Posted on Authorea 28 Feb 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158291220.08960122 — This a preprint and has not been peer reviewed. Data may be preliminary. agPark Yang Lee microcephaly Jiwon with patients Korean of analysis Genomic ri nut Wos akr 03.Cide ihmcoehl aeOC tteotrlmt of limits outer the at OFCs have microcephaly with Children perinatal a 2013). or birth with Parker, after children development & neuronal hand, (Woods, abnormal decrease other progressive represents insults a the microcephaly show brain then microcephaly On Secondary and primary (HC)s age. circumference conditions. as with head destructive maternal normal HC defined or with or neurogenesis is born of are environmental which failure microcephaly the with secondary cells, to due these associated occurs increased events of microcephaly neuropils, that primary mitosis prenatal of Most and deficiency improper conception 2013). by Walsh, or at caused & formed cells, (Gilmore, be cells may progenitor progenitor microcephaly of neuronal process, by this apoptosis During determined is divisions. brain cell ethnicity. the undergo Recognition of causes. and size 2001). its fundamental Holmes, investigate age, The & to sex, Leviton, than clinicians Allred, prompt lower for (Vargas, and can organs anomalies, (OFC) mean skeletal microcephaly major dysmorphism, circumference the of the facial in occipitofrontal below by anomalies accompany structural deviations an frequently congenital are delayed standard as which problems, psychomotor epilepsy, two defined including and manifestations, than developments, is neurologic various more show It microcephaly or with Patients percentile 2001). Vargas, third 2007; Holmes, (Abuelo, the problems & neurodevelopmental with Leviton, patients of Allred, phenotype prevalent a is Microcephaly Korea sequencing, 1 genome whole low-depth microarray, chromosomal sequencing, exome whole microcephaly, microcephaly. of causes underlying Keywords WES the diagnosing ethnicities. other for of approach microcephaly effective with an patients represents of had that analysis from patients CNV spectrum unrelated a genetic with Two different a inheritance. show microcephaly dominant with autosomal patients with microcephaly variants to novo all related de VPS13B be in were to present known these the was already were of in analyses were nine delay that CNV mutations variants and (30%); developmental pathogenic WES patients likely and the or 12 from hypotonia pathogenic in yield detected Infantile diagnostic we The WES, (CNV). sequencing With microcephaly. We variation exome primary 47.5%. number whole showed conducted (85%) causes. copy patients and genetic of Thirty-four images enrolled radiologic patients. We with analysis and patients. an often phenotypes Korean clinical and problems, in analyzed (WES) microcephaly neurodevelopmental We of microcephaly. with background with genetic patients patients and 40 the phenotypes of clinical the phenotype investigated prevalent comprehensively a is Microcephaly Abstract 2020 5, May 4 3 2 1 CGenome GC Institute Genome Samsung Hospital Guri University Hanyang Center Medical Samsung | Introduction , ACTG1 1 3 ogEnPark Eun Jong , hn-ekKi Chang-Seok , KMT2A , EP300 and , ee n1 te ains efudmttosi the in mutations found we patients, other 10 In gene. KMT2D 2 4 hn Lee Chung , n ehnLee Jeehun and , ee.Svnptet 1.% eedansda aigptoei Ns Korean CNVs. pathogenic having as diagnosed were (17.5%) patients Seven genes. 3 hRu Kim Reum Ah , 1 1 1 yn onKim Joon Byung , GNB1 , GNAO1 , TCF4 1 , Woong , ASXL1 , SMC1A , Posted on Authorea 28 Feb 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158291220.08960122 — This a preprint and has not been peer reviewed. Data may be preliminary. sn W ..2 ulctdraswr akdwt iadTos110 oa lgmn,bs quality base alignment, local GRCh37 1.130; build Tools Genome Picard Reference 2 with Human generate marked the was to were USA) against sequencing reads CA, and aligned duplicated Diego, were preparation; 0.7.12; San reads library BWA Inc., Sequence for using (Illumina used reads. Exon platform was paired-end All HiSeq2500 USA) Human Illumina bp Purification SureSelect CA, an DNA USA). on Clara, Genomic WI, performed Santa Wizard Madison, Technologies, a (Promega, using (Agilent instructions leukocytes V5 manufacturer’s blood the peripheral following from Kit extracted was DNA Genomic nelgnefrcide WS-) eedn nteaeo h ains fteesae eentavailable, pediatric not two by were assessed scales 2.2 status these clinical standards. If the of same on patients. Scale the based Wechsler the function using of or cognitive neurologists age or (BSID-III) the stage Development developmental on Infant estimated depending pheno- of we (WISC-V), and Scales Clinical children Development Bayley for using gauges. syndrome. Intelligence assessed epilepsy hearing body was affected anomalies, whole the and organ function heights, low-depth between and cognitive seizure, skeletal weights, impairment, or concordance dysmorphism, delay/cognitive evaluated measured CMA facial developmental hypotonia, We and and loss, infantile (CNV). examination patients followings; the variation same all included number the for types copy in WES congenital brain analyze HCs performed as tests, to We and such laboratory (LD-WGS) problems through taking. sequencing for condition perinatal history genome evaluated medical defined detailed were maternal with to and individuals patients or related imaging, excluded environment, affected We insults physical All and cerebral neurologists. teratogens, 2014 pediatric from infection, Korea. two January resulted by between Seoul, that microcephaly references, in with microcephaly Korean Center diagnosed age-matched OFC and Medical sex, features of Samsung clinical same microcephaly at for of 2018 definition mean a December the applying below microcephaly, deviations with dard patients pediatric recruited We rcpay etidt eiet lnclfaue soitdwt astv ee ocnrbt ogenetic to 2.1 mi- contribute with to patients genes Korean causative with of 2 associated features microcephaly. features phenotypic with cohort. clinical patients and microcephaly delineate of genomic a investigations findings. to on the tried imaging exclusively We analyze brain based comprehensively crocephaly. population and Asian to consanguinity, an aimed race, of in We of study differences no characteristics 2019). the al., been different analyzed et has covered and (Boonsawat there studies microcephaly (30/62) However, secondary patients microarray these and of chromosomal of primary 48.4% between on micro- Each variants in underlying based genetic variants phenotypes. genes and analysis causative severity with disease genetic clinical detected microcephaly established comprehensive of WES with recent causes and novel A microcephaly genetic in (CMA) variants the of dwarfism. found in causes primordial overlap They showed the cephalic families. authors were al. 137 the et that of addition, Shaheen out genes 38 In 2016). 