Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations


Joel J. Hughes, National Human Genome Research Institute (NHGRI)
Ebba Alkhunaizi, University of Toronto
Paul Kruszka, National Human Genome Research Institute (NHGRI)
Louise C. Pyle, The Children's Hospital of Philadelphia
Dorothy K. Grange, Washington University School of Medicine in St. Louis
Seth I. Berger, National Human Genome Research Institute (NHGRI)
Katelyn K. Payne, Riley Hospital for Children
Diane Masser-Frye, University of California, San Diego
Tommy Hu, National Human Genome Research Institute (NHGRI)
Michelle R. Christie, Texas Scottish Rite Hospital for Children
Nancy J. Clegg, Texas Scottish Rite Hospital for Children
Joshua L. Everson, University of Wisconsin-Madison
Ariel F. Martinez, National Human Genome Research Institute (NHGRI)
Laurence E. Walsh, Riley Hospital for Children
Emma Bedoukian, The Children's Hospital of Philadelphia
Marilyn C. Jones, University of California, San Diego
Catharine Jean Harris, University of Missouri
Korbinian M. Riedhammer, Klinikum rechts der Isar der Technischen Universität München
Daniela Choukair, Universitätsklinikum Heidelberg
Patricia Y. Fechner, University of Washington
Meilan M. Rutter, University of Cincinnati College of Medicine
Sophia B. Hufnagel, Childrens National Health System
Maian Roifman, University of Toronto
Gad B. Kletter, Mary Bridge Children's Hospital
Emmanuele Delot, Childrens National Health System
Eric Vilain, Childrens National Health System
Robert J. Lipinski, University of Wisconsin-Madison
Chad M. Vezina, University of Wisconsin-Madison
Maximilian Muenke, National Human Genome Research Institute (NHGRI)
David Chitayat, University of Toronto

Document Type

Journal Article

Publication Date



American Journal of Human Genetics






disorders of sex development; embryogenesis; encephalocele; facial dysmorphism; forebrain; holoprosencephaly; hypospadias; MYPT1; omphalocele; PPP1R12A


In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.

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