Delineating the expanding phenotype associated with SCAPER gene mutation R E S E A R C H L E T T E R Delineating the expanding phenotype associated with SCAPER gene mutation James Fasham1,2 | Gavin Arno3,4 | Siying Lin1 | Mingchu Xu5,6 | Keren J. Carss7,8 | Sarah Hull3,4 | Amelia Lane3 | Anthony G. Robson3,4 | Olivia Wenger9 | Jay E. Self10 | Gaurav V. Harlalka1 | Claire G. Salter1 | Lynn Schema11 | Timothy J. Moss12 | Michael E. Cheetham3 | Anthony T. Moore3,4,13 | F. Lucy Raymond8,14 | Rui Chen5,6 | Emma L. Baple1,2 | Andrew R. Webster3,4 | Andrew H. Crosby1 | NIHR Bioresource Rare Diseases Consortium8 1Medical Research, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom 2Peninsula Clinical Genetics Service, Royal Devon and Exeter Hospital (Heavitree), Exeter, United Kingdom 3UCL Institute of Ophthalmology, University College London, London, United Kingdom 4Moorfields Eye Hospital, London, United Kingdom 5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 6Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 7Department of Haematology, NHS Blood and Transplant Centre, University of Cambridge, Cambridge, United Kingdom 8NIHR BioResource – Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom 9New Leaf Center, Clinic for Special Children, Mount Eaton, Ohio 10Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom 11Division of Genetics and Metabolism, University of Minnesota Medical Center – Fairview, Minneapolis, Minnesota 12Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 13Ophthalmology Department, UCSF School of Medicine, Koret Vision Centre, San Francisco, California 14Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom Correspondence Andrew Crosby and Emma Baple, Medical Research, RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, United Kingdom. Emails: a.h.crosby@exeter.ac.uk, e.baple@exeter.ac.uk Andrew R. Webster, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom. Email: andrew.webster@ucl.ac.uk Funding information Fight for Sight UK, Grant/Award Numbers: 1511/1512 to AL, 2027 to ELB AHC, Early Career Investigator award to GA; Foundation Fighting Blindness; Medical Research Council, Grant/Award Numbers: G1001931 to ELB, G1002279 to AHC; Moorfields Eye Charity; National Centre for the Replacement, Refinement and Reduction of Animals in Research, Grant/Award Number: to AL; National Institute for Health Research, Grant/Award Numbers: Academic Clinical Fellowship to JF, NIHR BioResource - Rare Diseases project RG65966; Newlife Foundation for Disabled Children, Grant/Award Number: to AC EB; Retina UK; University of Exeter, Grant/Award Number: Vice Chancellor Scholarship to SL K E Y W O R D S : Brachydactyly, CCNA2–CDK2, Intellectual disability, Retinitis pigmentosa, SCAPER Received: 13 March 2019 Revised: 1 May 2019 Accepted: 5 May 2019 DOI: 10.1002/ajmg.a.61202 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2019 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc. Am J Med Genet. 2019;1–7. wileyonlinelibrary.com/journal/ajmga 1 https://orcid.org/0000-0002-7614-9202 https://orcid.org/0000-0002-6165-7888 https://orcid.org/0000-0003-1122-8396 https://orcid.org/0000-0002-6637-3411 https://orcid.org/0000-0001-6915-9560 mailto:a.h.crosby@exeter.ac.uk mailto:e.baple@exeter.ac.uk mailto:andrew.webster@ucl.ac.uk http://creativecommons.org/licenses/by/4.0/ http://wileyonlinelibrary.com/journal/ajmga A potential role for the cyclin A2–cyclin-dependent kinase 2 complex regulator S-phase cyclin A-associated protein residing in the endoplas- mic reticulum (SCAPER) in human disease was first suggested by Najmabadi et al. (2011), who identified a candidate homozygous frameshift SCAPER variant as the cause of nonsyndromic intellectual disability (ID) in a small Iranian family. We subsequently