104 of reported al., in out reces- et previously variants 11 (Rump autosomal genetic and in microcephaly that causal with revealed genes potentially patients It disease-causing the identified determined among phenotypes. (2019) prevalent study radiologic highly One and al., are exome clinical et disorders 2019). whole heterogeneous sive (Boonsawat used al., highly have cohorts et had studies sequencing, microcephaly Shaheen three who in 2016; next-generation only patients microcephaly al., date, of et To of et development (Hamdan causes Rump 2016). pattern genetic the identified 2019; al., investigate inheritance et With been to Thevenon recessive have 2011; (WES) microcephaly, 2013). al., sequencing autosomal et including al., an Najmabadi disorders, et 2014; showed neurodevelopmental al., Hussain of microcephaly Sajid causes of 2010; genetic causes al., et genetic cause exact (Darvish studies, the etiologies. determine 2014). previous to preferential al., In clues et the provide Hagen isolate can der clinicians causes, dysmorphism (von helps various facial microcephaly have them or of genetic between microcephaly anomalies or distinction accompanying of condition, addition, medical the categories maternal In and Both a or 2007), hypoxia group. (Abuelo, as age such causes problems their perinatal for infection, low congenital including and distribution normal the | aeil n Methods and Materials | | WES Patients 2 > stan- 2 × 100- Posted on Authorea 28 Feb 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158291220.08960122 — This a preprint and has not been peer reviewed. Data may be preliminary. s isnepeito loihs eeue odtrietepeitdipc fmses change. missense of impact predicted the determine to used of were pathogenicity algorithms, Gene the potential prediction database, Human the used missense ClinVar ExAC the use determine and we Various database, in to (http://www.hgmd.org/), variants. cited population, Project identified PubMed, 2018.02 sources Genomes general all as various release indi- 1000 or well using version, Korean the as conducted control professional 1100 (https://www.ncbi.nlm.nih.gov/clinvar/), was as a (HGMD) of review such in Database WGS literature databases variant Mutation from primary public A data a other gnomAD. control of of as and race-matched combined frequency well variant available on as the publicly LPV, based of viduals, assess PV, (BV) consists To segregation, variant which categories: functional, KRGDB, benign computational, data. five and population, other et into (LBV), including of (Richards variants and variant evidences, College (AMP) weighted classifying benign American Pathology of recommend likely the lines Molecular (VUS), guidelines of for significance These guidelines Association uncertain and and standards (ACMG) 2015). the Genomics al., to and according Genetics classified Medical were variants Candidate h eray20 ua eeec eune(Rh7h1)wsue o eoeassembly. sample. genome targeted for each used a of was status on number (GRCh37/hg19) 2.5 copy sequence sequenced the sequence reference values calculated and million we Human ratio 3.1 controls, bp, mapping 2009 for normal reference February 250 calling the target-specific The CNV and the of sample Using mode. target size single-read v1.38. the software target bp for DNAcopy 75 DNA a using in performed genomic to USA) was Briefly, CA, reads sheared Korea). (Illumina, known (Yongin, leukocytes, platform Genome 500 regions peripheral-blood NextSeq GC all Illumina from by for performed in extracted was used analyzed was build analysis was were genome CNV human resolution data LD-WGS-based NCBI The The higher using reported nomenclature. A variants. and probes ISCN USA) following structural (SNP) CA, resolution. (hg19) unbalanced Diego, Polymorphism Kb 37.1 San and (Illumina, Nucleotide 30 balanced 1.4.3.0 a Single version with KaryoStudio with and associated The array (CNC) be USA). genome CA, Changes to whole Diego, Number San a Copy (Illumina, on platform both HumanCytoSNP-12 employs Illumina an array using performed was CMA ?2allsi nmDo ?8allsi eesv,4 ADsoeo 1 rhge n l deleterious all and higher or ˜15 of models score 2.4 animal roles. from CADD neurodevelopmental data suggesting a with studies Muta- genes 4) functional affected and recessive, and/or 5) variants, (http://genetics.bwh.harvard.edu/pph2), if missense PolyPhen2 if alleles (http://mutationtaster.org/) (http://sift.jcvi.org), tionTaster [?]8 SIFT or in gnomAD predictions in alleles [?]2 efre ne h olwn odtos )tilct aawt optoei ain P) o likely nor (PV)s variant pathogenic no was with analysis data allele triplicate additional an 1) 2) panel variants, (LPV)s, (HPO)-terms gene conditions: genetic variant phenotype Ontology following in-silico candidate pathogenic microcephaly the Phenotype delineate (OMIM) an To under Human Man with in performed traits 1). analysis Inheritance Table phenotype Mendelian gene-specific (Supplementary selected Online a genes or for performed (HP:0000252) filtering Microcephaly we genes, for Finally, 903 con- Database variants of affecting Aggregation sequences. changes prioritize composed or site Genome (KRGDB) to variants, insertions/deletions was splice the (MAF) Database in-frame step sensus and frequency in Genome frameshifts, third allele [?]1% nonsense, Reference The missense, 10 minor MAF variantcausing Korean The than an removed. candidate frequency. the were less with short population (http://coda.nih.go.kr/coda/KRGDB/index.jsp) variants with or a low and variants (http://gnomad.broadinstitute.org/) generate with removed chosen (gnomAD) those to we carefully to Initially, strategy was limited 