Posted on Authorea 27 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160382404.49256311/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. htitreec fL rti ucindrn mroeei mar erlcetcl irto nthe in migration cell crest neural impairs staining embryogenesis immunohistochemical during via function pathway protein gut signaling developing endothelin of as the such interference in , that genetic HD-causative identified for several been encode for have that children modifier where a syndrome as L1 acts inheritance. with of verified associated model both had been Mendelian, who non previously a has suggests disease in however, Hirschsprung disease, HD in 12 the with cells least of associated at ganglion presentation are causatively lacks variable There that been and have colon obstruction. mutations distal functional pathogenic a of creating known segment thus which a prevalence plexuses, in myenteric a results and has States submucosal tract that United the gastrointestinal system the developing nervous in the births enteric of live the length same 5000 of in the malformation 1 share congenital approximately a of who is patients (HD) among disease even Hirschsprung variable, highly is syndrome variant. L1 pathogenic syndrome of L1 manifestation of in phenotypic mutations The major additional four that the causing suggesting agene- as #304100) complicated identified (OMIM X-linked been X-linked callosum and have #303350); corpus OMIM#303350); OMIM the (SPG1; (MASA; 1 of men- syndrome type sis #307000); thumbs conditions: OMIM adducted X-linked spastic (HSAS; and major hereditary Sylvius gait con- four complicated of shuffling aqueduct the includes are , the in that which of retardation, Mutations disease stenosis domains tal of to 1). due III spectrum (Figure a helix type congenital transmembrane encompasses X-linked fibronectin which a five by syndrome, portion by domain extracellular L1 chromo- The intracellular followed cause X small sequence. domains the a protein immunoglobulin on acid to amino found six nected 1253 is of a molecule has comprised and adhesion mammals) is cell other L1CAM (and humans The in development. some neuronal in involved molecule The both. disease. underlie Hirschsprung to and thought Introduction syndrome gene L1 are L1CAM with There the someone in . in mutations variant and with L1CAM thumbs disease, pathogenic adducted Hirschsprung novel hydrocephalus, coincident a and present congenital We syndrome with L1 manifesting of disorder cases X-linked rare an is syndrome L1 Abstract 2020 27, October 1 Andreone a VariantTeresa of L1CAM Novel Report a Syndrome: and L1 Case with New Infant an in Disease Hirschsprung an oi nvriyCr h hscaso an oi University Louis Saint of The - Care University Louis Saint L1CAM eeecdstemmrn lcpoenLCM acu-needn ellradhesion cellular calcium-independent a L1CAM, glycoprotein membrane the encodes gene 12 eetdsgodclnfo nat ihH a ensont akepeso fL1 of expression lack to shown been has HD with infants from colon sigmoid Resected . 1 L1CAM uain n ipypoe HD biopsy-proven and mutations L1CAM 13 eetees nhmn ahgncvratin variant pathogenic a humans in Nevertheless, . 1 oeta 2 ies-asn ainsi the in variants disease-causing 220 than More . a as idbhvoa n nelculimpairment intellectual and behavioral mild cause can 1 4 alr fnua rs el omgaeteentire the migrate to cells crest neural of Failure . ,11 5, ,2 6-10 2, 1, vdnefo uiemdlsuggests model murine a from Evidence . tde aesgetdthat suggested have Studies . 2 RET diinly hr r reports are there Additionally, . 5 h nopeepenetrance incomplete The . , SOX10 n eea genes several and L1CAM L1CAM L1CAM L1CAM gene gene has 3 . Posted on Authorea 27 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160382404.49256311/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 32 ain eut nanncnevtv mn cdsbttto fcsen ihagnn,rsligin resulting arginine, patient’s with Our cysteine HD. in of result substitution also necessarily acid not amino do al. non-conservative but et syndrome, a Kanemura L1 HD in cause by associated results may without described protein variant syndrome L1 was C312R the L1 of as patient’s domain (c.935G reported 3 our was mutation Ig of case DNA that locus Ig different but the A same 2006, affecting HD. the 2006 with at diagnosed Previous (p.Cys312Tyr) al. was et substitution one Basel-Vanagaite 1). only by but reported (Figure half-siblings, mutation 1) protein one (Table only L1CAM cells domain with neighboring 3 the the domain, on of proteins 3 of L1CAM type domain 8 with fibronectin (c.934T 3 interactions exon reported mutation homophilic (Ig) in previously to point Immunoglobulin (p.Cys312Arg) the domain missense this change the linked novel sequence have for a studies acid encodes report amino exon also newly-described This We a HD. in biopsy-proven results and syndrome L1 1) pathogenic (Table of disease cases Hirschsprung and described previously 13 are There sequencing Discussion targeted mucosa Subsequent muscularis the disease. in Hirschsprung seen for (NM were pathognomonic immunohistochemical patient’s trunks were esterase the nerve acetylcholine findings of absence hypertrophic and These the prominent calretinin for from 3). and The and L1 (Figure suffered biopsy negative propria. for rectal had both of lamina concern biopsy sections were patient rectal in consecutive to The staining 76 the fibers Due on age. neuritic of that cells weeks typical ganglion life. 6.5 determined of parentalof at of absence was performed In month the ultimately for it was first significant presentation. biopsy stay, was his rectal late a NICU during HD, patient’s coincident distension his the with syndrome abdominal of given with unlikely review diagnosis constipation deemed chart A intermittent initially 2C). on (Figure was and colon but of to retrospect considered loops failure was dilated and profoundly HD abdomen demonstrated of distended of radiographs weeks a was 11.5 Abdominal developed drain at he stool. ventriculitis/meningitis, placed ventricular pass for was external for admission shunt patient’s VP The hospital the new During in a sedation. until remained holiday” and He “shunt ventilation a by mechanical placed. age. followed for discharge, was to need drain prior infection. the removed and ventricular by malfunction external shunt typified VP an course for his and concern of During with removed treatment hospital was disability. full to shunt bilaterally admitted intellectual and was with VP hydrocephalus severe patient diagnosed with with The the ventriculoperitoneal also born life, wheelchair-bound was A also of remains child was week 2A). uncle The fifth and (Figure maternal thumbs hydrocephalus. visualized patient’s ven- adducted manage the be profound Notably, bilaterally to to demonstrated 2B). 2 (Figure with brain able DOL thumbs the diagnosed on not adducted of was placed was imaging was parents, callosum shunt resonance Caucasian corpus (VP) magnetic non-consanguineous the 1, to and DOL born On triculomegaly child utero. first in the when hydrocephalus was HD who for proband, suspicion The of index high syndrome. a L1 Report have have of Case should form to any clinicians found with that was patients emphasize for who also caring We syndrome HD. L1 of the diagnosed pathogenesis of clinically sequencing Subsequent targeted (c.934T with infection. by shunt variant syndrome infant ventriculoperitoneal L1 an a of for confirmation of to genetic admission case required during always disease rare is Hirschsprung a biopsy-proven biopsy syndrome. present L1 a diagnosed we Therefore, genetically HD. Here with to patients leads in always even presence HD, causative diagnose whose identified been not 0453:c.934T 000425.3): > L1CAM tpyoocsepidermidis Staphylococcus ;pCs1Ag.W ics h osberl fpathogenic of role possible the discuss We p.Cys312Arg). C; 1 oal,temtto eotdb ae-aaat ta.20 a rsn ntwo in present was 2006 al. et Basel-Vanagaite by reported mutation the Notably, . > L1CAM eedmntae rvosyurpre ain neo fthe of 8 exon in variant previously-unreported a demonstrated gene ;pCs1Ag(C312R). p.Cys312Arg C; uain nptet ihL ydoeadH,temjrt ffc the affect majority the HD, and syndrome L1 with patients in mutations ,2 -,14-19 6-8, 2, 1, etiuii/eigts h ain a rlne hospital prolonged a had patient The ventriculitis/meningitis. ee edsrb e ain ihgntclyconfirmed genetically with patient new a describe we Here, . 