reported a single patient with biallelic loss of function (LOF) SCAPER variants associated with retinal disease (Carss et al., 2017). Biallelic LOF vari- ants have since been associated with ID with or without retinitis pigmentosa (RP) in seven individuals from five families from Spain, Israel, and Iran (Hu et al., 2018; Tatour et al., 2017); in one individual from a Jordanian Arab family, a homozygous SCAPER gene variant was identified as the cause of nonsyndromic RP (Jauregui et al., 2019). More recently, Wormser et al. (2019) described a SCAPER gene variant associated with a Bardet–Biedl syndrome (BBS)-like presenta- tion comprising of ID, RP, short stature, obesity, and brachydactyly in eight individuals from two consanguineous Bedouin families belonging to the same tribe in southern Israel, alongside preliminary functional studies suggesting a possible role for SCAPER in ciliary dynamics and disassembly. In the current study, we describe clinical and genetic findings, including seven novel SCAPER variants, in six individuals of Amish, Caucasian, and South Asian descent. Together with our molec- ular data, our comprehensive phenotypic assessments enable a more detailed clinical comparison to be drawn between the patient cohort described here (including previously published individual G001284; Patient 3 in this study, (Carss et al., 2017) with the 17 individuals in whom SCAPER variants were recently defined (Hu et al., 2018; Jauregui et al., 2019; Najmabadi et al., 2011; Tatour et al., 2017; Wormser et al., 2019), permitting a more precise definition of the clin- ical phenotype arising from pathogenic SCAPER variation. Samples were taken with informed consent (study approved by the Ethics Committee of Akron Children's Hospital, Moorfields Eye Hospital and Baylor College of Medicine, in compliance with the Declaration of Helsinki) for deoxyribonucleic acid (DNA) extraction. Single nucleotide polymorphism (SNP) genotyping was performed (Patients 1 and 2) using the HumanCytoSNP-12 v2.1 beadchip array (Illumina, Cambridge, UK). In Patients 1 and 3–5, whole exome or whole genome sequencing (WES or WGS), variant alignment, calling, filtering, and prioritization was performed as previously described (Carss et al., 2017; Rawlins et al., 2019; Xu et al., 2015). Allele-specific primers were designed using Primer3 web software to evaluate segre- gation of the candidate SCAPER gene variants identified via dideoxy sequencing. Patient 6 underwent WES at GeneDx and was identified via GeneMatcher (Sobreira, Schiettecatte, Valle, & Hamosh, 2015) as part of the Matchmaker Exchange Repositories (Philippakis et al., 2015). All variants identified in the study have been submitted to Clin- Var (https://www.ncbi.nlm.nih.gov/clinvar/). Patients 1 and 2 are Ohio Amish siblings. Candidate variants identi- fied through WES of DNA from Patient 1 were cross-referenced with regions of autozygosity common to both affected siblings, identified through whole genome SNP genotyping. This identified only a single plausible candidate variant, located within the largest (18 Mb) shared region of autozygosity on chromosome 15 (rs1509805–rs4243078; chr15(GRCh38):g. 60281446-78374545), a novel homozygous duplica- tion in Exon 18 of the SCAPER gene, predicted to result in a frame- shift (NM_020843.2: c.2236dupA, p.(Ile746Asnfs*6) Chr15(GRCh38): g.76705914dupT; Figure 1). Dideoxy sequencing confirmed the pres- ence and co-segregation of this variant in both siblings. This variant was detected in heterozygous form in five unrelated individuals in a data- base of 116 regional Amish controls, corresponding to an estimated allele frequency of ~0.04, not uncommon for founder mutations within this population. WES/WGS performed in Patients 3–6, identified com- pound heterozygous SCAPER variants; c.1116delT, p.