1). threshold four-step were (Figure a variants validation using Next, experimental prioritized for and list filtered were Variants eairto n ain aln eecnutduigteGnm nlssTo i 340 n annotation v4.1g. and SnpEff v3.4.0; with Kit 2.3 Tool performed Analysis were Genome prediction the effect using variant conducted and were calling variant and recalibration | | | nepeaino addt eei ainsb E n Nsb M rLD-WGS or CMA by CNVs and WES by variants genetic candidate of Interpretation M n LD-WGS and CMA ain leigsesaddt analysis data and steps filtering Variant nsilico in enovo de ol,icuigSF,Plpe2 n uainatr l fwhich of all MutationTaster, and Polyphen2, SIFT, including tools, opudhtrzgu,hmzgu,o eiyosvrat,3) variants, hemizygous or homozygous, heterozygous, compound , 3 enovo de × coverage. allelic, , Posted on Authorea 28 Feb 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158291220.08960122 — This a preprint and has not been peer reviewed. Data may be preliminary. n iln ar(0) 1Pso Pswr dnie yWS(al ) h neiac atrsof patterns inheritance The 2). including (Table patients, WES 12 by In identified were families. LPVs 39 or from PVs (47.5%) patients 11 19 (30%), in pair established sibling was one diagnosis molecular A All age. and sex for range normal the ( in patients stature weight 15 short and/or in with height 3 identified patients age-matched microcephaly, with gradual and microcephaly, proportionate the sex primary With the on disproportionate below with based showed 1). were (Table microcephaly birth gauges birth secondary body at of after all presented (37.5%), cases HC patients as small identified 34 a were of microcephaly, six development with remaining 22:18) the and = microcephaly (female:male patients 40 Among he ainshdaeei rhppai ftecru alsmwt ircpay naohrthree another In were patients. cerebellum MRI. six microcephaly. and by in with pons structure found brain callosum the 3.2 normal were of corpus showed lesions patients hypoplasia the Thirty-four structural and of respectively. abnormal heterotopia, found, hypoplasia and subependymal or holoprosencephaly, patients, agenesis patients, all had LGS in patients with performed Three fre- patients seizure. were having neonatal of MRIs a with Half had Brain epilepsy, (LGS). patient intractable one syndrome epileptic showed and with Lennox-Gastaut provoked spasms, 11 diagnosed with infantile patients episode epilepsy, showed eight patients seizure were with six one There patients including only medications. 26 encephalopathy, antiepileptic had multiple the patients despite Among these seizures quent of illness. One febrile seizures. than by had more (67.5%) in patients evident Twenty-seven were features Dysmorphic (27.5%). etiology. ( patients discernible patients a of without half ( loss anomaly hearing ( heart sensorineural anomaly congenital skeletal including like anomalies, 8), movements accompanying = various involuntary showed other (42.5%) or patients special dystonia Seventeen received frequent tremor. patients showed or patients school-aged movements, ( Seven eight athetoid ( disorder chorea, patients clinic. and spectrum neuropsychiatric autistic Preschool-aged milestones, for a developmental milestones. treated in achieving were developmental patients reaching in Four seven in lagged and education. disabilities age) of also intellectual time below developmental mild 25) noticeable months the showed showed = one at (5 patients patients, Thirty-two age delay remaining average a old. the The years displayed Of 4.60 disability. delay. +- intellectual developmental 5.28 or and was delay hypotonia study this infantile in were participation patients all in observed this 3.1 in included 2014-07- patients no. pediatric (IRB all 3 of Hospital parents Seoul the Samsung from of obtained Board was study. Review consent Institutional informed the Written by 001-004). approved was study This addt ainsietfidi E aawr ofimduigsadr C n agrsequencing Sanger USA). sequence and MI, reference Arbor, the PCR to Ann 2.7 aligned standard Corporation, were using Codes data Sequence (Gene confirmed software request. were Sequencher upon available using data are sequences WES Primer in methods. identified variants Candidate oitrrtCV,w sdDV(tp/dvta.advaphm) DECIPHER (http://dgv.tcag.ca/dgv/app/home), DGV reported used those with compared were 2.6 findings we well clinical the as literature. addition, the In databases in CNVs, (https://www.ncbi.nlm.nih.gov/dbvar/) (https://www.omim.org/). OMIM dbVar as and interpret (https://decipher.sanger.ac.uk/), To | Results | | | | eei vlaini l ainswt microcephaly with patients all in evaluation Genetic phenotypes Clinical ti statement Ethic ofimto n aiaino addt variants candidate of validation and Confirmation n 8 0) hs etrswr la n1 ains(25)adntbyvgei 11 in vague notably and (42.5%) patients 17 in clear were features these 70%), 28, = n ) n lf i n/rplt ( palate and/or lip cleft and 4), = n 6 ipae ye3fiuet hiedrn hi nac.Cmo features Common infancy. their during thrive to failure 3 type displayed 26) = 4 rd n etl au.Teohr2 ains(62.5%) patients 25 other The value. centile )(al ) he ainsdeveloped patients Three 1). (Table 5) = n )o eairldsre ( disorder behavioral or 3) = n 1) = n n Posted on Authorea 28 Feb 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158291220.08960122 — This a preprint and has not been peer reviewed. Data may be preliminary. uigifny u,sefie ome eeomna ietns rdal,dffrn yeo ezrsand A disappeared seizures medications. spasms c.284T of antiepileptic epileptic This type of Her different gene. number Gradually, a medications. administered milestones. antiepileptic developmental being novo with meet despite treated to developed, was movements failed involuntary and she months but, 4 infancy, during of age the at -4 rsne ihpiaymcoehl n ogntlhatdsae n ipae 84 bdu- Mb 28.43 a displayed and disease, heart severe congenital by and characterized microcephaly 2007). syndrome Kleefstra, primary subtelomeric & with deletion 9q (Stewart, presented Kb seizure with 2,790 M-048 and associated a disease, previously showed heart and was congenital microcephaly, disease, region delay, heart developmental This congenital and 9q34.3. microcephaly at primary with presented M-017 2013). the al., contains et region (Beunders This microcephaly 7q11.21. The at deletion 3). facial the Kb (Table dysmorphic