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Exome sequencing identifies pathogenic variants of VPS13B in a patient with familial 16p11.2 duplication Dastan, Jila; Chijiwa, Chieko; Tang, Flamingo; Martell, Sally; Qiao, Ying; Rajcan-Separovic, Evica; Lewis, M. E S Nov 10, 2016

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CASE REPORT Open AccessExome sequencing identifies pathogenicvariants of VPS13B in a patient with familial16p11.2 duplicationJila Dastan1,3, Chieko Chijiwa1, Flamingo Tang3, Sally Martell2,3, Ying Qiao1,2, Evica Rajcan-Separovic2,3*and M. E. Suzanne Lewis1,3*AbstractBackground: The recurrent microduplication of 16p11.2 (dup16p11.2) is associated with a broad spectrumof neurodevelopmental disorders (NDD) confounded by incomplete penetrance and variable expressivity.This inter- and intra-familial clinical variability highlights the importance of personalized genetic counsellingin individuals at-risk.Case presentation: In this study, we performed whole exome sequencing (WES) to look for other genomicalterations that could explain the clinical variability in a family with a boy presenting with NDD who inheritedthe dup16p11.2 from his apparently healthy mother. We identified novel splicing variants of VPS13B (8q22.2)in the proband with compound heterozygous inheritance. Two VPS13B mutations abolished the canonicalsplice sites resulting in low RNA expression in transformed lymphoblasts of the proband. VPS13B mutationcauses Cohen syndrome (CS) consistent with the proband’s phenotype (intellectual disability (ID), microcephaly, facialgestalt, retinal dystrophy, joint hypermobility and neutropenia).The new diagnosis of CS has important health implication for the proband, provides the opportunity for moremeaningful and accurate genetic counselling for the family; and underscores the importance of longitudinallyfollowing patients for evolving phenotypic features.Conclusions: This is the first report of a co-occurrence of pathogenic variants with familial dup16p11.2. Our findingsuggests that the variable expressivity among carriers of rare putatively pathogenic CNVs such as dup16p11.2 warrantsfurther study by WES and individualized genetic counselling of families with such CNVs.Keywords: 16p11.2 duplication, Cohen syndrome, Neuro-developmental disorders, Variable expressivity, Whole exomesequencing, Case reportBackgroundChromosome microarray analysis of subjects with NDDhas uncovered a large number of rare copy numbervariations (CNVs); nevertheless, some pathogenic andputatively pathogenic CNVs detected in patients cannotcompletely explain complex patient phenotypes, particu-larly when an unaffected parent carries the samesubmicroscopic imbalance. One example of a suscepti-bility locus for NDD is the 16p11.2 region with ~600 kbdeletions and duplications observed in ~1 % of autismand 1.5 % of children diagnosed with significant devel-opmental or language delays compared to 0.04–0.07 %amongst control populations [1, 2]. Carriers of 16p11.2CNV manifest a broad spectrum of neurocognitive pheno-types, ranging from ID [1, 3, 4], autism spectrum disorder(ASD) [5, 6], schizophrenia [7], congenital anomalies [4, 8]to individuals without a specific phenotype [3, 4, 8]. Thereis familial coincidence of both phenotypically affected andunaffected carriers in some families [1, 7, 8]. The estimatedpenetrance of 16p11.2 deletion and duplication are* Correspondence: eseparovic@cw.bc.ca; suzanne.lewis@ubc.ca2Department of Pathology (Cytogenetics), Children’s and Women’s Hopsitalof BC and Children’s and Women’s Health Center of BC and Univeristy ofBritish Columbia, Vancouver, BC V5Z 4H4, Canada1Department of Medical Genetics, Children’s and Women’s Health Center ofBC and Children’s and Women’s Health Center of BC and Univeristy of BritishColumbia, Vancouver, BC V6H 3N1, CanadaFull list of author information is available at the end of the article© The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Dastan et al. BMC Medical Genetics  (2016) 17:78 DOI 