Abstract
Here we report novel mutations in ABCA4 with the underlying phenotype in a large French cohort with autosomal recessive Stargardt disease. The DNA samples of 397 index subjects were analyzed in exons and flanking intronic regions of ABCA4 (NM_000350.2) by microarray analysis and direct Sanger sequencing. At the end of the screening, at least two likely pathogenic mutations were found in 302 patients (76.1%) while 95 remained unsolved: 40 (10.1%) with no variants identified, 52 (13.1%) with one heterozygous mutation, and 3 (0.7%) with at least one variant of uncertain significance (VUS). Sixty-three novel variants were identified in the cohort. Three of them were variants of uncertain significance. The other 60 mutations were classified as likely pathogenic or pathogenic, and were identified in 61 patients (15.4%). The majority of those were missense (55%) followed by frameshift and nonsense (30%), intronic (11.7%) variants, and in-frame deletions (3.3%). Only patients with variants never reported in literature were further analyzed herein. Recruited subjects underwent complete ophthalmic examination including best corrected visual acuity, kinetic and static perimetry, color vision test, full-field and multifocal electroretinography, color fundus photography, short-wavelength and near-infrared fundus autofluorescence imaging, and spectral domain optical coherence tomography. Clinical evaluation of each subject confirms the tendency that truncating mutations lead to a more severe phenotype with electroretinogram (ERG) impairment (p = 0.002) and an earlier age of onset (p = 0.037). Our study further expands the mutation spectrum in the exonic and flanking regions of ABCA4 underlying Stargardt disease.
Highlights
Stargardt disease-1 (STGD1, Mendelian Inheritance in Man [MIM] 248,200) is a progressive autosIonmt
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Sequencing of ABCA4 in our cohort of 397 STGD1 patients identified a large number of allelic variants
Summary
Stargardt disease-1 (STGD1, Mendelian Inheritance in Man [MIM] 248,200) is a progressive autosIonmt. CScei.s2s0i1v8e, 1m9, xaFcOuRlaPrEdERegREeVnIeErWation linked to pathogenic mutations in ABCA4 (MIM2*o6f0215,691). A1.BICntAro4deuncctioodnes the transmembrane protein ABCA4 (ATP-binding cassette (ABC), subfamily A, member 4), located in the outer segment disk membranes of cone and rod photoreceptor cells [1–3]. Its loss canStaleragdardtot tdhiseedaseev-1elo(SpTmGeDn1t, oMf esnedveelriaanl rIenthineariltadnicseoridneMrsainnc[lMudIMin]g2S48T,G20D0)1,iscoanperoagnrdescsoivnee-rod dystroaupthoysA,oBamCnadAl 4rreeectneiscnsoiidtvieessmpthiagecmutrleaannr stdomesgeaemn[b4er–raa1nt1ieo].nprlointekiendAtoBpCaAth4o(gAeTnPic-bminudtiantigocnassisnetAteB(CAAB4C()M, sIuMb*f6a0m1i,l6y91A)., Gmievmenbetrh4e),lalorgcaetenduimn btheer oouf tvear rsieagnmtsenret pdoisrktemdeimnbAraBnCeAs o4f[c1o2n],emanodstroodf tphheomtorbeecienpgtoprocleyllms [o1r–p3h].isms, the idIetsnltoifissccaatinolneaodf ttorutheeddiesveealsoep-mcaeunstionfgsemvuertaaltiroetninsailsdoifstoerndecrhsainllcelnugdiinngg S[T5,G1D3,11,4c]o. Proaches, such as generation sequencing (NGS), the detectGioinvernatehse olafrAgeBnCuAm4bmeruotfavtiaorniasnhtsarveepgoreteadtliyniAnBcrCeAa4se[d12s]i,nmcoesittsofdtihsecmovbeeriynginp1o9ly9m7.oNrpehviesmrths,eless, homotzhyegidoeunstiofircacotimonpoofutrnude hdeisteearsoez-ycaguosuinsgmmuuttaattiioonnss aisreofrtenguclhaarllyendgeintegc[t5e,d13i,n14n].o more than 70–75% of STGD1 paWtieitnhtsth, ewahdilveenatsoigf nniefiwcaanntanlyutimcabl earpopfropaacthieesn,tssuccahrrays onnexlyt gaesnienrgalteioAn BseCqAu4enmciuntga(tNioGnSo),r tnhoene at all [15d–e1te9c]t.ioOnnrathtees ootfhAeBrChAa4nmd,usteavtieornaslhdaeveepgrineatrtloyniinccvreaarsieadntssinicne nitosnd-icscoodvienrgy rineg1i9o9n7s. Thoigfhuerrthdeergerexepolof rceonthfiedegnecneewticitchhmaroaleccteurlaisrtdicisagonfoAsBisC[3A24,3a3n].d broaden the spectrum of its pathogenic variants, wToe afunratlhyezredexaplloarregethFeregnecnhetcioc hcohratroacft3er9i7stSicTsGoDf 1ApBaCtAie4ntasnudsibnrgoaadecnomthbeinsapteioctnruomf moifcriotsarray analypsiasthaongdeSnaicnvgaerriasnetqsu, wenecainngal.yTzhede paularrpgoesFeroefntchhiscoshtuodrtyowf 3a9s7toSTrGepDo1rtpaaltlietnhtesnuosvinegl vaacroimanbtisniadtieonntified evaluoaftimnigcrtohaerirraypaanthaloygsiesnaincidtySawngitehr sineqsuielinccoinagn. The clinical features were analyzed and correlated with the genetic results
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