of 801 and LD-WGS Mb. epilepsy, an or 28.43 showed behaviors, autistic and and CMA disability, features, Kb intellectual by severe 312 CNV with between presented pathogenic was M-004 a Patient region have deletion to or found duplication were of (17.5%) size seven patients, 40 Of psy- profound and failure growth severe with dystonia intractable a from retardation, suffering chomotor (M-020) boy 4-year-old a 2016). In al., et (Petrovski seizures and hypotonia, the in LPV an with (M-011) girl 9-year-old a was There ailfaue n i o entse o h ain.Ti ain a rvosyrpre ob associated be to reported previously 2014). was al., and variant et intelligence This 3.4 c.2368C (Ansari normal variant. syndrome displayed The the Lange They for weight. de tested married. Cornelia been and not not with have height meaningful did who also a and uncles, feature, but speak maternal facial not HC unaffected could only two They were not eyelashes, There chin. in long small namely retardation and features, growth in ears, variant facial severe low-set distinctive showed bridge, showed and nasal They word wide syndrome. nose, small Lange synophrys, de Cornelia of suspected reported. been (c.2368C has the variant germline no dystonia. In but severe 2013), and and al., epilepsy problems and et intractable (Wang feeding unstable syndrome from severe was suffered showed respiration patient She the her c.3115C addition, support. Because In c.3115C ventilator home The hypotonia. thrive. and to congenital tracheostomy failure for a profound unit needed care she intensive weak, neonatal (c.3115C the PV a on M-039, patient In 2017). Holland, & Leach, in the in identified was 3.3 Using 2. 3). were Table (Table LPVs Supplementary LD-WGS or microcephaly: in or PVs with described nine associated CMA and previously by variants, genes CNV novel nine pathogenic in a detected showed were , LPVs (17.5%) or patients PVs seven WES, Another ( 1). dominant = autosomal were mutations these TCF4 enovo de | | P (c.284T LPV lnclpeoye fptet ihaptoei CNV pathogenic a with patients of phenotypes Clinical WES by determined PV/LPV a with patients the of phenotypes Clinical AUTS2 > , > SMC1A ain a rvosyrpre anya oai ain nptet ihmyelodysplastic with patients in variant somatic a as mainly reported previously was variant T ASXL1 SMC1A ;.r70r)wsietfidi aesbigpi M05P -5-)wowr clinically were who M-055-S) (M-055-P, pair sibling male a in identified was T;p.Arg790Trp) neietcecpaoah ains ugsigta uainhtpt(ra peh Gilbert, Spaeth, (Arya, hotspot mutation that suggesting patients, encephalopathy epileptic in > ain in variant T eehsbe eotdt eascae ihats,itleta iaiiy hr ttr,and stature, short disability, intellectual autism, with associated be to reported been has gene > , SMC1A > a eiyos h ains ohrhdti ain,i e ae twsheterozygous. was it case, her in variant, this had mother patients’ The hemizygous. was ee nw sacuaiegn fCrei eLnesnrm,a LPV an syndrome, Lange de Cornelia of gene causative a as known gene, ain a rvosyascae with associated previously was variant C ;.e9Po htwsasn rmtecnrldtbsswsietfidi the in identified was databases control the from absent was that C;p.Leu95Pro) GNAO1 enovo de , ASXL1 KMT2A ee c.607G A gene. P (c.607G LPV > ;.l13Tr fthe of T;p.Gln1039Ter) a beti h oto ouainadoccurred and population control the in absent was , VPS13B n enovo de > ) uooa eesv ( recessive autosomal 9), = > ;.l23r)ta a betfo h oto databases control the from absent was that A;p.Gly203Arg) hnein change A , CG,EP300 ACTG1, ains dnie ainsecp VadLVwere LBV and BV except variants Identified variants. 5 GNB1 ASXL1 GNAO1 enovo de ee h rsne ihifniespasms infantile with presented She gene. and , eewsietfid h a admitted was She identified. was gene eeenuoeeomna disability, neurodevelopmental severe a rvosyrpre aytimes many reported previously was KMT2D n ) n -ikdrcsie( recessive X-linked and 1), = AUTS2 iePso Pswere LPVs or PVs Five . ee n h deletion the and gene, GNB1 enovo de , GNAO1 This . GNB1 > de T n Posted on Authorea 28 Feb 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158291220.08960122 — This a preprint and has not been peer reviewed. Data may be preliminary. Atb eee,Cu hn 08.RX srqie o h omto fclai h erltube neural the in cilia of formation the a found for we required (M-100), patient is one In RFX7 2014). Kato, 2008). (c.2727 & This Stefanovic, Chen, Kato, 1995). Earwood, & al., (Manojlovic, et Chu, (Takeuchi Semenec, tube neural (Aftab, the of morphogenesis RFX7 normal for (M-001) required patient is a Jmj c.2123A In mice, genes. In candidate (Jmj). additional a four found revealed we data JARID2 exome microcephaly, trio primary familial with in search allele An oiattat.O h 0ptet nlddi hssuy 4ptet 8% a rmr microcephaly. structures ( primary symptom brain symptoms. had frequent accompanying normal (85%) frequent most showed CNV most patients were next others the by the 34 the were ones, was delay cases study, whereas novel developmental Seizure MRI, seven this and five brain and Hypotonia in patients. including by microcephaly. included WES Korean anomalies WES, despite patients by in structural by 40 various identified microcephaly found showed the (30%) variants of Six Of cases all causes 12 of traits. genetic with dominant nine identify 47.5%; The to was analyses rate analysis. CNV diagnostic and overall WES The used study This did study syndrome. this in that Lesch- 4 patient of with The patient characteristics Japanese 1990). clinical a Akaoka, the in & have Ogasawara, reported not Nishida, previously was Kamatani, (Fujimori, and databases syndrome we control Nyhan (M-122), the patient from one In absent was 1987). variant Caskey, (c.151C & variant An (Gibbs, hemizygous disorder a recessive metabolism. identified X-linked an purine is which in syndrome, involved Nyhan enzyme an tandem transferase, heterozygous A databases. HPRT1 control 2017). the a al., from found absent et we was (M-118), (Mahajani that patient development one brain In leukodystrophy. in of role duplication important genomic an plays lamina, LMNB1 the 2013). contains al., region et This (Bonnet 3.5 problems 2q23.1. behavioral hypertri- at and face, deletion impairment, the Kb speech the of 312 significant hypoplasia of a showed midline deletion and features, and eyebrows, disproportionate autistic bush with and and microcephaly disability chosis, 2012). intellectual and al., with retardation et presented mental (Hayashi M-116 females with in associated hypoplasia be cerebellar the to have and contains to region reported pontine found This was been MRI 2). has brain (Figure by Xp11.4p11.3 gene 2012). hypoplasia at al., cerebellar deletion and et Mb pontine 2.8 (Hoyer with a palate microcephaly a high-arched showing with (M-075) and Patients girl scalp hypotonia, A delays, sparse toenails. developmental hypertrichosis, or moderate fingernails features, show fifth facial to absent coarse reported at or with duplication hypoplastic associated Kb and and 368 hair, retardation a mental carried and by the palate, characterized contains cleft region 16p11.2 and This epilepsy, chromosome microcephaly, 6q25.3. 