An ACVR1R375P pathogenic variant in two families with mild fibrodysplasia ossificans progressiva

Frederick S Kaplan; Jay C Groppe; Meiqi Xu; O Will Towler; Eduardo Grunvald; Kenneth Kalunian; Staci Kallish; Mona Al Mukaddam; Robert J Pignolo; Eileen M Shore

doi:10.1002/ajmg.a.62585

An ACVR1^R375P pathogenic variant in two families with mild fibrodysplasia ossificans progressiva

Am J Med Genet A. 2022 Mar;188(3):806-817. doi: 10.1002/ajmg.a.62585. Epub 2021 Dec 2.

Authors

Frederick S Kaplan^{1

2

3}, Jay C Groppe⁴, Meiqi Xu^{1

3}, O Will Towler^{1

3}, Eduardo Grunvald⁵, Kenneth Kalunian⁶, Staci Kallish^{3

7}, Mona Al Mukaddam^{1

2

3}, Robert J Pignolo⁸, Eileen M Shore^{1

3

9}

Affiliations

¹ Department of Orthopaedic Surgery, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
² Department of Medicine, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³ The Center for Research in FOP & Related Disorders, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴ Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, Texas, USA.
⁵ Division of General Internal Medicine, The Department of Medicine, The University of California San Diego, San Diego, California, USA.
⁶ Division of Rheumatology, Allergy and Immunology, The Department of Medicine, UC San Diego School of Medicine, La Jolla, California, USA.
⁷ Division of Translational Medicine and Human Genetics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ The Department of Medicine, The Mayo Clinic, Rochester, Minnesota, USA.
⁹ Department of Genetics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 34854557
DOI: 10.1002/ajmg.a.62585

Abstract

Genetic variants are vital in informing clinical phenotypes, aiding physical diagnosis, guiding genetic counseling, understanding the molecular basis of disease, and potentially stimulating drug development. Here we describe two families with an ultrarare ACVR1 gain-of-function pathogenic variant (codon 375, Arginine > Proline; ACVR1^R375P ) responsible for a mild nonclassic fibrodysplasia ossificans progressiva (FOP) phenotype. Both families include people with the ultrarare ACVR1^R375P variant who exhibit features of FOP while other individuals currently do not express any clinical signs of FOP. Thus, the mild ACVR1^R375P variant greatly expands the scope and understanding of this rare disorder.

Keywords: ACVR1; activin receptor-like kinase 2 (ALK2); bone morphogenetic protein signaling; fibrodysplasia ossificans progressiva (FOP); heterotopic ossification.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activin Receptors, Type I / genetics
Humans
Mutation
Myositis Ossificans* / diagnosis
Myositis Ossificans* / genetics
Myositis Ossificans* / pathology
Phenotype

Substances

ACVR1 protein, human
Activin Receptors, Type I