2 L1CAM uain nptet ihbt 1syndrome L1 both with patients in mutations L1CAM 21 hs uain htaetthe affect that mutations Thus, . eervae oe pathogenic novel a revealed gene L1CAM > )adaioacid amino and A) uain nthe in mutations L1CAM L1CAM > )that C) 20 gene. gene Of . Posted on Authorea 27 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160382404.49256311/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. nmdfidpoen htipc eeial ucpil niiul.Yt hr r udeso pathogenic the of supporting hundreds further are there HD, Yet, coincident individuals. with susceptible syndrome genetically L1 impact of L1CAM that reports proteins of modified number in HD. small child’s a this that in to hypothesis implicated adds be case also (c.934T This might mutation mutation point This missense syndrome. novel L1 patient’s his our variant Therefore, pathogenic scores likely case. CADD a have to also 1 corresponds which homophilic Analysis 26.6, disrupt function. of L1CAM or altering conformation silico thus chain protein proteins, in side other L1CAM charged c.934T positively with affect the a protein likely has L1CAM of that very of one interactions could with heterophilic chain substitution or side This uncharged an with 4). acid (Figure amino an of exchange the oflc fItrs:Teatoshv ocnit fitrs odisclose. to interest of conflicts no References have authors The disclose. Interest: to of parents article Conflict from this Obtained to relevant publication: relationships for consent financial Patient no have authors histopathology study. The this and Disclosure: M. for radiology Financial Andreone, secured with was T. funding assisted report. No and case Source: care the Funding edited diagnostic and provided Braddock revised Besmer S. also and S. images. Andreone Andreone and T. Starnes, T. report S. report. case report. case this Guzman, the for case wrote case the Gauntner the T. identified reviewed Andreone patient. critically T. the and of Braddock management S. to Pinz, contributed H. Karumuri, disease. M. Gauntner, this T. of phenotypes major frontal the thumbs, Contributions: with clinicians— adducted Author familiar spectrum, as phenotypic be such wide particular—should features a across in exhibit manifests and pediatricians might with syndrome HD L1 and syndrome children Since with L1 all delay. diagnosed of developmental in are or diagnosis pursued who bossing Conversely, biopsy children syndrome. in rectal L1 considered and suspected be considered and be dysfunction should obstructive disease intestinal Hirschsprung that conclude We an of presence Nkkmr ,Ssk ,OaaT ta.Hrcsrn’ ies,arcloa ydoe n congen- and syndrome, acrocallosal disease, Hirschsprung’s al. et T, Okada mutation a F, with Sasaki disease Hirschsprung’s S, and Nakakimura Hydrocephalus 7. al. the et of R, Valero members R, for Maestro gene Del N, modifier Okamoto a 6. as acts L1cam RB. and Anderson syndromes M, associated Schachner disease, MX, Hirschsprung syndrome: Tan L1 AS, al. of Wallace et form 5. mild M, a Garcia-Barcelo causes E, L1CAM Sproat-Emison in mutation J, novel Amiel A 4. al. et M, Pisters M, Wevers M, Otter 3. Associa- S. Borrego G, Antinolo J, L1CAM- Agustin of de spectrum Carlos phenotypic L, the Garcia-Diaz R, Expanding Nunez-Torres RM, al. Fernandez et 2. MJ, Friez R, Straussberg L, Basel-Vanagaite 1. tlhdoehls eoto ainsadltrtr review. literature and patients 2 of report hydrocephalus: ital L1CAM. of development. system nervous enteric Motility during pathway signalling endothelin review. a genetics: report. case a Mutation a With Patient New a Gene. of doi:10.1002/ajmg.a.35244 Report L1CAM