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European Journal of Medical Genetics xxx (2014) 1e5

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European Journal of Medical Genetics

journal homepage: http: / /www.elsevier .com/locate/ejmg

Clinical report

Genotypeephenotype relationship in a child with 2.3 Mb de novointerstitial 12p13.33-p13.32 deletion

Isabella Fanizza a, Sara Bertuzzo b, Silvana Beri c, Elisabetta Scalera a, Angelo Massagli a,Maria Enrica Sali d, Roberto Giorda c, Maria Clara Bonaglia b,*

aChild Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Ostuni, Brindisi, ItalybCytogenetics Laboratory, Scientific Institute, IRCCS Eugenio Medea, Via Don Luigi Monza, 20, 23842 Bosisio Parini, Lecco, ItalycMolecular Biology Laboratory, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, ItalydChild Psychopathology Unit e Neuropsychology of Developmental Disorders, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy

a r t i c l e i n f o

Article history:Received 22 November 2013Accepted 15 April 2014Available online xxx

Keywords:12p13.33 DeletionCACNA1CSpeech delayArray-CGHInterstitial deletionMicrocephaly

* Corresponding author. Tel.: þ39 031 877 913; faxE-mail address: clara.bonaglia@bp.lnf.it (M.C. Bona

http://dx.doi.org/10.1016/j.ejmg.2014.04.0091769-7212/� 2014 Elsevier Masson SAS. All rights res

Please cite this article in press as: Fanizza I, edeletion, European Journal of Medical Gene

a b s t r a c t

Microdeletion 12p13.33, though very rare, is an emerging condition associated with variable phenotypeincluding a specific speech delay sound disorder, labelled childhood apraxia of speech (CAS), intellectualdisability (ID) and neurobehavioral problems.

Here we report a de novo 2.3 Mb interstitial 12p13.33-p13.32 deletion in a 5 year-old child with mildID, speech delay, microcephaly, muscular hypotonia, and joint laxity. In contrast to previously reportedpatients with 12p13.33 monosomy, our patient’s interstitial deletion spans the 12p13.33-12p13.32 regionwith the distal breakpoint within intron 12 of CACNA1C.

Phenotypeegenotype comparison between our case, previously reported patients, and subjects with12p13.33 deletions led us to propose that haploinsufficiency of CACNA1C may influence the variability ofthe patients’ phenotype, since the gene resulted disrupted or entirely deleted in the majority of reportedpatients. In addition, phenotypic features such as microcephaly, muscular hypotonia, and joint laxity aremainly present in patients with monosomy of 12p13.33 extending to the 12p13.32 portion. A commonregion of w300 kb, harbouring EFCAB4B and PARP11, is deleted in patients with microcephaly while asecond region of w700 kb, including TSPAN9 and PMTR8, could be associated with muscle hypotonia andjoint laxity. These data reinforce the hypothesis that multiple haploinsufficient genes and age-dependentobservation may concur to generate the variable phenotype associated with 12p13.33 deletion.

� 2014 Elsevier Masson SAS. All rights reserved.

1. Introduction

Deletions involving the distal portion of 12p are among the leastfrequent subtelomeric rearrangements detected in a selected groupof more than 11,000 patients with developmental disabilities[Ravnan et al., 2006]. The rarity of this rearrangement has beenlater confirmed following the advent of microarray-based tech-nology. To date, microdeletions detected by genome-wide arrayanalysis at 12p13.33, either de novo [Rooryck et al., 2009; Thevenonet al., 2013; Vargas et al., 2012] or inherited [Abdelmoity et al., 2011;Thevenon et al., 2013], have been reported in 12 index patients[Abdelmoity et al., 2011; Baker et al., 2002; MacDonald et al.,2010; Madrigal et al., 2012; Thevenon et al., 2013; Vargas et al.,

: þ39 031 877 499.glia).

erved.

t al., Genotypeephenotype retics (2014), http://dx.doi.org/

2012]. The phenotype, though variable, is mainly characterized byspeech delay with or without [Thevenon et al., 2013] intellectualdisability (ID) of variable degree and behavioural abnormalities.The recent findings of de novo and inherited interstitial deletionsof 2.76 Mb and 1.39 Mb [Abdelmoity et al., 2011; Thevenon et al.,2013], respectively, led to the identification of a new 12p13.33locus, including ELKS/ERC1, whose deletion is associated with thespeech disorder childhood apraxia of speech (CAS), also labelleddevelopmental verbal dyspraxia (DVD) [Thevenon et al., 2013].Here we report on a child with de novo 2.3 Mb interstitial12p13.33-p13.32 microdeletion, whose main phenotype is charac-terized by mild ID and speech delay. Comparative phenotypicevaluation of subjects with small deletions partially overlappingthe 12p13.33 locus allows us to propose that haploinsufficiency ofCACNA1C (MIM 114205) and other genes may influence thephenotypic variability of patients with monosomy of the 12p13.33subtelomeric region.

lationship in a child with 2.3 Mb de novo interstitial 12p13.33-p13.3210.1016/j.ejmg.2014.04.009

Table 1Cognitive assessment of the patient. Test reference: NEPSY-II (“A DevelopmentalNEuroPSYchological Assessment”) Italian Edition C. Urgesi, F. Fabbro, 2011; BVS-Corsi (“Batteria per la valutazione visiva e spaziale”) I.C. Mammarella, C. Cornoldi;BVN 5-11 (Batteria di Valutazione Neuropsicologica per l’età evolutiva) P. S. Bisiacchi,M. Cendron, M. Gugliotta, Tressoldi e Vio, 2005 Ed. Erickson.

Cognitive function Test Score

Executive functionsAttention Visual attention (Nepsy-II) 5 SSShort term memory Forward digit span (BVN 5e11) �2.4 SDWorking memory Backward digit span (BVN 5e11) �1.9 SDVisuo-spatial memory Test di Corsi (BVS-Corsi) �3.0 SD

LanguageComprehension of instructions (Nepsy-II) 1 SSSpeeded naming (Nepsy-II) <2 PercentilePhonological processing (Nepsy-II) 1 SSVerbal fluency (Nepsy-II) 2 SSRepetition of nonsense words (Nepsy-II) 1 SSOromotor sequences (Nepsy-II) 1 SS

MemoryNarrative memory (Nepsy-II) 4 SSSentence repetition (Nepsy-II) 3 SS

Sensorymotor functionImitating hand positions (Nepsy-II) 1 SSManual motor sequences (Nepsy-II) 1 SS

SD, standard deviation; SS: scaled scores.

I. Fanizza et al. / European Journal of Medical Genetics xxx (2014) 1e52

2. Clinical report

Informed consent was obtained from both parents of thepatient.

The five-year-old boy came to our attention for intellectualdisabilities and speech delay. He was born at 39 weeks ofgestation, after caesarean section, to non-consanguineous 26-year-old mother and 29-year-old father with unremarkablefamily history. Birth weight was 2160 g (3rd percentile). Hisyounger brother, now aged 15 months, has normal psychomotordevelopment.

At birth, he manifested severe breathing and feeding prob-lems and was transferred to the intensive care unit for ten days.Bartter syndrome was suspected. Early motor milestones werein range: he sat at between 6 and 9 months, walked at 15months, thought uncoordinatedly. Language and learning diffi-culties were noticed early. First words were pronounced at 2 1/2years.

At the age of 5 years (last evaluation), he hadmild ID. The IQ wascalculated by WPPSI-III (Wechsler Preschool and Primary Scale ofIntelligenceeThird Edition) with this result: full scale IQ 52; verbalIQ 53 (standard score: information 4, vocabulary 2, word reasoning1); performance IQ 62 (standard score: block design 3, matrixreasoning 4, picture concepts 6); processing Speed 52 (standardscore: symbol search 3, coding 1); general language 53 (receptivevocabulary 1, picture naming 3). A digit cancellation test (Nepsy-II“Visual Attention”) showed difficulties in distractor inhibition andselective and sustained attention, with long inspection time andslow motor performance. Forward and backward digit span scoreswere�2.4 SD and�1.9 SD respectively. Visuo-Spatial Memory (TestBVS e Corsi) was �3.0 SD. The patient had fine motor disorder:Nepsy-II scales “Imitating Hand Positions” 1 Scaled Scores (SS),“Manual Motor Sequences” 1 SS. The VABS showed global motorproblems: motor skills AE was 2 years 4 months. The oro-facialdyspraxia was exhibited using the Nepsy-II scale “Oromotor Se-quences” 1 SS. Linguistic assessment with a comprehensive battery(Nepsy-II) showed problems in “Comprehension of Instructions” 1SS, “Speeded Naming” < 2 Percentile, “Phonological Processing” 1SS, “Repetition of Nonsense Words” 1 SS, “Verbal Fluency” 2 SS.These difficulties had an important influence onmnemonic abilities(Nepsy-II) “Narrative Memory” 4 SS, “Sentence Repetition” 3 SS(Table 1).

The Vineland Adaptive Behaviour Scale (VABS) was adminis-tered to both parents. His global age equivalent (AE) was less than 2years 2 months; receptive language and expressive skills score was2 years 9 months; socialization AE was less than 1 year 11 months;daily living skills AE was 2 years 4 months; motor skills AE was 2years 4 months. His score on the “Child Global Assessment ofFunctioning Scale” (CGAS) was 40, corresponding to “Majorimpairment to functioning in several areas”. No behavioural ab-normalities were noticed.

His height was 104 cm (10e25th centile), weight 15 kg (3e10thcentile) and OFC 46 cm (�3 SD). He showed subtle facial dys-morphisms, including brachycephaly, low hairline, synophrys, longeyelashes, thin lips, ears with short and convoluted anti-helices andV-shaped notches, arched palate (Fig. 1A).

He presented diffuse muscular hypotonia, joint laxity, andglobal clumsiness. Flat-footedness bilaterally with enlargedbase and walking on tips were noticed. Brain MRI showed noabnormalities, except for a slight supratentorial asymmetry(right greater than left); EEG showed slow fronto-parietal ab-normalities in sleep starting bilaterally on a poorly modulatedbasic framework. Conventional cytogenetic studies showed anormal karyotype (46,XY); fragile-X molecular tests werenormal.

Please cite this article in press as: Fanizza I, et al., Genotypeephenotype redeletion, European Journal of Medical Genetics (2014), http://dx.doi.org/

3. Material and methods

3.1. Array-CGH analysis

Array-CGH was performed using the Agilent Human GenomeCGH Microarray Kit 180k (Agilent Technologies Inc., Santa Clara,CA) with a resolution of w100 kb. All nucleotide positions refer tothe Human Genome, Feb 2009 Assembly (hg19). Data analysis wasperformed using Agilent Cytogenomics version 2.5.8.1.

3.2. Real-time quantitative PCR

Specific target sequences were selected for Real-time quantita-tive PCR (qPCR) using Primer 3 software (http://frodo.wi.mit.edu/primer3/). A control amplicon was selected with the same param-eters in theMAPK1 gene on 22q11.2; size (approximately 60 bp) andTm (60 �C) were the same for all amplicons. qRT-PCR assays wereperformed using SYBR Green and analyzed on an ABI PRISM7900HT sequence detection system (Applied Biosystems, FosterCity, CA).

3.3. Genotyping

Genotyping of polymorphic loci (D12S1626, D12S314) in theproband and his parents was performed by amplification withprimers labelled with fluorescent probes (ABI 6-Fam and 8-Hex),followed by analysis on ABI 310 Genetic Analyzer (AppliedBiosystems).

4. Results

In the absence of an etiological diagnosis, array-CGH analysisperformed with a 180k oligo array platform revealed a copy num-ber loss of 2.3 Mb in chromosomal band 12p13.33-p13.32. Thedistal breakpoint at 2680541e2689277 Mb (hg19) disrupted CAC-NA1C (OMIM *114205) while the proximal breakpoint at 4990324e5005616 Mb (hg19) was located w30 kb from KCNA6 (OMIM

lationship in a child with 2.3 Mb de novo interstitial 12p13.33-p13.3210.1016/j.ejmg.2014.04.009

Fig. 1. (A) Photographs of the patient at the age of 5 years. (B) Array-CGH results: (left) array CGH profile of chromosome 12 showing an interstitial deletion at 12p13.3p13.2;(middle) enlargement of the 12p13.3p13.2 deleted region; (right) genes included in the deleted region are listed in light blue and orange; the genes discussed in the text (CACNA1C,PRTMT8, EFCAB4B, PARP11) are indicated with capital letters.

I. Fanizza et al. / European Journal of Medical Genetics xxx (2014) 1e5 3

*176257) (Figs. 1B and 2). qPCR performed on the patient and hisparents demonstrated that the 12p13.33-p13.22 deletion origi-nated de novo (not shown).

The final interpretation of the rearrangement was arr[hg19]12p13.33p13.32(2680541x2,2689277-4990324x1,5005616x2)dn.The deleted region includes about 25 UCSC genes (Fig. 2).

Fig. 2. Schematic representation of our patient’s deletion compared with previously reporte(GRCh37/hg19) are shown. White bars indicate inherited deletion, black bars de novo deletisharing microcephaly. The darker grey box indicates a common deleted region of w700 kb treported in Supplementary Table I.

