Lowe syndrome (LS) is an X-linked disorder affecting the eyes, nervous system and kidneys, typically caused by missense or nonsense/frameshift OCRL mutations. We report a 6-month-old male clinically suspected to have LS, but without the Fanconi-type renal dysfunction. Using a targeted-exome sequencing-first approach, LS was diagnosed by the identification of a deletion involving 1.7 Mb at Xq25-q26.1, encompassing the entire OCRL gene and neighboring loci

Goji, Aya

Horikawa, Hideaki

Imoto, Issei

Kagami, Shoji

Kohmoto, Tomohiro

Masuda, Kiyoshi

Nakagawa, Ryuji

Naruto, Takuya

Suga, Ken-ichi

Watanabe, Miki

English

Tokushima University Institutional Repository

OPENDATA REPORTExome-first approach identified a novel gloss deletionassociated with Lowe syndromeMiki Watanabe1,4, Ryuji Nakagawa2,4, Tomohiro Kohmoto1,4, Takuya Naruto1, Ken-ichi Suga2, Aya Goji2, Hideaki Horikawa1,3,Kiyoshi Masuda1, Shoji Kagami2 and Issei Imoto1,3Lowe syndrome (LS) is an X-linked disorder affecting the eyes, nervous system and kidneys, typically caused by missense ornonsense/frameshift OCRL mutations. We report a 6-month-old male clinically suspected to have LS, but without the Fanconi-typerenal dysfunction. Using a targeted-exome sequencing-first approach, LS was diagnosed by the identification of a deletioninvolving 1.7 Mb at Xq25-q26.1, encompassing the entire OCRL gene and neighboring loci.Human Genome Variation (2016) 3, 16037; doi:10.1038/hgv.2016.37; published online 10 November 2016Lowe syndrome (LS, the oculocerebrorenal syndrome of Lowe,OCRL; OMIM #309000) is a rare, X-linked disorder characterized bythe diagnostic triad of congenital cataracts, cognitive andbehavioral impairment and renal proximal tubulopathy in almostall affected males, with an estimated prevalence of 1 in 500,000 inthe general population.1–3 At birth, ocular involvement withbilateral cataracts and severe hypotonia were usually present, butthese findings may also manifest in unrelated disorders, includingcongenital infections, peroxisomal disorders, mitochondriopathies,congenital myotonic dystrophies or congenital myopathies.1Varying degrees of renal involvement (proximal renal tubulardysfunction of the Fanconi type) may not be clinically apparent inthe first few months of life, making differential diagnosis toexclude alternative disorders difficult.1LS is caused by mutations involving OCRL (OMIM #300535),which encodes a member of the inositol-5-phosphatase proteinfamily, OCRL1. OCRL locates to Xq25-q26.1 (hg19), and contains 24exons, 23 of which are for protein coding.4 LS is typicallyattributed to OCRL protein-truncating nonsense/frameshiftmutations or, less frequently, missense mutations involving thecatalytic domain. Approximately 6% of LS cases result from exonicdeletions, predominantly involving the 5′ region of OCRL.5,6Deletion of the entire OCRL gene has also been previouslydescribed in four affected males: some of these large-scaledeletion events were associated with more profound clinicalfeatures.6–9 Among them, only one case with an ~ 4 Mb deletionencompassing OCRL and several flanking genes were reported inaffected males with severe features of LS.9Recently, next-generation sequencing (NGS), particularly whole-exome sequencing (WES) or targeted-exome sequencing (TES),have been adopted in clinical testing for patients withundiagnosed congenital diseases suspected to be genetic inorigin. Single-nucleotide variations (SNVs) and small insertions/deletions (indels), as well as gross copy-number variations (CNVs)involved in a defect of disease-causing genes can be detectedusing WES/TES simultaneously.10 Here, we report a second case ofLS caused by a large deletion encompassing the entire OCRLgene and nearby loci, successfully detected by a TES-firstapproach using a disease-related exome panel with subsequentchromosomal microarray (CMA)-based fine mapping.11A 6-month-old male infant was the first child born to healthy,non-consanguineous Japanese parents with an unremarkablefamily history. After an uneventful pregnancy, he was delivered at38 weeks and 5 days of gestation by Cesarean section at a localhospital. He had a birth weight of 2,100 g (−2.5 s.d.), a length of44.5 cm (−2.0 s.d.) and a head circumference of 32 cm (−0.9 s.d.).Generalized hypotonia, right cryptorchidism and inguinal herniawere noted at birth. At the age of 13 days, mild corneal opacitieswere observed bilaterally. Because of these symptoms and beingunderdeveloped for his gestational age, congenital disease wassuspected and the infant transferred to our hospital at age49 days: when he weighed 3,530 g (−2.3 s.d.) and was 51.5 cm(−2.3 s.d.) in length. Cranial ultrasound was unremarkable.His clinical course was characterized by developmental delay,short stature, generalized hypotonia, and bilateral mild cornealopacity and congenital cataracts. Early remedial surgery wasrecommended after ophthalmologic examination to preventform-deprivation amblyopia. Blood investigation revealed ele-vated alkaline phosphatase (2,187 IU/l), whereas other laboratorytests, including assays for various metabolic disorders, wereunremarkable. Conventional chromosome G-banding analysispresented a normal 46,XY karyotype. At age 79 days, lensectomywas performed. At the age of 4 months, horizontal nystagmus wasconspicuous. Cranial ultrasound showed obscure corpus callosum,and enlarged bilateral lateral ventricles and subarachnoid space.By 6 months, he weighed 5,580 g (−2.7 s.d.) and was 60.9 cm(−2.9 s.d.) in length. He lacked head control. Blood and urine testswere essentially normal. The patient was suspected to have LSbecause of his bilateral dense congenital cataracts, infantilecongenital hypotonia, delayed development, short stature andmild ventriculomegaly,1–3 although no signs of renal tubulardysfunction were observed.1Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan; 2Department of Paediatrics, Graduate School of BiomedicalSciences, Tokushima University, Tokushima, Japan and 3Support Center for Advanced Medical Sciences, Graduate School of Biomedical Sciences, Tokushima University,Tokushima, Japan.Correspondence: I Imoto (issehgen@tokushima-u.ac.jp)4These authors contributed equally to this work.Received 3 September 2016; revised 16 September 2016; accepted 19 September 2016Citation: Human Genome Variation (2016) 3, 16037; doi:10.1038/hgv.2016.37Official journal of the Japan Society of Human Geneticswww.nature.com/hgvMolecular genetic analysis was performed on genomic DNAextracted from a blood sample after informed consent wasobtained from the parents. The study was approved by the EthicsCommittee at Tokushima University. We performed TES using aTruSight One Sequencing Panel (Illumina, San Diego, CA, USA) anda MiSeq (Illumina) with our pipeline for NGS data analysis, asdescribed previously.11,12 The detection of CNVs using TES datawith a resolution of a single exon to several exons, depending onexon sizes, was performed as described previously.10,11 Theseanalyses revealed no disease-causing SNVs or indels, but diddetect a deletion of all exons of the OCRL gene between positions128,674,407 and 128,724,257 of chromosome X (Xq25-q26.1,hg19), indicating the complete loss of at least the entire OCRLgene (Figure 1a). Validation and fine mapping of the deletedregion were performed by CMA using an Affymetrix CytoScan HDchromosome microarray platform (Affymetrix, Santa Clara, CA,USA), as described previously.10,11 CMA detected a completechromosomal deletion within Xq25–q26.1 as 46,XY.arr[hg19]Xq25q26.1(127,201,958–128,877,282) × 0 (Figure 1b). In additionto the entire OCRL gene, the deleted region comprises two genes,SMARCA1 (OMIM #300012) encoding a member of the SWI/SNFfamily of proteins involved in chromatin remodeling and APLNFigure 1. (a) An eXome-Hidden Markov Model v1.0 (XHMM, https://atgu.mgh.harvard.edu/xhmm/) analysis using TES data detected genomiccopy-number loss of the entire OCRL gene (24 target exons) located within Xq25-q26.1, suggesting an ~ 50 kb deletion (red horizontal bar).The x axis denotes the physical position and the y axis indicates the Z-score of principal component analysis (PCA)-normalized read depth.Purple circles connected by red lines show values for the individual subjected to TES in this study. Gray dots with gray connected linesrepresent the results of normalized read depth obtained from in-house control data (N= 126). (b) CMA using an Affymetrix Cytoscan HD arraydemonstrated a 1.7 Mb deletion within Xq25-q26.1 (red horizontal line). Weighted copy-number log2 ratio, genes and segmental duplicationsaround the deleted region are shown. Arrows indicate direction of transcription. Dashed lines indicate deletion break points. Among the fourgenes involved in deleted region, OCRL is the only locus included in the TruSight One sequencing panel for TES. Compared with TES-basedCNV detection, distal and proximal break points of the deleted region were shifted to distal and proximal sides, respectively, in CMA analysisbecause of lacking target exons other than those of OCRL within the deleted region. CMA, chromosomal microarray; CNV, copy-numbervariation; OCRL, oculocerebrorenal syndrome of Lowe; TES, targeted-exome sequencing.Lowe syndrome caused by gloss deletionM Watanabe et al2Human Genome Variation (2016) 16037 Official journal of the Japan Society of Human Genetics(OMIM #300297) specifying an endogenous ligand for the Gprotein-coupled apelin receptor, and the 5′ region of XPNPEP2(OMIM #300145) encoding aminopeptidase P (Figure 1b). Apelin isa neuropeptide expressed in the supraoptic and paraventricularnuclei.13 The patient presented no additional clinical symptoms ordysmorphic features besides LS consequent on deletion of theseOCRL-flanking loci.9 This deletion is not present in the HumanGene Mutation Database professional 2016.2 (HGMD, http://www.hgmd.org/) and ClinVar (http://www.ncbi.nml.nih.org/clinvar/),suggesting it to be novel. This deletion was not confirmed asde novo because of the unavailability of his mother’s DNA.LS should be suspected in infant males presenting withcongenital cataracts, severe hypotonia and renal tubular dysfunc-tion of the Fanconi type during early postnatal life.1–3 Earlydiagnosis and treatment of metabolic disturbances may reducethe morbidity and mortality implicated in this syndrome.14 For thediagnosis of LS, defects involving ocular, central nervous and renalsystems are requisite.1 In early infancy, it may be difficult toexclude alternative diagnoses because of a frequent lack of renalFanconi-type syndrome, as in the present case.1 Therefore,multiple genes possibly responsible for clinical manifestations,including OCRL, should be evaluated for the differential diagnosisof LS in some cases. In addition, genetic variations such asSNV/indels, gross insertion/deletion and translocations mayunderlie disease-causing gene defects. Considering that TES cansimultaneously detect both exonic SNVs/indels and CNVs inmultiple disease-causing genes in a diagnostic setting for humangenetic diseases,10,11 this TES-first approach can facilitate differ-ential diagnosis of LS for patients lacking distinctive manifesta-tions/symptoms, as observed in the present case, in a cost- andtime-effective manner.Previously, Addis et al.9 have reported a male patient with an~ 4 Mb microdeletion encompassing OCRL and flanking genes,such as DCAF12L1 (WDR40B), PRR32, ACTRT1 and SMARCA1, whowas diagnosed with LS at birth on the basis of typicaloculocerebrorenal manifestations and renal Fanconi disease(Figure 2). As in the present case, no additional clinical symptomsor dysmorphic features besides LS consequent on deletion ofthese flanking genes were presented until his death fromunknown causes at 5 months of age, although only SMARCA1 isthe commonly deleted flanking gene between the two cases.9On the basis of the phenotypes observed in two cases, therefore,it remained unclear whether patients with LS caused by glossdeletions present additional features besides LS that are able to beexplained by OCRL-flanking genes involved in the deleted regions.A small number of cases with LS caused by microdeletionscontaining OCRL and a few nearby genes suggest that largerdeletions around OCRL in males might be lethal (Figure 2).HGV DATABASEThe relevant data from this Data Report are hosted at the HumanGenome Variation Database at http://dx.doi.org/10.6084/m9.figshare.hgv.897.ACKNOWLEDGEMENTSWe thank the patient and his family for their participation in this study. Parts of thiswork were performed at the Cooperative Research Project Program of the MedicalInstitute of Bioregulation, Kyushu University. This work was supported by JSPSKAKENHI grant numbers 26293304 (II), 16K15618 (II), and 15K19620 (TN) from theMinistry of Education, Culture, Sports, Science and Technology, Japan.COMPETING INTERESTSThe authors