2. Academic Validation
  3. Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations

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

  • Am J Hum Genet. 2020 Jan 2;106(1):121-128. doi: 10.1016/j.ajhg.2019.12.004.
Joel J Hughes 1,  Ebba Alkhunaizi 2,  Paul Kruszka 3,  Louise C Pyle 4,  Dorothy K Grange 5,  Seth I Berger 6,  Katelyn K Payne 7,  Diane Masser-Frye 8,  Tommy Hu 1,  Michelle R Christie 9,  Nancy J Clegg 9,  Joshua L Everson 10,  Ariel F Martinez 1,  Laurence E Walsh 7,  Emma Bedoukian 4,  Marilyn C Jones 8,  Catharine Jean Harris 11,  Korbinian M Riedhammer 12,  Daniela Choukair 13,  Patricia Y Fechner 14,  Meilan M Rutter 15,  Sophia B Hufnagel 16,  Maian Roifman 2,  Gad B Kletter 17,  Emmanuele Delot 18,  Eric Vilain 18,  Robert J Lipinski 10,  Chad M Vezina 10,  Maximilian Muenke 1,  David Chitayat 2
Affiliations

Affiliations

  • 1 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, M5G 1X5, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, M5G 1X8, Canada.
  • 3 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: paul.kruszka@nih.gov.
  • 4 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 5 Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 6 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Genetic Medicine Research, Children's National Hospital, Washington, DC 20010, USA; Department of Genomics and Precision Medicine, George Washington University, Washington, DC 20037, USA.
  • 7 Division of Child Neurology, Riley Hospital for Children, Indianapolis, Indiana, 46202, USA.
  • 8 Department of Pediatrics, Division of Genetics, University of California San Diego-Rady Children's Hospital, San Diego, CA 92123, USA.
  • 9 Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
  • 10 Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA; Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • 11 Department of Pediatric Genetics, University of Missouri Medical Center, Columbia, MO 65212, USA.
  • 12 Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, Munich, 4JQ2+9Q, Germany; Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, Munich, 4JQ2+9Q, Germany.
  • 13 Division of Paediatric Endocrinology and Diabetology, University Children's Hospital, 69120 Heidelberg, Germany.
  • 14 Division of Pediatric Endocrinology, Seattle Children's Hospital, University of Washington, Seattle, WA 98105, USA.
  • 15 Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
  • 16 Rare Disease Institute, Children's National Hospital, Washington, DC 20010, USA.
  • 17 Pediatric Endocrinology, Mary Bridge Children's Hospital, Tacoma, WA 98404, USA.
  • 18 Center for Genetic Medicine Research, Children's National Hospital, Washington, DC 20010, USA; Department of Genomics and Precision Medicine, George Washington University, Washington, DC 20037, USA.
PMID: 31883643 DOI: 10.1016/j.ajhg.2019.12.004
Abstract

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.

Keywords

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

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