Disease: the Hirschsprung in and Hydrocephalus X-Linked of tion disease. associated rdcinagrtmta sessgntcvrat sbng rptoei—ilsaCD score CADD a pathogenic—yields or benign as variants genetic assesses that algorithm prediction uain ecie ncsso 1snrm ihu soitdHD associated without syndrome L1 of cases in described mutations > o 012(1:50E2.doi:10.1111/j.1365-2982.2011.01692.x 2011;23(11):E510-E522. Nov . L1CAM on uainuigteCmie noainDpnetDpein(AD tool—an (CADD) Depletion Annotation-Dependent Combined the using mutation point C L1CAM ora fHmnGenetics Human of Journal lnclcs reports case Clinical uainaoei o igotco Di hl ihpeoyi 1syndrome. L1 phenotypic with child a in HD of diagnostic not is alone mutation lnclGenetics Clinical ora fMdclGenetics Medical of Journal eemttosmyb novdi h ahgnsso D otlkl resulting likely most HD, of pathogenesis the in involved be may mutations gene > 5 togysgetn that suggesting strongly 15, mrcnJunlo eia eeisPr A Part Genetics Medical of Journal American 07Ag21;()11-27 doi:10.1002/ccr3.1038 2017;5(8):1213-1217. 2017-Aug . a 066()4449 doi:10.1111/j.1399-0004.2006.00607.x 2006;69(5):414-419. May . u 044()3437 doi:10.1007/s10038-004-0153-4 2004;49(6):334-337. Jun . 3 a 084()11.doi:10.1136/jmg.2007.053959 2008;45(1):1-14. Jan . L1CAM 22 h aoiyo uain eotdi Table in reported mutations of majority The . uain r nedptoei neach in pathogenic indeed are mutations > ora fPdarcSurgery Pediatric of Journal )cudb osdrdcuaieof causative considered be could C) p 2012;158A(4):816-820. Apr . ,2,23 21, 1, ergsretrlg and Neurogastroenterology niaigta the that indicating , May . Posted on Authorea 27 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160382404.49256311/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. kmt ta. 1997 al., et Okamoto al 1. Table Reference VsY,d al E,BsK,e l eoyepeoyecreain nL ydoe guide a syndrome: L1 in correlations - al. et KK, esti- Bos for framework HEK, general Walle A de J. YJ, Shendure Vos GM, 23. Cooper BJ, O’Roak P, mecha- Jain Molecular DM, M. Witten Yamasaki M, H, modular Kircher Kamiguchi 22. with T, protein Shofuda H, multi-domain Sakamoto A N, Okamoto region: Y, Kanemura extracellular 21. L1CAM The M. Grumet AVPR2 and J, L1CAM involving Haspel deletion 20. gene Contiguous E. Hatchwell J, Roohi AH, Severe Lane Disease: DH, Hirschsprung Tegay With 19. Hydrocephalus with al. patient et a Y, in Kanemura disease M, Nakazawa Hirschsprung’s T, of Takenouchi pathogenesis a 18. Complex L1CAM al. Is et R, aganglionosis: Giorda intestinal Y, and and Vos P, Hydrocephalus somatic Griseri for 17. al. Evidence et PJ. I, Willems Neilson E, Fransen RP, JJA, Kapur Holden MA, G, Parisi Camp 16. Van mutation a D, in with Chitayat patient L1 a L, molecule in disease Vits adhesion Hirschsprung’s 15. and cell Hydrocephalus neural M. Goto of Y, Wada expression N, ad- Impaired Okamoto cell 14. al. The et HM. Y, Takeda Young H, M, Kawano Schachner H, J, gene Ikawa 13. modifier Hemperly a AG, as Nikonenko acts KN, L1cam Turner RB. RB, Anderson Anderson M, 12. Wegner M, Schachner cases C, Three Schmidt F. Mora-Lopez AS, D, Wallace Arroyo 11. F, Rodriguez-Sanchez G, Gutierrez M, Ley-Martos R, Marin 10. FradzR,NnzTre ,Gnae-eee ,Atnl ,BreoS oe soito of association Novel S. associa- Borrego in G, mutation Antinolo L1CAM A, CE. Gonzalez-Meneses Shin R, Nunez-Torres H, RM, Ford Fernandez LM, 9. Randolph R, Woo YS, Guner S-R, Jackson 8. o eei oneln n uainanalysis. mutation doi:10.1136/jmg.2009.071688 and counselling genetic for variants. genetic human doi:10.1038/ng.2892 of hydrocephalus. pathogenicity relative X-linked the with mating syndrome L1 severe for criteria and nisms modes. binding doi:10.2741/1108 cooperative and insipidus. diabetes A nephrogenic Part with Genetics hydrocephalus X-linked causes Article. doi:10.1002/ajmg.a.35245 Spectrum. 2012;158A(4):812-815. Apr Hydrocephalus X-linked of End t(3;17)(p12;q11). translocation Genetics balanced Human a of and reflux vesico-ureteral hydrocephalus, doi:10.1002/ajmg.10185 disease? 