declare no conflict of interest.REFERENCES1 Loi M. Lowe syndrome. Orphanet J Rare Dis 2006; 1: 16.2 Lewis RA, Nussbaum RL, Brewer ED. Low syndrome. In: Pagon RA, Adam MP,Ardinger HH, Wallace SE, Amemiya A, Bean LJH et al. (eds). GeneReviews.University of Washington, Seattle: Seattle, WA, USA, 1993–2016, 2001 July 24[Updated 2012 February 23].3 Bökenkamp A, Ludwig M. The oculocerebrorenal syndrome of Lowe: an update.Pediatr Nephrol 2016; e-pub ahead of print 24 March 2016; doi:10.1007/s00467-016-3343-3.4 Attree O, Olivos IM, Okabe I, Bailey LC, Nelson DL, Lewis RA et al. The Lowe’soculocerebrorenal syndrome gene encodes a protein highly homologous toinositol polyphosphate-5-phosphatase. Nature 1992; 358: 239–242.5 Peces R, Peces C, de Sousa E, Vega C, Selgas R, Nevado J. A novel and de novodeletion in the OCRL1 gene associated with a severe form of Lowe syndrome.Int Urol Nephrol 2013; 45: 1767–1771.6 Coutton C, Monnier N, Rendu J, Lunardi J. Development of a multiplex ligationdependent probe amplification (MLPA) assay for quantification of the OCRL1gene. Clin Biochem 2010; 43: 609–614.7 Peverall J, Edkins E, Goldblatt J, Murch A. Identification of a novel deletion of theentire OCRL1 gene detected by FISH analysis in a family with Lowe syndrome. ClinGenet 2000; 58: 479–482.Figure 2. A map of the Xq25-q26.1 deletions observed in cases with LS. The RefSeq genes located around the deletions are indicated. The redhorizontal bar represents the deleted region observed in the present case. The four black bars represent the deleted regions in four previouslyreported cases with LS, whose deletions include the entire OCRL gene. In two cases,6,7 deletion of the OCRL gene was detected by multiplexligation-dependent probe amplification6 or fluorescence in situ hybridization,7 but their extent was not shown. The deleted region determinedby array-based comparative genomic hybridization is the estimated maximum extent.9 LS, Lowe syndrome; OCRL, oculocerebrorenalsyndrome of Lowe.Lowe syndrome caused by gloss deletionM Watanabe et al3Official journal of the Japan Society of Human Genetics Human Genome Variation (2016) 160378 Recker F, Zaniew M, Böckenhauer D, Miglietti N, Bökenkamp A, Moczulska A et al.Characterization of 28 novel patients expands the mutational and phenotypicspectrum of Lowe syndrome. Pediatr Nephrol 2015; 30: 931–943.9 Addis M, Meloni C, Congiu R, Santaniello S, Emma F, Zuffardi O et al. A novelinterstitial deletion in Xq25, identified by array-CGH in a patient with Lowesyndrome. Eur J Med Genet 2007; 50: 79–84.10 Morita K, Naruto T, Tanimoto K, Yasukawa C, Oikawa Y, Masuda K et al.Simultaneous detection of both single nucleotide variations and copy numberalterations by next-generation sequencing in Gorlin syndrome. PLoS ONE 2015;10: e0140480.11 Watanabe M, Hayabuchi Y, Ono A, Naruto T, Horikawa H, Kohmoto T et al.Detection of 1p36 deletion by clinical exome-first diagnostic approach. HumGenome Var 2016; 3: 16006.12 Okamoto N, Naruto T, Kohmoto T, Komori T, Imoto I. A novel PTCH1 mutation in apatient with Gorlin syndrome. Hum Genome Var 2014; 1: 14022.13 De Mota N, Reaux-Le Goazigo A, El Messari S, Chartrel N, Roesch D, Dujardin Cet al. Apelin, a potent diuretic neuropeptide counteracting vasopressin actionsthrough inhibition of vasopressin neuron activity and vasopressin release. ProcNatl Acad Sci USA 2004; 101: 10464–10469.14 Şimşek E, Şimşek T, Dallar Y, Can Ö, Willems PJ. A novel pathogenic DNAvariation in the OCRL1 gene in Lowe syndrome. J Clin Res Pediatr Endocrinol 2011;3: 29–31.This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images orother third party material in this article are included in the article’s Creative Commonslicense, unless indicatedotherwise in the credit line; if thematerial is not included underthe Creative Commons license, users will need to obtain permission from the licenseholder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/© The Author(s) 2016Lowe syndrome caused by gloss deletionM Watanabe et al4Human Genome Variation (2016) 16037 Official journal of the Japan Society of Human Genetics

Lowe syndrome caused by gloss deletion

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Lowe syndrome caused by gloss deletion

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