(Val373Serfs*21) (Chr15(GRCh38):g.76771874delA) and c.2179C>T, p.(Arg727*) (Chr15 (GRCh38):g. 76705971G>A) in Patient 3, c.1495+1G>A (Chr15(GRCh38): g.76765562C>T) and c.3224delC, p.(Pro1075Glnfs*11) (Chr15(GRCh38): g.76434165delG) in Patient 4, c.829C>T, p.(Arg277*) (Chr15(GRCh38):g. 76775061G>A) and c.3707_3708delCT, p.(Ser1236Tyrfs*28) (Chr15 (GRCh38):g.76376309_ 76376310delAG) in Patient 5, and c.2377C>T, p. (Gln793*) (Chr15(GRCh38):g.76702873G>A) and c.2166-3C>G (Chr15 (GRCh38):g.76705987G>C) in Patient 6. The SCAPER variants in each of these patients were confirmed to be biallelic by familial segregation analy- sis using dideoxy sequencing. None of these variants are present in the genome aggregation (gnomAD) or 1,000 genomes databases and those in Patients 1, 2, and 4–6 are novel. Table 1 summarizes the core phenotypical features of individuals not previously reported, aged between 18 months and 31 years (Patients 1, 2, and 4–6), provides additional clinical details for Patient 3 (Carss et al., 2017), and compares these to the clinical features of all SCAPER syndrome patients described to date. ID and developmental delay was present in all six affected individuals, and four patients also exhibited hyperactivity and attention deficit hyperactivity disorder (ADHD). Autism and dyspraxia were each noted in one individual. Neuroimaging performed in Patients 1, 3, 5, and 6 revealed no abnor- malities. Additional dysmorphic features noted in both Amish siblings (Patients 1 and 2) included inverted nipples, brachydactyly, camptodactyly, proximally placed thumbs (Figure 1), and a characteris- tic facial appearance with frontal bossing and almond-shaped eyes; growth parameters were all normal. Patients 1, 3, and 4–6 all pres- ented between the ages of 10–23 with a reduction in night vision and visual field deficits; Patient 2 (18 months) described no visual symp- toms at the time of presentation. Fundus examination in Patients 3–6 revealed findings typical of RP including optic disc pallor, attenuated retinal vessels and intraretinal mid-peripheral bone-spicule pigmenta- tion, and loss of photoreceptor outer segments with retained central macular structure on optical coherence tomography imaging (Figure 1; Table S1). Additional variable ocular features described in some patients with SCAPER syndrome include cataracts (in two individuals) and myopia and keratoconus in one individual each. Our clinical and genetic studies in six affected individuals, includ- ing additional new clinical details for Patient 3, (Carss et al., 2017) take the total number of SCAPER syndrome patients described to date to 23. Although the extent for which clinical data is available for the pre- viously reported patients is variable, our detailed clinical phenotyping allows a more comprehensive clinical comparison to be made with the previously reported cases, confirming the presence of a variable 2 FASHAM ET AL. https://www.ncbi.nlm.nih.gov/clinvar/ pattern of dysmorphic features associated with SCAPER syndrome. It is now clear that the cardinal clinical features of the disorder include mild/moderate ID and developmental delay particularly affecting speech and language and motor milestones. Hyperactivity appears to be a common feature, with some affected individuals receiving a for- mal diagnosis of ADHD. Early adult onset RP is also a key clinical find- ing, and the retinal phenotype appears remarkably consistent. In all individuals for whom we have data, progressive loss of night vision begins in first or second decade of life. Together with studies in mice demonstrating expression of SCAPER in multiple retinal layers, partic- ularly in the retinal pigment epithelium and photoreceptor inner and outer segments, this supports a role for SCAPER in photoreceptor function and/or maintenance (Tatour et al., 2017). Tapering fingers, brachydactyly and proximally placed thumbs, described in eight individuals from two consanguineous Bedouin fami- lies of the same tribe in southern Israel, were also identified as a con- sistent feature in the two Amish siblings, confirming the association of this feature with the SCAPER syndrome. Short stature and obesity were also a common feature amongst the affected Bedouin patients, and this constellation of clinical features including RP, obesity, short stature, ID, developmental delay, and brachydactyly has consequently led to a suggested diagnosis of BBS in these individuals. Although there is some overlap between the clinical features characteristic of ciliopathies and those seen in SCAPER syndrome, the Amish siblings (who are of normal height and weight for age) demonstrate that the digital, retinal, and cognitive abnormalities may occur independently of short stature and obesity. The other common primary features of BBS, including renal anomalies, postaxial polydactyly, hypogonadism (males), and genital abnormalities (females) have not been reported in association with SCAPER mutation (Forsythe & Beales, 2013). The dysmorphic facial features and inverted nipples, noted on examination of both Amish siblings, have not been previously noted in other indi- viduals with SCAPER variants. Recently, a single individual homozygous for a c.2023-2A>G SCAPER variant presenting with nonsyndromic RP and no evidence of ID was reported in this journal (Jauregui et al., 2019). The same c.2023-2A>G SCAPER gene variant has also been reported previ- ously in association with RP, ADHD, and mild ID (Tatour et al., 2017) indicating the variability in the presence and severity of the extraocular features associated with the SCAPER syndrome FIGURE 1 (a) Simplified pedigree of the Amish family investigated, with electropherograms showing the SCAPER c.2236dupT sequence variant in all affected and unaffected individuals in generations VI and VII (black arrow identifies the duplicated nucleotide). (b) Pictorial representation of the single nucleotide polymorphism (SNP) genotypes across the ~18.1 Mb chromosome 15q21-22 region identified in this family. (c–j) Clinical features of SCAPER syndrome patients. (c, d) Brachydactyly, camptodactyly, and proximally placed thumbs identified on examination of patient 1. (e, f) ocular imaging and investigations from patient 3 illustrating features of RP (e: Right eye, f: Left eye) fundus photograph (Optos plc, Dunfermline, UK) showing optic disc pallor, attenuated retinal vessels and mid-peripheral bone spicule pigmentation (g: Right eye, h: Left eye) FAF imaging showing mid-peripheral hypoautofluorescence with a central ring of hyperautofluorescence demarcating the surviving outer retinal structures. (i: Right eye, j: Left eye) optical coherence tomography (Spectralis-OCT, Heidelberg Engineering, Heidelberg, Germany) of the central retina demonstrating loss of photoreceptor outer segments with retained central macular structure corresponding to FAF findings. FAF, fundus autofluorescence; OCT, optical coherence tomography; SCAPER, S-phase cyclin A-associated protein residing in the endoplasmic reticulum FASHAM ET AL. 3 T A B L E 1 A co m p ar is o n o f cl in ic al fi n d in g s o f al la ff e ct e d in d iv id u al s w it h b ia lle lic p at h o g e n ic S C A P E R v ar ia n ts G e n o ty p e E th n ic it y S e x A g e (y e ar s) a W e ig h t (k g ,S D S ) H e ig h t (c m ,S D S ) O F C (c m ,S D S ) B M I (S D S ) W al k e d (m o n th s) S p e e ch d e la y ID B e h av io r is su e s A b n o rm al n e u ro im ag in g R P B ra ch y d ac ty ly O th e r cl in ic al fi n d in g s N aj m ab ad i p .