2010). motor with primary have al., with to associated et presented reported (Shinawi as M-074 been microcephaly have OMIM and duplication at seizures, 16p11.2 anomalies, a registered with congenital was Patients delays, region 614671). (MIM This syndrome duplication 16p13.3p11.2. at plication | Discussion | diinlcniaemcoehl genes microcephaly candidate Additional rgltr atrX)i ebro h euaoyfco RX aiyo rncito factors transcription of family (RFX) X factor regulatory the of member a is X7) factor (regulatory 70u;.l91hfTr8 nthe in 2730dup;p.Gly911PhefsTer58) > hpxnhn unn hshrbslrnfrs )ecdshpxnhn-unn phosphoribosyl hypoxanthine-guanine encodes 1) phosphoribosyltransferase guanine (hypoxanthine lmnB)ecdsoeo h w -yelmnpoen ai 1 e opnn ftenuclear the of component key a B1, Lamin protein. lamin B-type two the of one encodes B1) (lamin jmniadA-ihitrcindmi otiig2 shgl oooost os Jumonji mouse to homologous highly is 2) containing domain interaction AT-rich and (jumonji ain in variant C MBD5 JARID2 LMNB1 eehsbe eotdt eascae ihitleta iaiiy seizures, disability, intellectual with associated be to reported been has gene a betfo h oto databases. control the from absent was ARID1B skont etecueo uooa oiatautostdemyelinating adult-onset dominant autosomal of cause the be to known is > ;.r5Tr htwsihrtdfo i ohr hsc.151C This mother. his from inherited was that T;p.Arg51Ter) enovo de ee hc sacuaiegn o onSrssnrm,wihis which syndrome, Coffin-Siris for gene causative a is which gene, RFX7 n 7 5) n 1ptet a nrcal seizures. intractable had patients 11 and 65%), 27, = ain (c.2123A variant eeta a betfo h oto databases. control the from absent was that gene enovo de 6 ain (c.1091T variant HPRT1 > CASK ;.y78e)i the in C;p.Tyr708Ser) eemtto stecueo Lesch- of cause the is mutation gene ee n eeino the of deletion and gene, ARID1B > ;.e34r)i hsgene this in C;p.Leu364Pro) enovo de ulcto aebeen have duplication enovo de n autosomal and JARID2 MBD5 variant CASK gene. gene, > T Posted on Authorea 28 Feb 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158291220.08960122 — This a preprint and has not been peer reviewed. Data may be preliminary. a xesvl iae codn oabanutaoormpromdo h eoddyo ie h showed She life. of ventricle day fourth second the the and & on cm, performed Esch, 32.2 was ultrasonogram Van birth brain at Davis, a HC to Her Devriendt, according complications. dilated (Cristofoli, perinatal extensively without manifestations of was term cases severe at born most show was chromosome, She a and X found rare We the et very 2018). (Hayashi on Vermeesch, hypotonia pontine located are and with is males faces, microcephaly this this affected including dysmorphic with Because nystagmus, disabilities, patient 2017). intellectual syndrome, The X-linked al., (MICPCH) of outgrowth. hypoplasia range dendritic cerebellar wide and and a branching, genetic showed (15%) causative axon variant patients a gene have regulation, six to the neurotransmitter found In was in patient size. involved one brain the only small MRI, in despite brain mutation structures by observed brain abnormalities normal repair structural showed damage with patients 34 DNA study, or and this neurotransmission, In neurogenesis reported myelination, centrosome-related 2013). as neuronal Parker, microcephaly, than in & involved to rather (Woods, pre- are lead excitability, process be genes may neuronal to These genes found of various 2019). were regulation that genes al., suggests no et and This (Shaheen microcephaly. diverse, previously with microcephaly. were patients study of Korean this causes among in dominant prevalent identified highly genes are microcephaly-associated disorders The dominant autosomal that suggest CASC5 nMP ee aebe eeld(aaaa,Be as,21) norptet,n uain were mutations 2019). no patients, al., loci our et 18 In Shaheen and 2018). 2013; Walsh, (MCPH), al., & microcephaly et Bae, primary Hussain (Jayaraman, recessive revealed Sajid in been autosomal 2010; identified have as al., genes microcephaly et MCPH neurodevelop- of (Darvish in on cases focused period mainly classified fetal Previous and They the families respectively. in consanguineous inheritance Two in defects recessive pattern. microcephaly mental X-linked inheritance congenital dominant and with autosomal recessive dealt an autosomal studies showed for variants with patients detected associated genetic to the therapies. were the of information targeted variants most provide determine for study, may help present opportunities it the including can addition, In counseling, analysis In genetic study CNV prognosis. and recent and the decisions A 2017). WES predict reproductive al., and via causes future study. et underlying disease microcephaly this the (Tsoutsou the diagnosing of of microcephaly of to diagnosis with approach primary mechanism results effective A with that the mostly patients the to microcephaly. with be 53 comparing may consistent of in analysis rate is CNVs CNV analyses with diagnostic CNVs which probable CNV WES 7 47.8% 2019), pathogenic Therefore, and 20.8% and WES a al., of definite combined – with et rate study, 11 13.2 similar disorders, previous (Jiao showed diagnostic was a be neurologic (32.7%) The to rate rare to alone According This of WES reported (2019). 