Please cite this article in press as: Fanizza I, et al., Genotypeephenotype redeletion, European Journal of Medical Genetics (2014), http://dx.doi.org/

5. Discussion

Including the present case, 13 index patients have been reportedwith terminal or interstitial microdeletions spanning 12p13.33(Fig. 2), associated with an emerging condition mainlycharacterized by ID, speech delay, and variable psychiatric

d patients. The screenshot spans the terminal 6.5 Mb of chromosome 12p. UCSC geneson. The light grey box indicates the common deleted region of 300 kb among patientshat could be associated to muscle hypotonia and joint laxity. The list of OMIM genes is

lationship in a child with 2.3 Mb de novo interstitial 12p13.33-p13.3210.1016/j.ejmg.2014.04.009

Table 2Additional phenotypic features in patients with 12pter deletion spanning the12p13.2 region.

Cases Joint laxity Muscular hypotonia Microcephaly

Current case þ þ þVargas et al. [2012] þ ND þMadrigal et al. [2012] ND þ þPz-6, Thevenon et al. [2013] þ þ �Pz-9, Thevenon et al. [2013] þ ND þPz-7, Thevenon et al. [2013] ND ND þTotal 4/6 4/6 5/6

þ, Present; � not present; ND, nor defined.

I. Fanizza et al. / European Journal of Medical Genetics xxx (2014) 1e54

manifestations [Abdelmoity et al., 2011; Baker et al., 2002;MacDonald et al., 2010; Madrigal et al., 2012; Rooryck et al.,2009; Thevenon et al., 2013; Vargas et al., 2012]. A very recentgenotypeephenotype characterization proposed ERC1/ELSKS as agood candidate gene for childhood apraxia of speech (CAS), aspecific speech sound disorders diagnosed in five patients out ofnine analyzed [Thevenon et al., 2013].

As in previously reported cases, the first symptom observed inour patients was speech delay, with first words uttered at age of 40months, associatedwithmoderate ID and earlymotor milestones inrange.

Unlike previously published interstitial deletions, the 2.3 Mbinterstitial deletion of 12p13.33p13.32 reported in this study coversthe proximal portion of the 5 Mb subtelomeric region commonlyinvolved in 12p13.33 microdeletions (Fig. 2). Our patient’s distaldeletion breakpoint is located in intron 12 of CACNA1C (Fig. 2),w500 kb distant from ERC1ELKS.

If we compare the distribution of the reported breakpoints,three cases [Abdelmoity et al., 2011; Rooryck et al., 2009; Thevenonet al., 2013] have their centromeric breakpoints within CACNA1C(OMIM *114205) (Fig. 2). Two breakpoints are located in intron 3[Abdelmoity et al., 2011; Rooryck et al., 2009]. The genomicarchitecture of this region and absence of segmental duplicationsexclude the presence of a deletion hotspot in CACNA1C. However,all but two deletions [Baker et al., 2002; Thevenon et al., 2013]span this gene. The CACNA1C gene encodes the alpha-1 subunit ofa voltage-dependent calcium channel mediating the entry of cal-cium ions into excitable cells and is involved in a variety of calcium-dependent processes, including muscle contraction, hormone andneurotransmitter release, gene expression, cell motility, cell divi-sion, and cell death. Very rare exonic mutations have been associ-ated with Timothy syndrome (TS, OMIM 601005), a multisystemdisorders mainly characterized by a long QT interval that results incardiac arrhythmias in association with cognitive impairment,autism and major developmental delay in many patients [Splawskiet al., 2005]. None of the subjects with haploinsufficiency ofCACNA1C, including our patient, showed any phenotypic featuresof TS, with the exception of one with moderately shortened QTcinterval (330 ms) [Rooryck et al., 2009]. These observationssuggest that, in contrast with gain-of-function de novo mutationsin CACNA1C, resulting in a distinct form of TS [Splawski et al., 2005],CACNA1C deletions may have different functional consequences.Our patient with interstitial deletion overlapping the proximalportion of the commonly deleted 12p13.33 region sharesintellectual disability and language delay with all otherindividuals with a deletion spanning the terminal 5 Mb of 12p(Fig. 1). Since CACNA1C is deleted in most patients, we suggestthat this gene may play a primary role in these major phenotypicfeatures. In addition, behavioural anomalies (autism spectrumdisorder, ADHD, anxiety, psychosis) have been reported in mostpatients [Thevenon et al., 2013; Vargas et al., 2012; Velinov et al.,2008]. Our patient, at five years of age, does not show anybehavioural anomalies so far. However, two patients [Vargaset al., 2012; Velinov et al., 2008] developed psychiatricmanifestation in their teens and a psychosis-associated locus of2 Mb that included CACNA1Cwas delineated [Vargas et al., 2012]. Inaddition, numerous genome-wide association studies indicate thatpolymorphisms in CACNA1C confer an increased risk for psychiatricdisorders [Franke et al., 2010; Gershon et al., 2013;Szczepankiewicz, 2013]. It would be reasonable to postulate thatpatients with haploinsufficiency of this gene may also be at riskof psychiatric disorders when older; a careful psychiatric follow-up of young patients will clarify the issue.