10.1186/s12881-016-0340-046.8 % and 27.2 %, respectively [2]. Multiple studiesdemonstrated the power of WES to find the genetic etiologyof clinical variability among such patients. WES helped todiscover that the presence of variants on the non-CNV con-taining homolog chromosome may unmask biallelic muta-tions in an autosomal recessive condition [9, 10], or thatdamaging variants in other parts of the genome may con-tribute to such variable expressivity [11]. The results of thesestudies suggest that inconsistent phenotypes in patients withknown pathogenic CNVs or with CNVs inherited from anunaffected parent may indicate the co-occurrence ofsecondary genomic events elsewhere in the genome.In this study, we report that pathogenic variants ofVPS13B located at chromosome 8 in a boy with NDDcarrying a familial dup16p11.2 contribute to the clinicalvariability in this family.Case presentationThe proband is an 11 year old boy introduced to our clinicwith global developmental delay and verbal apraxia at theage of four. He is the third of four-children of non-consanguineous parents of Chinese descent. His motherand his paternal grand-mother have a history of recurrentspontaneous pregnancy losses with unknown cause. Hisparents and three siblings are apparently healthy (Fig. 1a).The proband was born after 39 weeks of uneventful preg-nancy via caesarean section for fetal distress with Apgarscores of 8 and 9 at one and five minutes after birth,respectively. His birth weight was 2175 gram (<3rd per-centile (%ile)), length was 47 cm (10th %ile) and occipito-frontal circumference (OFC) was 34 cm (25th %ile). Thepatient exhibited feeding difficulty, low muscle tone, bilat-eral ptosis, club foot, bilateral undescended testes, andflexion contracture of hand and wrist. The proband’s la-boratory diagnostic workup was normal and included rou-tine karyotype, subtelomeric FISH, fragile X, biochemicalassessment, cranial MRI and CT scan. AffymetrixGenome-Wide Human SNP Array 6.0 revealed a 709.2 kbduplication of 16p11.2 (29,425,199–30,134,432) in theproband, confirmed by FISH and parental studies indicat-ing maternal inheritance. The proband’s siblings were nottested for dup16p11.2 per the family’s request.We examined the mother who is a carrier of dup16p11.2for the possibility that apparently healthy carrier parentsmight have some unnoticed clinical features, and for thepresence of phenotypic commonality with his child. Sheshowed no sign of ID, ASD, psychiatric disorder (anxiety,depression, obsessive-compulsive disorders (OCD)),underweight or microcephaly. She was also negative forhistory of other dup16p11.2 features including epilepsy,speech and motor delay, and congenital anomalies.Genetic testingDNA samples of family trios were sent to PerkinElmerCompany for exome enrichment using the TruSeqExome Enrichment Kit (Agilent v5 + UTR), followed bypaired-end sequencing (Illumina HiSeq 2000, readlength of 100 bp). Using Golden Helix (GH) software(SNP & Variation Suite 7.7.8), the WES data from asingle VCF file for sequenced family members wasanalyzed (Additional file 1: Figure S1). Two novelsplicing mutations of VPS13B (8q22.2) with compoundheterozygous inheritance were identified in the probandand subsequently confirmed by Sanger sequencing(Fig. 1b). A sequence variant of c.1426-1G > A located inthe acceptor splice site of intron 10 was identified inFig. 1 a Family pedigree. b Sanger sequencing analysis of VPS13B variants. I) Proband and his mother are carriers of splicing mutation ofc.1426-1G > A. II) Proband and his father are carriers of splicing mutation of c.4157 + 1G > T (sequences of reverse strands are shown)Dastan et al. BMC Medical Genetics  (2016) 17:78 Page 2 of 6Proband A and his mother. The second variant, anucleotide change of G > T at c.4157 + 1 situated in thedonor site of intron 27, was inherited from his father.Mutations and/or CNVs in the VPS13B gene lead to arare autosomal recessive condition called Cohen syn-drome (CS) [12].Functional prediction tools used for WES data