2013). diagnosis al., al been 47.5%. enable et et has to Shoukier better Boonsawat microcephaly, 2019; 30% by al., primary from et study including rate (Jang recent diagnostic disorders, a the neurodevelopmental in microcephaly. increased in of reported analysis causes that CNV diverse. genetic highly et to the the were Vissers determining study, study 2019; this in this in WES Leao, found In of variants & the utility Alonso, reports, the Matos, previous reconfirms based in (Marques study causes, identified cost genetic those This extensive economic to presumed Similar and Leao, diseases & 2017). epilepsy, yield complex Alonso, al., and for diagnostic Matos, test ataxia, of Marques first-line disease, 2015; considerations The the al., muscle be on et et should with (Farwell (Farwell 2017). WES causes associated review Thus, genetic al., closely medical the heterogeneous 2019). et more have with clinical to are Vissers associated neurodevelopmental of known disorders genes are level in 2019; neurologic which disease, and/or WES Leao, Some the filtering, of of & 2015). bioinformatic yield distinctiveness al., Alonso, depth, phenotypic diagnostic read as Matos, the such sequence (Marques general, factors 2019; phenotype, In several 29% al., on et to 2019). (Boonsawat depends 17.5% to microcephaly al., yield related of from et causes genes and ranges Shaheen genetic 30% and was of disorders 2016; phenotype LPVs) reports and al., OMIM (PVs previous et WES 900 in of over Rump found yield Hagen are diagnostic that der the to there study, (von present comparable database, the was features In OMIM syndromic the date. hereditary to to entered various According microcephaly with 2014). or al., non-syndromic et as present can Microcephaly , PHC1 MCPH1 CASK , CDK6 , WDR62 ee The gene. , CENPE CASK , CDK5RAP2 , CASK SASS6 uaintruhCAi eaeptetwt IPHsyndrome. MICPCH with patient female a in CMA through mutation eeecdsammrn-soitdgayaekns n is and kinase guanylate membrane-associated a encodes gene , MFSD2A , CEP152 7 , ANKLE2 , ASPM , , CENPJ CIT CASK or , , WDFY3 STIL uainaefmls and females, are mutation , CEP63 genes . u results Our , CEP135 , Posted on Authorea 28 Feb 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158291220.08960122 — This a preprint and has not been peer reviewed. Data may be preliminary. nai . oe . er,Q,Wlimo,K,Adig,R,Myet .M,...FitzPatrick, pheno- CdLS-like . . . and M., (CdLS) A. syndrome Meynert, Lange de R., Cornelia Aldridge, in K., heterogeneity Williamson, Genetic at Q., Ferry, (2014). ClinVar G., R. human novel Poke, D. in of characterization M., and available Identification Ansari, (2008). N. openly Chen, & 2148-8-226 factors. S., are transcription J. RFX Chu, syndromes. tissue-specific L., study Semenec, Microcephaly S., Aftab, this of (2007). https://doi.org/10.1016/j.spen.2007.07.003 D. findings Abuelo, the support References analysis, Microcephaly]. that or [Korean NRF- name collection, submission [https://www.ncbi.nlm.nih.gov/clinvar/], (NRF-2014M3C9A2064619, data data Founda- ICT design, study Research The and this National Science in Statement the of manuscript. role Availability the Data of Ministry no of preparation had Program the or body publish, by Research to funding funded decision Science The (NRF) Basic by Korea 2017R1A2B4005276). of supported tion was research This of diagnosis facilitate to con- Acknowledgments important Inter- study is microcephaly. causes. This clinicians of heterogeneous and causes patients. phenotypically underlying geneticists and Korean the genotypically molecular in with between inheritance condition cooperation microcephaly of a recessive disciplinary mode is autosomal predominant microcephaly studies, that was other firmed time/cost-effective dominant Unlike and autosomal useful considerations. is rare; treatment microcephaly was and with patients diagnosis for genetic CMA to In and for WES difficult conducting is reported function. that useful been it conclude rarely be We gene which have may verify translocation, microcephaly. translocation study balanced of balanced to not and this causes and mosaicism studies was genetic in mosaicism somatic However, additional as VUSs somatic found CMA. of through VUSs or detected WES cases the the of microcephaly by identify determine of confirm study of not to some did functional cause small LPVs, we a was genetic or addition, study Second, PVs the our as determining in microcephaly. classified in patients of not of Although causes number genetic the performed. for First, might ethnic rate background between limitations. racial detection several differ the had may of study microcephaly consideration This results. Therefore, of WES spectrum interpreting of similar. in 75% are genetic study, helpful characteristics the our be clinical In that if frequent. suggest even an was had results groups, inheritance pair These sibling recessive patients one autosomal for only which inheritance. al., previously dominant; in et reported autosomal (Boonsawat Europe, were those variants report or from recent detected East peculiarities a Middle genetic in different features problems, the showed to behavioral in similar study disorders, was our movement of which However, half addition, noted, about 2019). were In and disorder patients, course. spectrum the clinical autism The of intractable and 65% Asia. an including in East studies, showed observed in previous was patients in microcephaly Epilepsy these reported of delay. were causes were developmental that genetic characteristics and members, the clinical hypotonia same delineating infantile family the study showed consanguineous first study the this no in is patients and with This microcephaly, study. microcephaly this with in for patients enrolled criteria 2). Korean the (Figure homogeneous five-month year with the Racially one at consistent of assessed was was age hypoplasia, milestones the MRI midline developmental eyebrows, at of brain arched level achievement as Her her such and features hypoplasia, micrognathia. facial pontocerebellar dysmorphic and and philtrum, gauges body long all in growth poor M vltoayBiology Evolutionary BMC 8 eiasi eiti Neurology Pediatric in Seminars :2.https://doi.org/10.1186/1471- 8:226. SMC1A eevratwt X-linked with variant gene 14(3):118-127. Posted on Authorea 28 Feb 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158291220.08960122 — This a preprint and has not been peer reviewed. Data may be preliminary. aah,S,Uhr,D . aioo . iuo . hnn . uuua . nzw,J (2017). J. Inazawa, (MICPCH). . . hypoplasia intellectual . with cerebellar S., patients and Fukumura, 41 pontine Y., in