Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.

Fecha de publicación: 01/01/2023 Fecha Ahead of Print: 02/11/2022

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

Loong, Lucy
Tardivo, Agostina
Knaus, Alexej
Hashim, Mona
Pagnamenta, Alistair T.
Alt, Kerstin
Bohrer-Rabel, Helena
Cole, Trevor
Distelmaier, Felix
Edery, Patrick
Ferreira, Carlos R.
Jezela-Stanek, Aleksandra
Kerr, Bronwyn
Kluger, Gerhard
Krawitz, Peter M.
Kuhn, Marius
Lemke, Johannes R.
Lesca, Gaetan
Lynch, Sally Ann
Maxton, Caroline
Mierzewska, Hanna
Nicolai, Joost
Pal, Deb K.
Ploski, Rafal
Quarrell, Oliver W.
Rydzanicz, Malgorzata
Sabir, Ataf
Smigiel, Robert
Stegmann, Alexander P. A.
Stewart, Helen
Stumpel, Constance
Szczepanik, Elzbieta
Tzschach, Andreas
Wolfe, Lynne
Taylor, Jenny C.
Murakami, Yoshiko
Kinoshita, Taroh
Bayat, Allan
Kini, Usha

Grupos

Investigación Traslacional en Genética

Leader

Francisco Martínez Castellano

Abstract

PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported. METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp). RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period. CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

Datos de la publicación

ISSN/ISSNe:: 1098-3600, 1530-0366
Tipo:: Article
Páginas:: 37-48
DOI:: 10.1016/j.gim.2022.09.007
Factor de Impacto:: 2,877 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Loong, Lucy:: 1 Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom, Reino Unido.
Tardivo, Agostina:: National Center of Medical Genetics, National Administration of Health Laboratories and Institutes, National Ministry of Health, Buenos Aires, Argentina
Knaus, Alexej:: Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany
Hashim, Mona:: NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Pagnamenta, Alistair T.:: NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Alt, Kerstin:: Genetikum, Center for Human Genetics, Neu-Ulm, Germany
Caro-Llopis, Alfonso:: 6 Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain, España.
Cole, Trevor:: West Midlands Clinical Genetics Unit, Birmingham Women's and Children's NHS FT and Birmingham Health Partners, Birmingham, United Kingdom
Distelmaier, Felix:: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University, Düsseldorf, Germany
Edery, Patrick:: Department of Medical Genetics, Lyon University Hospital, Lyon, France
Jezela-Stanek, Aleksandra:: Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
Kluger, Gerhard:: Genetikum, Center for Human Genetics, Neu-Ulm, Germany
Krawitz, Peter M.:: Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany
Kuhn, Marius:: Genetikum, Center for Human Genetics, Neu-Ulm, Germany
Lemke, Johannes R.:: Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
Lesca, Gaetan:: Department of Medical Genetics, Lyon University Hospital, Lyon, France
Lynch, Sally Ann:: Department of Clinical Genetics, Children's Health Ireland (CHI) at Crumlin, Dublin, Ireland
Martinez, Francisco:: 6 Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain, España.
Maxton, Caroline:: Praxis für Neuropädiatrie, Hamburg, Germany
Mierzewska, Hanna:: Clinic of Pediatric Neurology, Institute of Mother and Child, Warsaw, Poland
Monfort, Sandra:: 6 Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain, España.
Orellana, Carmen:: Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain
Pal, Deb K.:: Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
Ploski, Rafal:: Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
Quarrell, Oliver W.:: Department of Clinical Genetics, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom
Rosello, Monica:: 6 Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain, España.
Rydzanicz, Malgorzata:: Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
Sabir, Ataf:: West Midlands Clinical Genetics Unit, Birmingham Women's and Children's NHS FT and Birmingham Health Partners, Birmingham, United Kingdom
Smigiel, Robert:: Division Pediatric Propedeutics and Rare Disorders, Department of Pediatrics, Wroclaw Medical University, Wroclaw, Poland
Stegmann, Alexander P. A.:: Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands
Stewart, Helen:: Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
Szczepanik, Elzbieta:: Clinic of Pediatric Neurology, Institute of Mother and Child, Warsaw, Poland
Tzschach, Andreas:: Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Taylor, Jenny C.:: NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Murakami, Yoshiko:: Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
Kinoshita, Taroh:: Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
Bayat, Allan:: Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Dianalund, Denmark

Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark
Kini, Usha:: Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom