable penetrance. The study by Jorgez et al. Hucthagowder 2012 60,672,255 63,144,695 (2014) included seven patients with microdeletions around 2p15; et al. six patients exhibited genitourinary defects. The smallest deletion Piccione et al. 2012 P1 60,604,088 68,391,261 represented the shortest region of overlap among the patients and included OTX1, which might be responsible for the observed geni- P2 60,347,280 62,852,277 tourinary defects. Although the deletion in patient two reported in Hancarova et al. 2013 60,689,977 61,127,979 this study includes OTX1, the patient did not exhibit any genitou- Florisson et al. 2013 P1 55,661,474 62,509,701 rinary defects. Moreover, the two patients described by Wohlleber P2 58,532,874 65,503,931 et al. (2011) did not exhibit any genitourinary defects either. There- fore, the phenotypic penetrance of genitourinary defects might be Fannemel et al. 2014 61,500,346 61,733,075 less than 100% in patients with deletions in this region. Jorgez et al. 2014 #1 63,277,168 63,343,150 Four patients described by Jorgez et al. (2014) had chromosomal #2 62,970,000 68,020,000 deletions that extended to the 2p16.1-2p15 boundary region. Their #3 61,130,000 63,520,000 clinical features were typical of the 2p15-p16.1 microdeletion syndrome, suggesting that the 2p16.1-2p15 boundary region is respon- #4 60,070,000 66,380,000 sible for the characteristic features (Fig. 3). #5 61,060,000 65,660,000 In this study, we identified the smallest deletion of 2p15 in patient #6 61,570,000 64,320,000 1. Upon combining it with the deletion region identified in patient #7 62,890,000 65,910,000 2, we narrowed the shortest region of the microdeletion overlap to Present study P1 61,495,220 61,733,075 a 114-kb region of chr2:61 618 699-61 733 075. In the overlap region, only two genes are located, the ubiquitin-specific protease P2 61,618,699 65,142,743 34 gene (USP34) and the exportin 1 gene (XPO1). Most of the †Genomic positions of chromosome 2 are uniformly translated previously identified 2p15-p16.1 microdeletions included this USP34 XPO1 into build19. region (Fig. 3). Therefore, and are the candidate genes most likely responsible for the characteristic features. Some patients have deletions that do not include USP34 and XPO1, namely the patients reported by de Leeuw et al. (2008), dysplasia/pachygyria, renal anomalies (multicystic kidney, Hancarova et al. (2013), and Prontera et al. (2011). However, the hydronephrosis), digital camptodactyly, visual impairment, strabis- clinical features of these patients are quite similar to those of the mus, neuromotor deficits, communication and attention impair- patients whose deletions are restricted to the small regions ments, and a distinctive pattern of craniofacial features. Since the described above, though they do not overlap. A long-range control publication of their study, over 10 patients with 2p15-p16.1 of gene expression due to a genomic-positional effect might explain microdeletion have been reported that they share similar clinical this observation (Kleinjan and van Heyningen 2005). manifestations (Chabchoub et al. 2008; de Leeuw et al. 2008; The original report of 2p15-p16.1 microdeletion syndrome sug- Liang et al. 2009; Felix et al. 2010; Prontera et al. 2011; gested an association with autistic features (Rajcan-Separovic et al. Hucthagowder et al. 2012; Piccione et al. 2012; Florisson et al. 2007). Many patients with this microdeletion syndrome exhibit 2013; Hancarova et al. 2013; Fannemel et al. 2014). All of the autistic features, including the two patients described in the present patients were diagnosed with the genotype-first approach using study. However, most patients exhibit severe intellectual disability, chromosomal microarray testing and all deletions were of de and their autistic features cannot be evaluated with any battery of novo origin, indicating that copy number losses in this region are tests. Patient 1 in this study had the shortest deletion in the 2p15- pathogenic. p16.1 region, but his developmental delay was severe. Compared to patients with 2p15-p16.1 microdeletion syndrome, patients whose microdeletions occur closer to the centromeric BRAIN MALFORMATION regions exhibit different clinical features (Fig. 3). Wohlleber et al. (2011) described two patients with microdeletions in 2p14-p15. The Brain structural abnormalities were observed in 7 of 14 patients deletion regions in the two patients do not overlap with those in the (50%) with 2p15-p16.1 microdeletion syndrome (Table 3). Among

Fig. 3 Genome map of the region around 2p15- p16.1 depicting the aberrations identified in the patients. Bars with arrows on both ends indicate the locations of the genes. Red bars, blue bars, and gray bars indicate the deletion regions identified in the present study, previous studies, and a study by Jorgez et al. (2014), respec- tively. The shaded gray bars indicate the deletions identified in patients with facial features typical of 2p15-p16.1 microdeletion syndrome. Whereas the parental origins of the deletions in patient 2 in this study and in patients #1 and #2 in the study by Jorgez et al. (2014) were not examined, the de novo origin of all other deletions was confirmed.

