Heterozygous variant in WNT1 gene in two brothers with early onset osteoporosis
Christie G. Turin,
Kyu Sang Joeng,
Staci Kallish,
Anna Raper,
Stephanie Asher,
Philippe M. Campeau,
Amna N. Khan,
Mona Al Mukaddam
Affiliations
Christie G. Turin
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., 4th floor, Philadelphia, PA 19104, USA; Corresponding author.
Kyu Sang Joeng
Mckay Orthopaedic Research Laboratory and Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA 19104, USA
Staci Kallish
Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 5100 Silverstein, Philadelphia, PA 19104, USA
Anna Raper
Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 5100 Silverstein, Philadelphia, PA 19104, USA
Stephanie Asher
Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 5100 Silverstein, Philadelphia, PA 19104, USA
Philippe M. Campeau
Department of Pediatrics, University of Montreal, Montreal, QC, Canada
Amna N. Khan
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., 4th floor, Philadelphia, PA 19104, USA; Section of Endocrinology, The Corporal Michael J. Crescenz VA Medical Center, 3900 Woodland Ave, Philadelphia, PA 19104, USA
Mona Al Mukaddam
Departments of Medicine and Orthopaedic Surgery, The Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania. 3737 Market St., 3rd floor, Philadelphia, PA 19104, USA
Osteoporosis is a multifactorial disorder characterized by low bone mass and strength, leading to increased risk of fracture. The WNT pathway plays a critical role in bone remodeling by enhancing osteoblastic differentiation, which promotes bone formation, and inhibiting osteoclastic differentiation, decreasing bone resorption. Therefore, genetic alterations of this pathway will lead to impaired bone homeostasis and could contribute to varying response to treatment. We present the case of two brothers with early osteoporosis who were found to have a heterozygous variant of unknown significance in the WNT1 gene, c.1060_1061delCAinsG (p.H354Afs*39). This finding demonstrates that frameshift variants in WNT1 may also act in a dominant fashion leading to decreased bone mass.
