RESEARCH ARTICLE Ptosis as a unique hallmark for autosomal recessive WNT1-associated osteogenesis imperfecta Sheela Nampoothiri 1 | Brecht Guillemyn 2 | Nursel Elcioglu 3,4 | Sujatha Jagadeesh 5 | Dhanya Yesodharan 1 | Beena Suresh 5 | Serap Turan 6 | Sofie Symoens 2 | Fransiska Malfait 2 1 Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Cochin, Kerala, India 2 Department of Biomolecular Medicine, Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium 3 Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey 4 Department of Medicine, Eastern Mediterranean University Medical School, Mersin, Turkey 5 Department of Clinical Genetics, Mediscan Systems, Chennai, Tamil Nadu, India 6 Department of Pediatric Endocrinology, Marmara University Medical School, Istanbul, Turkey Correspondence Sheela Nampoothiri, Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, AIMS Ponekkara PO, Cochin 682041, Kerala, India. Email: sheelanampoothiri@aims.amrita.edu and Fransiska Malfait, Center for Medical Genetics, Ghent University Hospital, 0K5, Corneel Heymanslaan 10, 9000 Ghent, Belgium. Email: fransiska.malfait@ugent.be Funding information Research Foundation Flanders , Grant/Award Number: 1842318N; Universitair Ziekenhuis Gent, Grant/Award Number: 08/01M01108 Osteogenesis imperfecta (OI) is a heritable connective tissue disorder, mainly characterized by bone fragility and low bone mass. Defects in the type I procollagen-encoding genes account for the majority of OI, but increasingly more rare autosomal recessive (AR) forms are being identi- fied, which are caused by defects in genes involved in collagen metabolism, bone mineralization, or osteoblast differentiation. Bi-allelic mutations in WNT1 have been associated with a rare form of AR OI, characterized by severe osteoporosis, vertebral compression, scoliosis, fractures, short stature, and variable neurological problems. Heterozygous WNT1 mutations have been linked to autosomal dominant early-onset osteoporosis. In this study, we describe the clinical and molecu- lar findings in 10 new patients with AR WNT1-related OI. Thorough revision of the clinical symp- toms of these 10 novel patients and previously published AR WNT1 OI cases highlight ptosis as a unique hallmark in the diagnosis of this OI subtype. KEYWORDS collagen, osteogenesis imperfecta, ptosis, WNT1 1 | INTRODUCTION Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that is mainly characterized by bone fragility with multiple fractures and variable short stature. Extraskeletal manifestations include blue sclerae, dentinogenesis imperfecta, hearing impairment, easy bruising, and joint hypermobility. The phenotypic spectrum of OI ranges from mild forms with only few fractures, to severe and even perinatal lethal forms (Forlino & Marini, 2016; Kang, Aryal, & Marini, 2017; Marini et al., 2017). The majority of OI cases are inherited in an autosomal dominant (AD) manner and are caused by heterozygous mutations in either COL1A1 or COL1A2, the genes encoding the major fibrillar type I (pro)collagen (Kang et al., 2017). With the exception of IFITM5 (AD inheritance, function in bone mineralization), mutations in non- collagen genes are associated with autosomal recessive (AR) forms of OI, which are nowadays categorized based on the cellular pathways in which their molecular functions are executed: involvement in bone mineralization (SERPINF1), collagen modification (CRTAP, P3H1, and PPIB), collagen processing and cross-linking (SERPINH1, FKBP10, PLOD2, and BMP1), and osteoblast differentiation and function (SP7, TMEM38B, WNT1, CREB3L1, and SPARC; Forlino & Marini, 2016; Kang Sheela Nampoothiri and Brecht Guillemyn contributed equally to this study, Nursel Elcioglu and Sujatha Jagadeesh contributed equally to this study. Received: 19 October 2018 Revised: 7 February 2019 Accepted: 15 February 2019 DOI: 10.1002/ajmg.a.61119 Am J Med Genet. 2019;1–7. wileyonlinelibrary.com/journal/ajmga © 2019 Wiley Periodicals, Inc. 1 brought to you by CORE View metadata, citation and similar papers at core.ac.uk provided by Ghent University Academic Bibliography