analysisanticipate the effect of non-synonymous variants (codingregion). However, both variants of VPS13B are locatedat canonical splice sites. ALAMUT software predictedthat two intronic variants of VPS13B would result inskipping of the exon 11 and 27. To confirm this pre-diction, we performed PCR on cDNA samples of pro-band and a control using two separate sets of primerscovering exons 9–12 and 26–29 of VPS13B, followedby Sanger sequencing of the PCR products. This con-firmed that both variants abolish the canonical splicesites and create aberrant RNA sequences (Fig. 2).Real-time quantitative PCR (qPCR) for VPS13B demon-strated reduced expression in the proband compared totwo controls (Additional file 1: Material and methods).The mother also showed reduced RNA expression com-pared to one control (Fig. 3). Other family memberswere not available for VPS13B or dup16p11.2 testing.The VPS13B gene, also known as COH1 (OMIM:607817), is approximately 864 kb in length and locatedon chromosome 8q22.2. It consists of 62 exons encodinga transmembrane protein of 4022 amino acids [12].VPS13B is a peripheral membrane protein that is requiredfor function, orientation and structural integrity of theGolgi apparatus and thus plays a role in vesicle-mediatedsorting and intracellular protein transport [13, 14]. Homo-zygous or compound heterozygous mutations/CNVs ofVPS13B cause CS [12].Intronic point mutations within donor and acceptorsites at mRNA splice junctions typically cause mRNAmis-splicing, leading to subsequent nonsense-mediatedmRNA decay (NMD), and altered protein with effect onthe clinical phenotype [15]. Indeed, Sanger sequencingof RT-PCR product corresponding to each specificVPS13B variant demonstrated that both variants createFig. 3 Expression study of VPS13B gene. The mean RNA expressionof VPS13B calculated from three different time-series of RNA extractionin the proband, his mother and two normal controls. The relativeexpression of VPS13B is <0.5 fold in the proband and >0.6 fold in hismother. Error bars indicate standard errors from three replicatesFig. 2 Sanger sequencing of RT-PCR products of proband and control, using primers covering exons 9–12 and 26–29 of VPS13B. a The variant ofc.1426-1G > A disrupted the following sequences and caused frameshift in the proband. The orange arrow shows the first bp of exon 11 in thenormal control. b The variant of 4157 + 1G > T disrupted following sequences, and caused frameshift in the proband. The orange arrow showsthe first bp of exon 27 in the normal controlDastan et al. BMC Medical Genetics  (2016) 17:78 Page 3 of 6aberrant RNA sequences and frameshift and thus prob-ably lead to NMD. Moreover, the RNA expression levelof VPS13B in the proband was significantly reducedcompared to two controls. VPS13B expression in hismother was intermediate between the proband and onecontrol, suggesting that partial loss-of-function in car-riers of autosomal recessive disorders is not sufficient toproduce a complete disease phenotype.Absence of dup16p11.2 -related phenotype in themother, presence of some CS features in the proband,and the discovery of pathogenic VPS13B mutationswarranted re-evaluation of our patient at 10 years of age.CS has a broad clinical phenotype spectrum includingID, microcephaly, hypotonia, dysmorphic facial features,truncal obesity, slender extremities, joint hypermo-bility, myopia, retinal dystrophy, intermittent isolatedneutropenia, and happy personality. Neutropenia ischaracterized as a neutrophil count of <1.5 × 109/Lin children and <1.8 × 109/L in adults [16]. The facialgestalt includes down-slanting palpebral fissures, wave-shaped eyelids, thick eyebrows and eyelashes, low hairline,prominent and beak-shaped nose, malar hypoplasia, shortTable 1 Clinical phenotypes of proband, and their presence/absence among reported cases of CS and dup16p11.2Reported findings inpatientsProband’s clinicalfindingsCohensyndromedup16p11.2Pregnancy/birth Reduced fetal activity + -Low birth weight + -Feeding difficulty + -Neurocognitive DD/IDab + +ASDb + +Happy/friendlydispositiona+ -Hypotoniab + +Verbal apraxia + -Motor delayb + +Poor motor coordination + +Brisk reflexes + -Build/stature Underweightb(≤4y/o)- +Short stature + +Truncal obesitya(childhood)+ -Cranium/hair Microcephalyab(postnatal)+ +Flat occiput - -Double hair whorls - -Low hairlinea(anterior)+ +Thick haira + -Forehead/face/noseNarrow forehead + -Micrognathia/mildretrognathia+ +Malar hypoplasia + -Depressed nasal root - -Short triangular nose - -Mouth/oralregionSmall mouth + -Thick upper lip + -Short/smooth philtruma + +High-arched palate + +Thickened alveolarridges- -Prominent upper centralincisors+ -Eye/eye globe/visionHypertelorism + +Ptosis (bilateral) + -Blepharophimosis - -Wave shaped eyelidsa + -Thick eyebrowa + -Long/thick eyelashesa + -Table 1 Clinical phenotypes of proband, and their presence/absence among reported cases of CS and dup16p11.2(Continued)Myopiaa + +Diffuse retinaldystrophya+ -Ears/hearing Large ears + +Posteriorly rotatedears+ +Auricular pits + +Hearing loss(unilateralsensorineural)+ -Abdomen/thorax Diastasis recti - -Hypoplastic nipples - -Extremities/musculoskeletalSlender extremities/tapered fingersa+ +Joint hypermobilitya + +Club foot (bilateral) + -Sandal gap + +Scoliosis + +Genitalia/urinarytractHypospadias - +Cryptorchidism + +Haematology/ImmunologyChronic anemia + -Recurrent infection(UTI)+ -Intermittent neutropeniaa + -aDiagnostic criteria for CSbMost observed findings among patients with dup16p11.2Dastan et al. BMC Medical Genetics  (2016) 17:78 Page 4 of 6philtrum, high-arched palate, maxillary prognathia andprominent central incisors [17–19]. Patients with CSgrimace when they are asked to smile [12, 20]. Other signsand symptoms include short stature and scoliosis [12, 20].In addition, individuals with CS have high rates of ASD orautistic features [21]. The estimated prevalence of CS is1:105,000 [22], however, its frequency may be considerablyhigher due to the fact that patients are often not diag-nosed until they reach their teenage or adult years. Theearly diagnosis of CS is challenging because facial featuresare less noticeable in pre-school age, truncal obesitymay evolve in late-childhood, neutropenia is rarelyidentified due to its intermittent pattern and absenceof clinical consequences, and diagnosis of retinal dys-trophy usually occurs in later childhood [16, 17, 20].Reverse phenotyping of our patient at 10 years of ageunequivocally confirmed a pattern of features consist-ent with CS (Table 1). Table 1 shows the presence orabsence of clinical features observed in our probandrelative to patients with CS [17, 18, 20–24], ordup16p11.2 [4, 8, 25–27].Being underweight is a known feature of dup 16p11.2.Although the proband was underweight at birth, hisweight changed with age to the 5–10th %ile at the age of10. He also developed truncal obesity with slenderextremities, mild scoliosis, and evolving facial gestaltconsistent with CS. Similar to the report by El Chehadeh-Djebbar et al. [17], our study suggests that some CSfeatures are age-dependent and evolve later in childhood(Table 2).ConclusionInherited dup16p11.2 by itself cannot explain the variableexpressivity among NDD patients when their carrierparents are unaffected. We utilized WES in a familywith a child presenting with NDD carrying dup16p11.2inherited from his unaffected mother, and searched forsequence changes that could explain this clinical varia-bility. We discovered that compound heterozygous vari-ants of VPS13B contribute to the proband’s phenotypicfeatures. The new CS diagnosis helps in screening andearlier management of scoliosis, periodontal disease andtooth loss, early cataract, vision loss, and premature aging[24] in the proband; and provides more informed geneticcounselling for the family.Our study suggests that NDD patients with dup16p11.2may show additional pathogenic SNVs in their genome,which significantly influence phenotype heterogeneityand the genetic counselling of families with putativelypathogenic CNVs