https://doi.org/10.1371/journal.pone.0181791 with etiologies Chinen, genetic microcephaly S., other and Mizuno, and disability mutations K., CASK Tanimoto, of T., investigation Comprehensive D. Uehara, S., Hayashi, L. in- Novel J. (2012). Michaud, J. pon- Inazawa, with microcephaly (MICPCH). and 011-1047-0 . hypoplasia retardation . . . mental . cerebellar with . A., patients and Hata, in L., tine Y., CASK of Makita, Patry, mutations J., and Takanashi, C., duplications Y., tragenic disability. Chinen, Nassif, N., intellectual Okamoto, H., severe S., Hayashi, Daoud, or moderate M., in J. mutations Capo-Chichi, https://doi.org/10.1371/journal.pgen.1004772 novo M., De Srour, (2014). development. F., neuronal for F. lessons and Hamdan, microcephaly of Biol causes Dev Genetic Rev locus (2013). Lesch-Nyhan Interdiscip A. the C. Wiley Walsh, at & mutations C., of E. localization Gilmore, guanine and Identification Hypoxanthine cleavage. (1987). A T. ribonuclease C. (1990). Caskey, by & I. A., Akaoka, R. for Gibbs, & identified Japanese. N., syndrome among Lesch-Nyhan Ogasawara, time Tang, causing first Y., substitution the nucleotide Nishida, . . . deficiency: N., phosphoribosyltransferase B., Kamatani, conditions. Davis, (2018). genetic S., model-based Tippin undiagnosed Fujimori, inheritance C., R. with with E. primary families sequencing with unselected Chao, J. exome https://doi.org/10.1038/gim.2014.154 families 500 diagnostic Z., 17(7):578-586. from Iranian family-centered Powis, Vermeesch, results of 112 D., utility of analysis: El-Khechen, Enhanced & study L., genetic (2015). S., Shahmirzadi, molecular S. H., S. D., and Abedini, K. clinical S., Esch, Farwell, A Ghasemi-Firouzabadi, M., (2010). Van microcephaly. Mohseni, H. B., Najmabadi, microcephaly. syndromic E., G. Monajemi, . with . E. S., . Esmaeeli-Nieh, cases H., Davis, Darvish, in K., mutations https://doi.org/10.1002/humu.23536 Devriendt, CASK Elu- Novel F., (2019). A. (2013). microcephaly. Rauch, secondary P. and Cristofoli, . Jonveaux, primary . . in S., landscape Azzarello-Burri, genetic . Medicine . L., and . in Gogoll, spectrum phenotypic B., S., the Oneda, Lejczak, of K., cidation Steindl, M., P., Joset, Beri, P., disorders. Boonsawat, C., neurodevelopmental Sis- disability Vigouroux, in intellectual mutations E., of . . MBD5 Bresso, . form Genetics of A., E., syndromic spectrum Khan, M. terminus. a Extended Talkowski, Ali C cause C., A., the AUTS2 J. Bonnet, for in Rosenfeld, role deletions M., critical Exonic L. https://doi.org/10.1016/j.ajhg.2012.12.011 a Pardo, suggest (2013). C., epileptic and A. Golzio, GNAO1-associated E. E., (2017). termans, Voorhoeve, D. K. G., Holland, Beunders, & L., J. Leach, phenotype. c.607G L., distinct disorders: D. movement Gilbert, and mosaicism. C., encephalopathy Spaeth, of R., levels Arya, predicted and observed https://doi.org/10.1136/jmedgenet-2014-102573 with types 11)15-41 https://doi.org/10.1038/ejhg.2013.22 21(12):1457-1461. 19:0325.https://doi.org/10.1038/s41436-019-0464-7 21(9):2043-2058. ora fMdclGenetics Medical of Journal plpi Disorders Epileptic Science ua Genetics Human ()4148 https://doi.org/10.1002/wdev.89 2(4):461-478. 3(79:0-0.https://doi.org/10.1126/science.3563511 236(4799):303-305. 91:77.https://doi.org/10.1684/epd.2017.0888 19(1):67-75. ua Genetics Human 71)8388 https://doi.org/10.1136/jmg.2009.076398 47(12):823-828. > 45:8-8.https://doi.org/10.1007/bf00195826 84(5):483-486. ain ersnsapoal uainhtptwt a with hotspot mutation probable a represents variant A mrcnJunlo ua Genetics Human of Journal American 9 3()9-1.https://doi.org/10.1007/s00439- 131(1):99-110. ora fMdclGenetics Medical of Journal ua Mutation Human lsGenetics Plos uoenJunlo Human of Journal European lSOne PloS eeisi Medicine in Genetics 10(10):e1004772. 12(8):e0181791. 39(7):993-1001. 51(10):659-668. 92(2):210-220. Genetics Posted on Authorea 28 Feb 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158291220.08960122 — This a preprint and has not been peer reviewed. Data may be preliminary. hnw,M,Lu . ag .H,Se,J,Blot .W,Sot .A,...Lpk,J .(2010). R. J. Lupski, . . . A., behavioural D. Scott, delay, W., developmental size. J. global head Belmont, abnormal with J., and associated https://doi.org/10.1136/jmg.2009.073015 Shen, epilepsy, rearrangements H., dysmorphism, S. 16p11.2 problems, Kang, reciprocal P., Recurrent S. Liu, F. Alkuraya, M., . Shinawi, . . S., M. Zaki, microcephaly. H., congenital M. of G. https://doi.org/10.1038/s41436-018-0140-3 delineation Abdel-Salam, phenotypic Hansen, and S., Genomic Alsahli, N., . (2019). . families. Ewida, . S., M., microcephaly Maddirevula, Toliat, . R., . Pakistani Reza Shaheen, . E., in B., Janzen, heterogeneity I., J. Anjum, Genetic Verheij, M., https://doi.org/10.1111/j.1399-0004.2012.01932.x Farooq, J., S., (2013). etio- A. Bakhtiar, L. the Marriam Essen, M., establishing microcephaly. van Hussain, for and Sajid F., approach disability L. powerful intellectual a with Johansson, is patients K., https://doi.org/10.1186/s12920-016-0167-8 sequencing in K. Whole-exome diagnosis Dijk-Bos, Pathology. logical (2015). Molecular van (2016). A. Gold- for B. O., Q. recommendation Association Sikkema-Raddatz, L. Jazayeri, consensus the Neurodevelopmen- A. P., and joint Committee, Genomics Severe a . Rump, . and . . variants: . Genetics Cause . sequence Medical Medicine M., J., of in GNB1 of Gastier-Foster, Genetics College S., interpretation Bialer, American in Das, the the D., B., for of Mutations Bick, guidelines S., Cogne, and Novo Bale, Standards N., K., De Aziz, H. S., Anyane-Yeboa, H. Seizures. Germline Richards, Ropers, and T., C. Hypotonia, . (2016). https://doi.org/10.1016/j.ajhg.2016.03.011 . . Myers, Disability, B. W., tal S., Chen, D. S., Kury, stein, S. disorders. S., cognitive Abedini, recessive Petrovski, T., for genes Zemojtel, novel 50 M., reveals https://doi.org/10.1038/nature10423 Garshasbi, sequencing Deep H., to Hu, (2011). applied sequencing H., next-generation of Najmabadi, yield Diagnostic (2019). M. Leao, disorders. formation & the neurological I., for Alonso, required C., is Matos, RFX7 Marques (2014). Y. tube. Kato, neural & the B., in Stefanovic, cilia A., of (2017). Kato, corticogenesis. R., L. whole- Earwood, embryonic Gasparini, Z., of during & Manojlovic, combination A., neurons The Contestabile, into D., differentiation