The patient described here also shows microcephaly (-3DS),diffuse muscular hypotonia, and joint laxity. Interestingly, we

Please cite this article in press as: Fanizza I, et al., Genotypeephenotype redeletion, European Journal of Medical Genetics (2014), http://dx.doi.org/

noticed that these phenotypic features are mainly reported in pa-tients with 12p subtelomeric deletions extending to the 12p13.32portion (Table 2). In particular, the six patients wheremicrocephalywas reported, share a 300 kb common region of deletion between3,700,000 and 4,000,000 containing the EFCAB4B (OMIM *614178)and PARP11 genes (Fig. 2, shaded in light grey). EFCAB4B is highlyexpressed in lung, thymus and spleen and is a Caþ-channel regu-lator [Serru et al., 2000], while poly (ADP-ribose) polymerasefamily, member 11 (PARP11) expression and function arerelatively unknown.

A larger common deleted region of w700 kb containing twoadditional OMIM genes, TSPAN9 (OMIM *613137), and PRMT8(OMIM *610086) (Fig. 2, shaded in darker grey) could be associatedto muscle hypotonia and joint laxity (Table 2). The protein encodedbyTSPAN9 is expressed inmegakaryocytes andplatelets andbelongsto the tetraspanin (TM4SF) family, playing a role in the in celladhesion, migration, and signalling [Srikanth et al., 2010]. PRMT8(arginine methyltransferase 8) is the only brain-specific PRMT pro-tein in vertebrates [Lee et al., 2005] and is neuron-specific [Tanedaet al., 2007]. Different studies demonstrated that prmt8 playscritical roles at early embryonic stages before the development ofthe nervous system both in mouse [Aubert et al., 2003] andzebrafish [Lin et al., 2013] models. The function of prmt8 dependson its methyltransferase activity and its N-terminus [Lin et al.,2013]. Thus we may hypothesize that any or all of these genescould contribute to the neurological features of our patient and ofthe other subjects whose deletions include them (Fig. 2).

6. Conclusion

In conclusion, we identified a de novo 2.3 Mb interstitial deletionof 12p13.33-p13.32 associated with ID, speech delay, microcephaly,muscular hypotonia, and joint laxity. The deletion breakpoints ofthe current case led us to propose that haploinsufficiency of CAC-NA1C may have a primary role in all major phenotypic features,such as ID speech and language delay, since the gene results dis-rupted or entirely deleted in most hitherto reported patients withsubtelomeric 12p13.33 microdeletions. Additional most commonlyobserved phenotypic features (microcephaly, joint laxity, hypoto-nia) cannot be definitely associated to a specific gene or locus.Within-family variable expressivity, age-dependent presentation,and combined functional effects of multiple haploinsufficient genescan concur to the observed phenotypic variability.

Acknowledgements

We would like to gratefully acknowledge the family partici-pating in this study.

Appendix A. Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejmg.2014.04.009.

lationship in a child with 2.3 Mb de novo interstitial 12p13.33-p13.3210.1016/j.ejmg.2014.04.009

I. Fanizza et al. / European Journal of Medical Genetics xxx (2014) 1e5 5

References

Abdelmoity AT, Hall JJ, Bittel DC. 1.39 Mb inherited interstitial deletion in 12p13.33associated with developmental delay. Eur J Med Genet 2011;54:198e203.

Aubert J, Stavridis MP, Tweedie S, O’Reilly M, Vierlinger K, Li M, et al. Screening formammalian neural genes via fluorescence-activated cell sorter purification ofneural precursors from Sox1-gfp knock-in mice. Proc Natl Acad Sci USA2003;100:11836e41.