showing variable expressivity andincomplete penetrance. Genomic microarray is a valuablefirst-tier test for the postnatal evaluation of individualswith NDD including ID, ASD, and/or multiple congenitalanomalies. However, coupling of microarray with WES orwhole genome data analyses will facilitate a more compre-hensive and accurate analysis of genetic causes of NDD,heighten understanding of the etiology of variableexpressivity among NDD patients, and optimize clinically-informed and effective genetic counselling and persona-lized management options.Additional fileAdditional file 1: Figure S1: Filtering strategies used for analysis of WESdata; Additional material and methods. (DOCX 83 kb)Abbreviations%ile: Percentile; ASD: Autism spectrum disorder; CNV: Copy number variation;CS: Cohen syndrome; Dup: Microduplication; ID: Intellectual disability;NDD: Neurodevelopmental disorders; NMD: Nonsense-mediated mRNAdecay; OCD: Obsessive-compulsive disorders; OFC: Occipito-frontalcircumference; qPCR: Real-time quantitative PCR; WES: Whole exomesequencingAcknowledgmentsWe would like to thank the families and the patients for their invaluablecooperation and participation.FundingThis work was supported by funding from the Canadian Institutes for HealthResearch (CIHR) (Project Number: MOP-74502), BC Children’s HospitalFoundation (Project Number: KRZ75146) and BC Child and Family ResearchInstitute (CFRI) (Project Number: 20R20410).Availability of data and materialAll relevant data are included in the manuscript and Additional file 1.Authors’ contributionSML and ERS designed and initiated the study, monitored data collectionand analysis for the study and revised the paper. JD contributed to the studydesign, analysed both clinical and WES data, implemented the technical methods,drafted and revised the paper. CC contributed to family recruitment, samplecollection and genetic counselling. FT and YQ helped with utilizing Goldenhelix software. SM helped with technical parts. All authors read and approvedthe final manuscript.Competing interestsThe authors declare that they have no competing interests.Consent for publicationConsent for publication of respective case presentations was obtained foreach participant.Table 2 Evolving clinical features of probandEvolving features 4y/o 10y/oWeight <3rd %ile 5–10th %ileOval face No YesTruncal obesity No YesDown-slanting, wavy palpebral fissures No YesShort and smooth philtrum No YesLong slender distal extremities/fingers No YesSpine abnormality No YesDastan et al. BMC Medical Genetics  (2016) 17:78 Page 5 of 6Ethics approval and consent to participateThe family was recruited through the B.C. Provincial Medical GeneticsProgram and Child & Family Research Institute of BC Children’s andWomen’s Health Center. Ethics approval for clinical research involvinghuman subjects was obtained through the Clinical Research Ethics Boardof the University of British Columbia (Vancouver, B.C.). Samples fromanonymized unaffected male and female individuals were used ascontrols for expression studies. Written informed consents were obtainedfrom each participant.Author details1Department of Medical Genetics, Children’s and Women’s Health Center ofBC and Children’s and Women’s Health Center of BC and Univeristy of BritishColumbia, Vancouver, BC V6H 3N1, Canada. 2Department of Pathology(Cytogenetics), Children’s and Women’s Hopsital of BC and Children’s andWomen’s Health Center of BC and Univeristy of British Columbia, Vancouver,BC V5Z 4H4, Canada. 3BC Children’s Hospital Research Institute, Vancouver,BC V6H 3N1, Canada.Received: 3 May 2016 Accepted: 20 October 2016References1. 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Brain MRI abnormalities and spectrumof neurological and clinical findings in three patients with proximal 16p11.2microduplication. Am J Med Genet A. 2014;164A(8):2003–12.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Dastan et al. BMC Medical Genetics  (2016) 17:78 Page 6 of 6

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