Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of(6)

Microarray analysis unmasked two siblings with pure hereditary spastic paraplegia shared a run of homozygosity region onchromosome 3q28–q29

354W.Yuetal./JournaloftheNeurologicalSciences359(2015)351–355

Fig.2.(A)Thesiblingswithacompletesimilarregionofrunofhomozygosity(ROH)onchromosome3whichisabsentintheirmother.(B)SNPdatadisplayedinChASshowingtheROHfrom3q28.3to3qter.

thevariantswerelikelypathogenicsincetheywerenotinclinedtoaf-fectsplicesitesaccordingtothedataofHSF.

4.Discussion

Inthisresearch,wedescribetwopatientsfromanon-consanguineousfamilywithpurespasticparaplegia.Afterexcludingthecontributionofcopynumbervariationincludingdeletionsandduplications,anROHonchromosome3q28–q29wasidenti ed.Theregionwasabout7.7Mbonthechromosome3:190172058–197851260including68geneswhichpartiallycoincidedwithSPG14region.Theoverlappingregionincluded8genes(IL1RAP,GEMC1,SNAR-I,OSTN,UTS2D,CCDC50,PYDC2andFGF12).Subsequently,theROHregionwascon rmedbymicrosatelliteanalysis.

Longcontiguousstretchesofhomozygositycanbeassociatedwithconsanguinityoruniparentaldisomy,bothofwhichincreasetheriskofautosomalrecessivediseases[11].TheconservativeclinicalsetathresholdsforROHbetween3and10Mb,whenasecondchromosomehadaROHN10Mb,indicatingidentitybydescentandconsideringex-clusionofpatientsfromuniparentaldisomy[12,13].OurpatientIII-1hasa7.7MbROHonthelongarmofchromosome3and11.4MbROHonthechromosome6p(SupplementFig.1),whichwaslikelytoindi-catehomozygositybyvirtueofparentaldescentfromacommonances-tor[14–16].

AR-HSPcausedbySPG14ischaracterizedbyprogressivespasticity,hyperre exia,andmildlower-limbhypertonicitywiththe30yearsaverageageofonset[9].Allaffectedmembersshowedneuropsycho-logicalimpairmentandbilateralpescavusandnonedisplayedabnor-malitiesonelectroencephalography[9].Thetwosiblingsinourstudyexperiencedonsetat9and7yearsold,respectively.Themainclinicalmanifestationsofthetwopatientswerespasticparaplegiaofthelowerlimbs,partiallyaccompaniedwithpescavus,amyotrophy,andmildnystagmus.AllofthesemanifestationsinourpatientsindicatedapureformofHSP.AlthoughitisnotpossibletoinferthatthesamegeneisresponsibleforSPG14andthediseaseinourfamily.Phenotypi-calvariabilitycausedbyalleleheterogeneityhasbeenobservedinmanydisordersincludingHSP[17–19].

TheexomesequencingresultsrevealedthattherewasnopathogenicmutationintheROHregionandotherchromosomes.Sangersequencingcon rmedtheexomesequencingresultoftheeightgenes(IL1RAP,GEMC1,SNAR-I,OSTN,UTS2D,CCDC50,PYDC2andFGF12)inROH,andnocausativemutationwasfoundinpromoterregionsofthosegenes.Sincethemicroarrayanalysisdetecteda7.7MbROHregiononchromo-some3q28–q29andsubsequentlycon rmedbymicrosatellitemarkers.WespeculatedthattheintervalofSPG14mightbelongerthanpreviousthoughtfromchromosome3:190172058tochromosome3:197851260.Therewere68genesintheROHregion,someofwhichseemtoberelat-edwithspasticparaplegia.PreviousstudiesshowedthatFGF12knockoutmicedisplaymuscleweaknessandFGF12-/-/FGF14-/-mice