Delineating the expanding phenotype associated with SCAPER gene mutation

Author(s): Fasham, James; Arno, Gavin; Lin, Siying; Xu, Mingchu; Carss, Keren J; Hull, Sarah; Lane, Amelia; Robson, Anthony G; Wenger, Olivia; Self, Jay E; Harlalka, Gaurav V; Salter, Claire G; Schema, Lynn; Moss, Timothy J; Cheetham, Michael E; Moore, Anthony T; Raymond, F Lucy; Chen, Rui; Baple, Emma L; Webster, Andrew R; Crosby, Andrew H; NIHR Bioresource Rare Diseases Consortium

A potential role for the cyclin A2-cyclin-dependent kinase 2 complex regulator S-phase cyclin A-associated protein residing in the endoplasmic 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 variants 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 presentation 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 molecular 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 clinical 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.
Our clinical and genetic studies in six affected individuals, including 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 previously 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 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 formal diagnosis of ADHD. Early adult onset RP is also a key clinical finding, 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, particularly 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 families of the same tribe in southern Israel, were also identified as a consistent 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  Height, weight, BMI and OFC Z-scores were calculated using a Microsoft Excel add-in to access growth references based on the LMS method (Pan & Cole, 2012) using a reference European population (Cole, Freeman, & Preece, 1998 Abnormal MRI findings include mildly enlarged lateral ventricles and several loci of irregular signal in the brain parenchyma above the tentorium, in the posterior white matter and along the ependyma. c Also patient G001284 (Carss et al., 2017). (