Baker E, Hinton L, Callen DF, Haan EA, Dobbie A, Sutherland GR. A familial crypticsubtelomeric deletion 12p with variable phenotypic effect. Clin Genet 2002;61:198e201.

Franke B, Vasquez AA, Veltman JA, Brunner HG, Rijpkema M, Fernández G. Geneticvariation in CACNA1C, a gene associated with bipolar disorder, influencesbrainstem rather than gray matter volume in healthy individuals. Biol Psychi-atry 2010;68:586e8.

Gershon ES, Grennan K, Busnello J, Badner JA, Ovsiew F, Memon S, et al. A raremutation of CACNA1C in a patient with bipolar disorder, and decreased geneexpression associated with a bipolar-associated common SNP of CACNA1C inbrain. Mol Psychiatry 2013 Aug 27. http://dx.doi.org/10.1038/mp.2013.107 [Epubahead of print].

Lee J, Sayegh J, Daniel J, Clarke S, Bedford MT. PRMT8, a new membrane-boundtissue-specific member of the protein arginine methyltransferase family. J BiolChem 2005;280:32890e6.

Lin YL, Tsai YJ, Liu YF, Cheng YC, Hung CM, Lee YJ, et al. The critical role of proteinarginine methyltransferase prmt8 in zebrafish embryonic and neural develop-ment is non-redundant with its paralogue prmt1. PLoS One 2013;8:e55221.

MacDonald AH, Rodríguez L, Aceña I, et al. Subtelomeric deletion of 12p: descrip-tion of a third case and review. Am J Med Genet A 2010;152:1561e6.

Madrigal I, Martinez M, Rodriguez-Revenga L, Carrió A, Milà M. 12p13 rearrange-ments: 6 Mb deletion responsible for ID/MCA and reciprocal duplicationwithout clinical responsibility. Am J Med Genet A 2012;158A:1071e6.

Please cite this article in press as: Fanizza I, et al., Genotypeephenotype redeletion, European Journal of Medical Genetics (2014), http://dx.doi.org/

Ravnan JB, Tepperberg JH, Papenhausen P, Lamb AN, Hedrick J, Eash D, et al. Sub-telomere FISH analysis of 11 688 cases: an evaluation of the frequency andpattern of subtelomere rearrangements in individuals with developmentaldisabilities. J Med Genet 2006;43:478e89.

Rooryck C, Stef M, Burgelin I, et al. 2.3 Mb terminal deletion in 12p13.33 associatedwith oculoauriculovertebral spectrum and evaluation of WNT5B as a candidategene. Eur J Med Genet 2009;55:446e9.

Serru V, Dessen P, Boucheix C, Rubinstein E. Sequence and expression of seven newtetraspans. Biochim Biophys Acta 2000;1478:159e63.

Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, et al. Severearrhythmia disorder caused by cardiac L-type calcium channel mutations. ProcNatl Acad Sci USA 2005;102:8089e96.

Srikanth S, Jung H-J, Kim K-D, Souda P, Whitelegge J, Gwack Y. A novel EF-handprotein, CRACR2A, is a cytosolic Ca(2þ) sensor that stabilizes CRAC channelsin T cells. Nat Cell Biol 2010;12:436e46.

Szczepankiewicz A. Evidence for single nucleotide polymorphisms and their asso-ciation with bipolar disorder. Neuropsychiatr Dis Treat 2013;9:1573e82.

Taneda T, Miyata S, Kousaka A, Inoue K, Koyama Y, Mori Y, et al. Specific regionaldistribution of protein arginine methyltransferase 8 (PRMT8) in the mousebrain. Brain Res 2007;1155:1e9.

Thevenon J, Callier P, Andrieux J, Delobel B, David A, Sukno S, et al. 12p13.33microdeletion including ELKS/ERC1, a new locus associated with childhoodapraxia of speech. Eur J Hum Genet 2013;21:82e8.

Vargas H, Beldia G, Korosh W, Sudhalter V, Iqbal A, Sanchez-Lacay JA, et al. A 4.5 Mbterminal deletion of chromosome 12p helps further define a psychosis-associated locus. Eur J Med Genet 2012;55:573e6.

Velinov M, Beldia G, Gu H, Tsiouris JA, Jenkins EC, Brown WT. Psychotic manifes-tations in a patient with mental retardation and a 6.2 megabase deletion at thedistal short arm of chromosome 12. CNS Spectr 2008;13:515e9.

lationship in a child with 2.3 Mb de novo interstitial 12p13.33-p13.3210.1016/j.ejmg.2014.04.009