Tonelli, (2019). https://doi.org/10.1038/s41598-017-05078-6 Pietri modulate Y. 7(1):4897. De levels Jin, F., B1 Marinaro, . Lamin C., . . Giacomini, disorders. D., S., neurological Sun, Mahajani, rare of S., diagnosis Li, the enables R., sequencing Genetics Wang, variation Clinical number H., copy Microcephaly. and Zhang, Primary sequencing H., exome of Sun, Genetics The Q., (2018). Jiao, A. Genetics C. Human Walsh, and & in Genomics I., Study of B. Multicenter Bae, Microarray Prospective D., Chromosomal A Jayaraman, (2019). Anomalies: H. J. Congenital Park, Disabil- Multiple Delay/Intellectual Developmental and . With . Korea. . Disorders, Patients A., in Spectrum Test Kwon, Autism Diagnostic H., ity, Clinical Chae, First-Tier J., a Park, as intellectual E., Analysis Han, of Haploinsufficiency Y., cause Kim, frequent (2012). W., A. a Jang, Reis, is complex, . chromatin-remodeling . . SWI/SNF-a A., the Wiesener, of C., disability. Zweier, member B., a Popp, ARID1B, S., Endele, of B., A. Ekici, J., Hoyer, naso aoaoyMedicine Laboratory of Annals mrcnJunlo ua Genetics Human of Journal American 62:4-5.https://doi.org/10.1111/cge.13548 96(2):140-150. 75:0-2.https://doi.org/10.1038/gim.2015.30 17(5):405-424. ora fCiia Neuroscience Clinical of Journal ehnsso Development of Mechanisms 91720 https://doi.org/10.1146/annurev-genom-083117-021441 19:177-200. 93:9-1.https://doi.org/10.3343/alm.2019.39.3.299 39(3):299-310. mrcnJunlo ua Genetics Human of Journal American 03:6-7.https://doi.org/10.1016/j.ajhg.2012.02.007 90(3):565-572. 10 3:83.https://doi.org/10.1016/j.mod.2014.02.001 132:28-37. 71-8 https://doi.org/10.1016/j.jocn.2019.06.041 67:14-18. ora fMdclGenetics Medical of Journal eeisi Medicine in Genetics lnclGenetics Clinical M eia Genomics Medical BMC Nature cetfi Reports Scientific 478(7367):57-63. 98(5):1001-1010. nulReview Annual 47(5):332-341. 83(5):446-451. 21(3):545-552. 9:7. Posted on Authorea 28 Feb 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158291220.08960122 — This a preprint and has not been peer reviewed. Data may be preliminary. M05 eosrtstemcoehl ihpnieadcrbla yolsai h 2wihe sagittal weighted T2 the in the hypoplasia containing cerebellar and Xp11.4p11.3 pontine at with view. deletion microcephaly Mb the 2.8 demonstrates (M-075) a shows CMA (OMIM) (a) analysis Man gene-specific in 2 Phenotype a Inheritance Human Figure was Mendelian traits phenotype Online step selected or last genes. for (HP:0000252) phenotype filtering The insertions/deletions genes, microcephaly Microcephaly in-frame 903 for sequences. of and (HPO)-terms composed site Ontology frameshifts, panel splice selected gene nonsense, in-silico consensus were an missense, affecting frequency with causing third changes population variants The or low prioritize variants, with (http://coda.nih.go.kr/coda/KRGDB/index.jsp). to Ko- variants (KRGDB) was the and Database or step (http://gnomad.broadinstitute.org/) Genome stage (gnomAD) ASXL1 Reference first Database Aggregation rean TET2, the Genome the in to removed according (2013). were coverage Z. 10x Xiao, 1 Figure . . . L., Legends Figure Fang, microcephaly. Investigating T., (2013). https://doi.org/10.1136/archdischild-2012-302882 A. Qin, Parker, 713. syndromes. & Z., G., myelodysplastic C. Xu, Woods, with the P., of Chinese R. review in and Gale, https://doi.org/10.1016/j.leukres.2012.10.004 mutations study Kaindl, X., two-center EZH2 a . Ai, . and . childhood: B., J., J. in Hennermann, Wang, microcephaly N., to Didonato, approach H., . Bernuth, . Diagnostic . in von literature. G., J., testing (2014). Liebe, H. genetic M. M., conventional Yntema, Pivarcsi, phe- A. versus T., M., sequencing Kleefstra, Hagen, exome J., microcephaly: der von of E. Congenital study Kamsteeg, utility H., clinical J. (2001). neurology. A Schieving, pediatric B. M., (2017). infants. J. L. M. K. newborn Willemsen, Nimwegen, Holmes, van of & L., sample Vissers, A., consecutive Leviton, a N., https://doi.org/10.1067/mpd.2001.115314 in E. features Allred, (2017). notypic E., H. Fryssira, J. . Vargas, . syndromic . unknown S., with Amenta, children A., in hybridization Mitrakos, genomic microcephaly. M., comparative Braoudaki, array high-resolution K., of Giannikou, whole-exome Application M., clinical Tzetis, toward Riv- E., disorders: Tsoutsou, neurodevelopmental . . severe . test. diagnostic in S., first-line Chehadeh-Djebbar, odyssey a El Diagnostic as F., sequencing Feillet, syndrome. (2016). M., B. formation. Lefebvre, J. tube deletion A., iere, neural Masurel-Paulet, Y., for subtelomere Genetics Duffourd, required J., jumonji, Medical Thevenon, gene, 9q Higashinakagawa, mouse & novel in chromosome J., a Motoyama, of Seminars S., capture The Development Kondo, trap C: R., Gene Tsuchiya, (1995). Y., Part T. Katoh-Fukui, (2007). Y., Yamazaki, T., T. Takeuchi, Genetics. Kleefstra, Medical in CGH of & Array https://doi.org/10.1002/ajmg.c.30148 (2013). Journal copy R., B. pathogenic Zirn, American to D. clues . . phenotypic . Stewart, there B., are Zoll, disability: J., intellectual Schroder, variants? or J., number Wickert, delay developmental B., with Auber, patients N., Klein, M., Shoukier, hoooa irary(M)adbanmgei eoac mgn MI fptetM-075. patient of (MRI) imaging resonance magnetic brain and (CMA) microarray Chromosomal eeainpoeso addt ain ituigafu-tpsrtg.Vrat ihls than less with Variants strategy. four-step a using list variant candidate a of process Generation eeomna eiieadCidNeurology Child and Medicine Developmental (0:2112.https://doi.org/10.1101/gad.9.10.1211 9(10):1211-1222. eiti Research Pediatric lnclGenetics Clinical eeisi Medicine in Genetics 22:5-6.https://doi.org/10.1038/pr.2017.65 82(2):253-260. 31:36.https://doi.org/10.1111/j.1399-0004.2012.01850.x 83(1):53-65. lnclGenetics Clinical 99:0516.https://doi.org/10.1038/gim.2017.1 19(9):1055-1063. 11 68:3-4.https://doi.org/10.1111/dmcn.12425 56(8):732-741. 96:0-0.https://doi.org/10.1111/cge.12732 89(6):700-707. rhvso ies nChildhood in Disease of Archives CASK ora fPediatrics of Journal ekmaResearch Leukemia ee b ri R fpatient of MRI Brain (b) gene. 145C(4):383-392. 139(2):210-214. 37(3):305-311. ee and Genes 98(9):707- Posted on Authorea 28 Feb 2020 — CC BY 4.0 — https://doi.org/10.22541/au.158291220.08960122 — This a preprint and has not been peer reviewed. Data may be preliminary. 12