@article{f23b3eb2039244f5b3116cf9bd52f0f0,
title = "Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations",
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",
author = "Hughes, {Joel J.} and Ebba Alkhunaizi and Paul Kruszka and Pyle, {Louise C.} and Grange, {Dorothy K.} and Berger, {Seth I.} and Payne, {Katelyn K.} and Diane Masser-Frye and Tommy Hu and Christie, {Michelle R.} and Clegg, {Nancy J.} and Everson, {Joshua L.} and Martinez, {Ariel F.} and Walsh, {Laurence E.} and Emma Bedoukian and Jones, {Marilyn C.} and Harris, {Catharine Jean} and Riedhammer, {Korbinian M.} and Daniela Choukair and Fechner, {Patricia Y.} and Rutter, {Meilan M.} and Hufnagel, {Sophia B.} and Maian Roifman and Kletter, {Gad B.} and Emmanuele Delot and Eric Vilain and Lipinski, {Robert J.} and Vezina, {Chad M.} and Maximilian Muenke and David Chitayat",
note = "Funding Information: We thank the families for their participation in this publication. This work was supported by the National Human Genome Research Institute Intramural Research program. Work in the R.J.L. lab was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health (NIH) under award numbers R01ES026819 and T32ES007015. Work in the CMV lab was supported by NIH grant U01DK110807. E.D. E.V. M.R. and P.F. are supported in part by the Disorder of Sex Development Translational Research Network (R01 HD093450). The DSD whole-genome sequencing project was funded by the Gabriella Miller Kids First Initiative (XO1HL132384, E.V.). We are grateful for the help of Linda Ramsdell, MS, CGC (Seattle Children's Hospital) and Kimberly Kennedy, RN (Cincinnati Children's Hospital) for individuals 11 and 12. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the NIH, and by the National Cancer Institute (NCI), the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/10/19. Funding Information: We thank the families for their participation in this publication. This work was supported by the National Human Genome Research Institute Intramural Research program. Work in the R.J.L. lab was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health ( NIH ) under award numbers R01ES026819 and T32ES007015 . Work in the CMV lab was supported by NIH grant U01DK110807 . E.D., E.V., M.R., and P.F. are supported in part by the Disorder of Sex Development Translational Research Network ( R01 HD093450 ). The DSD whole-genome sequencing project was funded by the Gabriella Miller Kids First Initiative ( XO1HL132384 , E.V.). We are grateful for the help of Linda Ramsdell, MS, CGC (Seattle Children{\textquoteright}s Hospital) and Kimberly Kennedy, RN (Cincinnati Children{\textquoteright}s Hospital) for individuals 11 and 12. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the NIH , and by the National Cancer Institute ( NCI ), the National Human Genome Research Institute ( NHGRI ), the National Heart, Lung, and Blood Institute ( NHLBI ), the National Institute on Drug Abuse ( NIDA ), the National Institute of Mental Health ( NIMH ), and the National Institute of Neurological Disorders and Stroke ( NINDS ). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/10/19. Publisher Copyright: {\textcopyright} 2019",
year = "2020",
month = jan,
day = "2",
doi = "10.1016/j.ajhg.2019.12.004",
language = "English",
volume = "106",
pages = "121--128",
journal = "American journal of human genetics",
issn = "0002-9297",
number = "1",
}