(T y r1 1 8 fs *) /p . (T y r1 1 8 fs *) Ir an N A N A N A N A N A N A N A N A ✓ N A N A N A N A N A T at o u r (A :I I: 1 ) c. 2 0 2 3 -2 A > G / c. 2 0 2 3 -2 A > G A ra b F 2 4 N A N A N A N A N o rm al N A M ild (I Q 6 4 ) A D H D M R I: N o rm al ✓ N A N il T at o u r (A :I I: 2 ) c. 2 0 2 3 -2 A > G / c. 2 0 2 3 -2 A > G A ra b F 2 3 N A N A N A N A N o rm al N A M ild (I Q 5 6 ) A D H D N A ✓ N A N il T at o u r (B :I I: 1 ) p .(I le 9 9 1 fs *) / p .(I le 9 9 1 fs *) S p an is h F 3 4 N A N A N A N A 2 4 N A M o d N o n e re p o rt e d C T : N o rm al ✓ N A A lo p e ci a ar e at a T at o u r (C :I I: 4 ) p .(G lu 6 2 0 d e l)/ p .(S e r1 2 1 9 A sn ) S p an is h M 1 5 N A N A N A N A D e la y e d N A ✓ N o n e re p o rt e d N A ✓ N A N A H u (f am ily 1 6 6 ; 3 in d iv id u al s) p .(A rg 1 2 0 *) / p .(A rg 1 2 0 *) B al o ch N A N A N A N A N o rm al N A N A N A ✓ N A N A N A N A N A Ja u re g u i c. 2 0 2 3 -2 A > G / c. 2 0 2 3 -2 A > G A ra b M 1 1 N A N A N A N A N A N A N o N o N P ✓ N A N A W o rm se r (P 1 :V 5 ) p .(L e u 9 3 6 *) / p .(L e u 9 3 6 *) B e d o u in F 3 4 7 8 (+ 1 .9 ) 1 4 5 (− 3 .1 ) N o t re d u ce d 3 7 .1 (+ 3 .1 ) N A ✓ M o d N A N P ✓ ✓ G e n u v al g u m /g e n u v ar u m W o rm se r (P 1 :V 6 ) p .(L e u 9 3 6 *) / p .(L e u 9 3 6 *) B e d o u in M 2 8 7 8 (+ 0 .7 ) 1 5 7 (− 3 .1 ) N o t re d u ce d 3 1 .6 (+ 2 .3 ) N A ✓ M o d N A N P ✓ ✓ G e n u v al g u m /g e n u v ar u m W o rm se r (P 1 :V 7 ) p .(L e u 9 3 6 *) / p .(L e u 9 3 6 *) B e d o u in M 2 4 9 8 (+ 2 .2 ) 1 6 3 (− 2 .2 ) N o t re d u ce d 3 6 .9 (+ 3 .0 ) N A ✓ M o d N A N P ✓ ✓ G e n u v al g u m /g e n u v ar u m W o rm se r (P 1 :V 8 ) p .(L e u 9 3 6 *) / p .(L e u 9 3 6 *) B e d o u in M 1 7 9 2 (+ 2 .2 ) 1 5 5 (− 2 .9 ) N o t re d u ce d 3 8 .3 (+ 3 .3 ) N A ✓ M o d N A N P ✓ ✓ G e n u v al g u m /g e n u v ar u m W o rm se r (P 2 :I II 1 ) p .(L e u 9 3 6 *) / p .(L e u 9 3 6 *) B e d o u in F 4 8 8 6 .6 (+ 2 .5 ) 1 4 6 (− 3 .0 ) N o t re d u ce d 4 0 .6 (+ 3 .5 ) N A ✓ S e v N A N P ✓ ✓ N il W o rm se r (P 2 :I II 2 ) p .(L e u 9 3 6 *) / p .(L e u 9 3 6 *) B e d o u in F 4 7 6 2 (+ 0 .4 ) 1 4 9 (− 2 .5 ) N o t re d u ce d 2 7 .9 (+ 1 .6 ) N A ✓ S e v N A N P ✓ ✓ G e n u v al g u m /g e n u v ar u m W o rm se r (P 2 :I II 7 ) p .(L e u 9 3 6 *) / p .(L e u 9 3 6 *) B e d o u in F 2 9 5 7 .8 (+ 0 .1 ) 1 3 2 (− 5 .2 ) N o t re d u ce d 3 3 .2 (+ 2 .8 ) N A ✓ S e v N A N P ✓ ✓ N il W o rm se r (P 2 :I V 1 ) p .(L e u 9 3 6 *) / p .(L e u 9 3 6 *) B e d o u in M 1 0 2 9 .5 (− 0 .3 8 ) 1 2 9 (− 1 .5 ) N o t re d u ce d 1 7 .7 (+ 0 .7 ) N A ✓ M o d A D H D M R I: ab n o rm al b S u sp e ct e d ✓ G e n u v al g u m /g e n u v ar u m P at ie n t 1 p .(I le 7 4 6 fs *) / p .(I le 7 4 6 fs *) A m is h M 1 3 .7 6 8 .9 (+ 1 .9 ) 1 6 6 .3 (+ 0 .7 ) 5 6 .4 (+ 0 .3 9 ) 2 4 .9 (+ 2 .0 ) 2 4 ✓ M o d H y p e ra ct iv it y M R I: N o rm al N o ✓ P ro xi m al ly p la ce d th u m b s. S h o rt fi ft h fi n g e rs ,p e s p la n u s, fr o n ta lb o ss in g , al m o n d -s h ap e d e y e s, an d in v e rt e d n ip p le s P at ie n t 2 p .(I le 7 4 6 fs *) / p .(I le 7 4 6 fs *) A m is h F 1 .5 8 .6 (− 2 .2 ) 7 8 .5 (− 0 .7 ) 4 7 (− 0 .9 2 ) 1 4 (− 2 .5 ) 2 2 ✓ M ild H y p e ra ct iv it y N P N A (a g e ) ✓ P ro xi m al ly p la ce d th u m b s, sh o rt fi ft h fi n g e rs ,p e s p la n u s, fr o n ta lb o ss in g , al m o n d -s h ap e d e y e s, an d in v e rt e d n ip p le s (C o n ti n u e s) 4 FASHAM ET AL. T A B L E 1 (C o n ti n u e d ) G e n o ty p e E th n ic it y S e x A g e (y e ar s) a W e ig h t (k g ,S D S ) H e ig h t (c m ,S D S ) O F C (c m ,S D S ) B M I (S D S ) W al k e d (m o n th s) S p e e ch d e la y ID B e h av io r is su e s A b n o rm al n e u ro im ag in g R P B ra ch y d ac ty ly O th e r cl in ic al fi n d in g s P at ie n t 3 c (G C 1 7 2 0 6 ) p .