56. Hirschsprung in gene modifier syndrome. CRASH in mosaicism germline mouse L1CAM. Article. developing of the disease. in Hirschsprung’s cells in doi:10.1016/s0022-3468(97)90703-x crest fibers 1997;32(4):542-545. neural nerve of extrinsic migration the chain for required is gut. L1 molecule hesion development. system nervous doi:10.1016/j.nbd.2010.08.006 enteric during gene. L1CAM the Xq28 in doi:10.1007/s00431-015-2560-2 the mutations novel at 2015;174(11):1541-1544. two and duplication syndrome a L1 with with male a in disease Hirschsprung region. and encephalopathy neonatal severe disease. Hirschsprung’s doi:10.1007/s00383-009-2420-0 and 2009;25(9):823-825. hydrocephalus X-linked with tion doi:10.1016/j.jpedsurg.2007.12.069 2008;43(5)E13. Gastroenterology eot of Reports m eia Genetics Medical Bmc ora fMdclGenetics Medical of Journal o 06155:0-1.doi:10.3171/ped.2006.105.5.403 2006;105(5):403-412. Nov . L1CAM a 0713()5458 doi:10.1002/ajmg.a.31536 2007;143A(6):594-598. Mar . p 091()4340 doi:10.1038/ejhg.2008.191 2009;17(4):483-490. Apr . p 06104:2113.doi:10.1053/j.gastro.2006.01.002 2006;130(4):1221-1232. Apr . uain nPtet ihL ydoeadHrcsrn Disease Hirschsprung and Syndrome L1 with Patients in Mutations e 221;13.doi:10.1186/1471-2350-11-137 2010;11137. 22 Sep . rnir nBioscience-Landmark in Frontiers mrcnJunlo eia Genetics Medical of Journal American u 973()6061 doi:10.1136/jmg.34.8.670 1997;34(8):670-671. Aug . ua Mutation Human ora fMdclGenetics Medical of Journal erbooyo Disease of Neurobiology 4 mrcnJunlo eia eeisPr A Part Genetics Medical of Journal American 9819;(UP.1):S284-S287. 1998;0(SUPPL. 1998 . aueGenetics Nature eiti ugr International Surgery Pediatric ora fPdarcSurgery Pediatric of Journal uoenJunlo of Journal European mrcnJunlo Medical of Journal American e 2003;8:S1210-S1225. Sep . e 2010;40(3):622-633. Dec . a 2010;47(3):169-175. Mar . e 52002;108(1):51- 15 Feb . a 2014;46(3):310-+. Mar . uoenJournal European ora of Journal Apr . Nov . Sep . . c.2421 Mutation 2422delTG xn18 Exon Intron/Exon p.Gly808ArgfsX9 change Protein Domain Fn-2 ADScore CADD - Posted on Authorea 27 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160382404.49256311/v1 — This a preprint and has not been peer reviewed. 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> > A A xn8 Exon xn1 Exon xn16 Exon xn18 Exon xn13 Exon xn3 Exon - xn7 Exon xn22 Exon 15 Intron 15 Intron 18 Exon 15 Exon p.Cys312Arg p.Gln21X p.Gly698Arg p.Pro756Leufs95X p.Arg558X p.Val31Ala deletion p.Pro240Leu p.Gln992X Unknown Unknown p.Val752Met p.Arg632Pro Ig-3 N-terminus Fn-1 Fn-2 Ig-6 N-terminus - Ig-3 Fn-4 N/A N/A Fn-2 Fn-1 26.6 15.2 28.2 - 10.0 24.5 - 25.8 21.5 23.7 23.7 26.1 23.2 Posted on Authorea 27 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160382404.49256311/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 6 Posted on Authorea 27 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160382404.49256311/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. agincls tiigptencnitn ihHrcsrn disease. Hirschsprung submucosal Cal- with or A (B) consistent propria pattern lamina (*). the bundles staining nerve within a rectal hypertrophic neurofibrils cells, and demonstrating of ganglion plexus stain absence submucosal revealing eosin the stain and in immunohistochemical Hematoxylin cells retinin (A) ganglion of magnification. absence 10x with at mucosa biopsy colon of Histopathology 3. Figure 7 Posted on Authorea 27 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160382404.49256311/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. mn cdsrcue fcsen n riie oecagdv.ucagdsd groups. side uncharged vs. charged Note arginine. and cysteine of structures acid Amino 4. Figure B 8 Posted on Authorea 27 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160382404.49256311/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 9 Posted on Authorea 27 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160382404.49256311/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 10