them, three patients showed hypoplasia of the corpus callosum. Table 3 Brain anomalies in patients with 2p15-p16.1 Complete agenesis of the corpus callosum was observed for the first microdeletion syndrome time in 2p15-p16.1 microdeletion syndrome in patient 1 of this study (Fig. 1). Thus, brain structural abnormalities, especially those Authors Brain abnormalities related to the corpus callosum, are characteristic of this syndrome. Rajcan-Separovic P1 Bilateral perisylvian cortical dysplasia et al. P2 Dysmyelination GENE FUNCTION Cortical dysplasia The smallest deletion region in patients with 2p15-p16.1 Small anterior pituitary and pons microdeletion syndrome includes only two genes: USP34 and XPO1. Hucthagowder et al. Simplified gyral pattern USP34 is an ubiquitin-specific protease that functions in Wnt Hypoplasia of the corpus callosum signaling and removes ubiquitin modifications from ubiquitinated Piccione et al. P2 White matter malacia with cerebral proteins (Lui et al. 2011). Although this pathway is associated with atrophy multiple human diseases, including cancer, the functional relevance of USP34 haploinsufficiency to the neurological features of 2p15- Hypoplastic corpus callosum p16.1 microdeletion syndrome is unknown. Florisson et al. P1 Simplified gyral pattern XPO1, also called chromosome region maintenance protein 1 Hypoplasia of the corpus callosum (CRM1), is one of the nuclear transport receptors. Eukaryotic cells Small aspects of the cerebelum and are compartmentalized into the cytosol and the nucleus, and communication between the compartments is essential for cell mainte- pons nance (Raices and D’Angelo 2012). While seven nuclear export Jorgez et al. P4 Cerebral atrophy proteins have been identified, XPO1 uniquely mediates the export Colpocephaly of almost all major tumor suppressor proteins (Muqbil et al. 2014). Enlarged cisterna magna Inhibition of XPO1 is one approach to restoring the nuclear locali- Present patients P1 Complete agenesis of the corpus zation, activation, and function of multiple tumor suppressor proteins. Leptomycin B was the first natural agent identified that callosum irreversibly inhibits XPO1 (Kau and Silver 2003). However, the

Table 4 Summary of the genes located on the neighboring region of 2p15-p16.1 microdeletions

Symbol Gene name Location† RefSeq Summary BCL11A B-cell CLL/lymphoma 11A chr2:60,684,329-60,780,633 The corresponding mouse gene may function as a leukemia disease gene. PAPOLG poly(A) polymerase gamma chr2:60,983,365-61,029,221 This gene encodes a member of the poly(A) polymerase family. REL v-rel reticuloendotheliosis viral chr2:61,108,752-61,150,178 Mutation or amplification of this gene oncogene homolog is associated with B-cell lymphomas. PUS10 pseudouridylate synthase 10 chr2:61,167,548-61,244,328 Function as the most common posttranscriptional nucleotide modification found in RNA. PEX13 peroxisomal biogenesis factor 13 chr2:61,244,812-61,279,125 Related to peroxisome biogenesis disorder 11A (Zellweger). KIAA1841 chr2:61,293,363-61,365,169 N/A AHSA2 AHA1, activator of heat shock 90 kDa chr2:61,404,553-61,414,686 N/A protein ATPase homolog 2 USP34 ubiquitin specific peptidase 34 chr2:61,414,590-61,697,849 N/A XPO1 exportin 1 chr2:61,705,069-61,765,369 This cell-cycle-regulated gene encodes a protein that mediates leucine-rich nuclear export signal (NES)-dependent protein transport. FAM161A family with sequence similarity 161 chr2:62,051,983-62,081,278 Mutations in this gene cause autosomal recessive retinitis pigmentosa-28. CCT4 chaperonin containing TCP1, subunit 4 chr2:62,095,262-62,115,806 The chaperonin containing the TCP1 ring complex. COMMD1 copper metabolism (Murr1) domain chr2:62,132,803-62,363,205 A regulator of copper homeostasis, containing 1 sodium uptake, and NF-kappa-B signaling. B3GNT2 UDP-GlcNAc:betaGal beta-1,3-N- chr2:62,423,262-62,451,866 This encodes a member of the acetylglucosaminyltransferase 2 beta-1,3-N- acetylglucosaminyltransferase family. TMEM17 transmembrane protein 17 chr2:62,727,356-62,733,604 N/A EHBP1 EH domain binding protein 1 chr2:62,900,986-63,273,621 The encoded protein may play a role in endocytic trafficking.

†Genomic locations are referred to build19. N/A, not available. functional relevance of XPO1 haploinsufﬁciency to the neurologi- identiﬁcation of pathogenic mutations in the 2p15-p16.1 region will cal features of 2p15-p16.1 microdeletion syndrome is unclear. help elucidate genes that contribute to the neurological features of USP34 and XPO1 have functional relevance to cancer, but roles this syndrome. for these genes in neurological functions have not been reported. We checked the Human Genetic Variation Browser (HGVB, http:// www.genome.med.kyoto-u.ac.jp/SnpDB) to determine whether ACKNOWLEDGMENTS gene variants leading to loss-of-function had been reported. However, there were no such variants in the regions of USP34 and We would like to express our gratitude to the patients and their XPO1. families for their cooperation. This work was mainly supported by The region neighboring the 2p15-p16.1 microdeletion does not a grant from the Precursory Research for Embryonic Science and include genes with relevance to neurological functions (Table 4), Technology (PRESTO), Japan Science and Technology Agency and the genes responsible for the neurological features of 2p15- (JST), Kawaguchi, Japan and was partially supported by a Grant- p16.1 microdeletion syndrome are unknown. Diagnosis of addi- in-Aid for Young Scientists (B) (24791090), from the Japan Society tional patients with 2p15-p16.1 microdeletion syndrome and for the Promotion of Science (JSPS), a grant from the Japan

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