(A rg 7 2 7 *) / p .(V al 3 7 3 fs *) S o u th A si an F 2 8 2 5 th ce n ti le 3 rd ce n ti le N A N A 1 1 ✓ M o d A D H D , au ti sm , an d se lf - h ar m M R I: N o rm al ✓ N A N il P at ie n t 4 (G C 1 5 5 7 2 ) c. 1 4 9 5 + 1 G > A / p .(P ro 1 0 7 5 fs *) C au ca si an F 3 1 N A N A 5 7 (9 5 th ce n ti le ) N A 1 5 ✓ M ild D y sp ra xi a N P ✓ N A N il P at ie n t 5 p .(A rg 2 7 7 *) /p . (S e r1 2 3 6 fs *) N A (U n it e d S ta te s) F 1 7 N A N A N A O b e se N A N A ✓ N A M R I: N o rm al ✓ N A N il P at ie n t 6 p .(G ln 7 9 3 *) / c. 2 1 6 6 -3 C > G N A (U n it e d S ta te s) F 2 4 6 3 .6 (+ 0 .6 ) 1 6 2 .6 (− 0 .2 ) N A 2 4 (+ 0 .6 3 ) 1 5 – 1 8 Y e s M ild (I Q 5 0 – 6 0 s) A D H D M R I: N o rm al ✓ N A M o d e ra te e cz e m a w it h se v e re sk in -p ic k in g b e h av io r S u m m ar y 8 /1 2 o b e se 1 2 /1 2 2 0 /2 1 8 /1 1 A ll n o rm al 1 6 /1 7 1 0 /1 0 A b b re v ia ti o n s: A D H D ,a tt e n ti o n -d e fi ci t h y p e ra ct iv it y d is o rd e r; B M I, b o d y m as s in d e x; C T ,c o m p u te ri ze d to m o g ra p h y ; F ,f e m al e ; ID ,i n te lle ct u al d is ab ili ty ; IQ ,i n te lli g e n ce q u o ti e n t (W e ch sl e r A d u lt In te lli g e n ce S ca le ); M ,m al e ; M o d ,m o d e ra te ; M R I, m ag n e ti c re so n an ce im ag in g ; N A ,n o t av ai la b le ; N P ,n o t p e rf o rm e d ; O F C ,o cc ip it o fr o n ta l ci rc u m fe re n ce ; R P ,r e ti n it is p ig m e n to sa ; S D S ,s ta n d ar d d e v ia ti o n sc o re s; S e v , se v e re . N o te .A d u lt s w it h a B M I > 2 5 ar e cl as si fi e d as o v e rw e ig h t, th o se > 3 0 ar e cl as si fi e d as o b e se ; th e ✓ sy m b o li n d ic at e s th e p re se n ce o f a fe at u re in an af fe ct e d su b je ct . H e ig h t, w e ig h t, B M I an d O F C Z -s co re s w e re ca lc u la te d u si n g a M ic ro so ft E xc e l ad d -i n to ac ce ss g ro w th re fe re n ce s b as e d o n th e L M S m e th o d (P an & C o le ,2 0 1 2 ) u si n g a re fe re n ce E u ro p e an p o p u la ti o n (C o le , F re e m an ,& P re e ce ,1 9 9 8 ). a R e fe rs to ag e o f e xa m in at io n . b A b n o rm al M R I fi n d in g s in cl u d e m ild ly e n la rg e d la te ra l v e n tr ic le s an d se v e ra ll o ci o f ir re g u la r si g n al in th e b ra in p ar e n ch y m a ab o v e th e te n to ri u m ,i n th e p o st e ri o r w h it e m at te r an d al o n g th e e p e n d y m a. c A ls o p at ie n t G 0 0 1 2 8 4 (C ar ss e t al ., 2 0 1 7 ). FASHAM ET AL. 5 (Table 1). However, this may also be accounted for by the difficulties in conclusively defining milder developmental delay in some situa- tions, when more subtle clinical findings may not be identified if not specifically assessed. Conversely, associated ocular pathology may remain undetected or unrecognized in individuals with ID, as such individuals often have difficulty recognizing or articulating their visual symptoms. This highlights the importance of visual screening and ophthalmological assessment in these patients. Other common ocular features include cataracts (in particular posterior subcapsular cataracts, which are commonly associated with RP; (Pruett, 1983) and strabismus, with nystagmus and keratoconus noted in a single patient. The high incidence of cataracts, a potentially treatable cause of sight loss, again supports the case for screening in early childhood. The allele frequency (~0.04) of the Ohio Amish SCAPER founder mutation suggests that, despite no previous reports, this disorder represents an underrecognized cause of RP and mild ID within this community. This further highlights the importance of careful clinical evaluation in children and adults with ID and enables targeted genetic testing for this SCAPER variant for Amish individuals with this clinical presentation. Together with our clinical review of all previ- ously published patients, this study expands the molecular spectrum of disease-causing SCAPER variants and enables a clearer delineation of the core (and variable) phenotypical features of SCAPER syndrome to be characterized. Our findings also highlight the importance of prompt visual screening and ophthalmic assessment in all individuals with SCAPER-associated disease. Despite the increasing numbers of individuals identified with SCAPER syndrome, the precise functions of SCAPER in human growth and development are not fully under- stood. Further studies to elucidate the precise molecular and devel- opmental roles of this molecule in human growth and skeletal, retinal, and brain development and function, will yield important insights into the clinical heterogeneity increasingly observed in SCAPER-associated disease. ACKNOWLEDGMENTS First and foremost, we would like to thank the patients and their fami- lies for their participation in and support of this study. We thank Kirsty McWalter at GeneDx (GeneMatcher and Matchmaker Exchange). This work was supported by the Medical Research Council (MRC Grants G1001931 to ELB and G1002279 to AHC). This paper presents inde- pendent research funded by the National Institute for Health Research (NIHR) through the NIHR BioResource – Rare Diseases project [grant number RG65966] and NIHR Academic Clinical Fellowship to J.F.) The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Fight For Sight (Grants 1511/1512 to A. L., 2027 to E. L. B. and A. H. C., and Early Career Investigator award to G. A.), Newlife Foundation for Dis- abled Children (grant to E. L. B. and A. H. C.). Further support was pro- vided by NIHR Biomedical Centre of UCL Institute of Ophthalmology and Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, The Foundation Fighting Blindness (United States), and Retina UK. S. L. is supported by the University of Exeter Vice Chancellor Scholarship and F. L. R. is supported by Cam- bridge NIHR Biomedical Research Centre and National Centre for the Replacement Refinement and Reduction of Animals in Research (NC3Rs). AUTHOR CONTRIBUTIONS J. F., G. A., S.L. contributed equally to this work. E. L. B., A .R. W., and A. H. C. contributed equally to this work. ORCID James Fasham https://orcid.org/0000-0002-7614-9202 Gavin Arno https://orcid.org/0000-0002-6165-7888 Siying Lin https://orcid.org/0000-0003-1122-8396 Emma L. Baple https://orcid.org/0000-0002-6637-3411 Andrew R. Webster https://orcid.org/0000-0001-6915-9560 REFERENCES Carss, K. J., Arno, G., Erwood, M., Stephens, J., Sanchis-Juan, A., Hull, S., … Raymond, F. L. (2017). Comprehensive rare variant analysis via whole- genome sequencing to determine the molecular pathology of inherited retinal disease. American Journal of Human Genetics, 100(1), 75–90. https://doi.org/10.1016/j.ajhg.2016.12.003 Cole, T. J., Freeman, J. V., & Preece, M. A. (1998). 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Am J Med Genet Part A. 2019;1–7. https://doi. org/10.1002/ajmg.a.61202 FASHAM ET AL. 7 https://doi.org/10.1038/s41431-018-0306-0 https://doi.org/10.1038/s41431-018-0306-0 https://doi.org/10.1002/humu.22844 https://doi.org/10.1002/humu.22844 https://doi.org/10.1136/jmedgenet-2017-104632 https://doi.org/10.1136/jmedgenet-2017-104632 https://doi.org/10.1038/s41431-019-0347-z https://doi.org/10.1038/s41431-019-0347-z https://doi.org/10.1167/iovs.15-16778 https://doi.org/10.1167/iovs.15-16778 https://doi.org/10.1002/ajmg.a.61202 https://doi.org/10.1002/ajmg.a.61202 Delineating the expanding phenotype associated with SCAPER gene mutation ACKNOWLEDGMENTS AUTHOR CONTRIBUTIONS REFERENCES