Deep-Phenotyping the Less Severe Spectrum of PIGT Deficiency and Linking the Gene to Myoclonic Atonic Seizures

Frontiers in Genetics

Artem Borovikov¹  Artem Sharkov²  Aneta Karasińska³  Maria Giżewska⁴  Wendy Mitchell⁵  Eva Morava⁶  Guido Rubboli⁷  Allan Bayat⁸  Rikke S. Møller⁸  Jan Henje Döring⁹  Steffen Syrbe⁹  Ewa Obersztyn^1,10  Paula Goldenberg^1,12  Amber Begtrup^1,13  Manuela Pendziwiat^1,15  Pia Zacher^1,16 

[1] 0Research Centre for Medical Genetics, Moscow, Russia;1Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, Moscow, Russia;2Department of Dermatology, The Nicolas Copernicus State Hospital, Koszalin, Poland;3Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University, Szczecin, Poland;4Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States;5Department of Clinical Genomics, Laboratory of Medicine and Pathology, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States;6Department of Clinical Medicine, Faculty of Medical and Health Sciences, University of Copenhagen, Copenhagen, Denmark;Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark;Department of General Pediatrics, Division of Child Neurology and Inherited Metabolic Diseases, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany;Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland;Department of Neuropediatrics, Children’s Hospital, University Medical Center Schleswig-Holstein, University of Kiel, Kiel, Germany;Division of Medical Genetics, Massachusetts General Hospital, Boston, MA, United States;GeneDx, Gaithersburg, MD, United States;Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark;Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany;The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany;

关键词: myoclonic-atonic seizures;    generalized seizures;    disease severity;    developmental delay;    glycosylphosphatidylinositol biosynthesis defects;    inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiency;   

DOI  :  10.3389/fgene.2021.663643

来源: DOAJ

【 摘 要 】

The two aims of this study were (i) to describe and expand the phenotypic spectrum of PIGT deficiency in affected individuals harboring the c.1582G>A; p.Val528Met or the c.1580A > G; p.Asn527Ser variant in either homozygous or compound heterozygous state, and (ii) to identify potential genotype-phenotype correlations and any differences in disease severity among individuals with and without the PIGT variants. The existing literature was searched to identify individuals with and without the two variants. A detailed phenotypic assessment was performed of 25 individuals (both novel and previously published) with the two PIGT variants. We compared severity of disease between individuals with and without these PIGT variants. Twenty-four individuals carried the PIGT variant Val528Met in either homozygous or compound heterozygous state, and one individual displayed the Asn527Ser variant in a compound heterozygous state. Disease severity in the individual with the Asn527Ser variant was compatible with that in the individuals harboring the Val528Met variant. While individuals without the Asn527Ser or Val528Met variant had focal epilepsy, profound developmental delay (DD), and risk of premature death, those with either of the two variants had moderate to severe DD and later onset of epilepsy with both focal and generalized seizures. Individuals homozygous for the Val528Met variant generally became seizure-free on monotherapy with antiepileptic drugs, compared to other PIGT individuals who were pharmaco-resistant. Two patients were diagnosed with myoclonic-atonic seizures, and a single patient was diagnosed with eyelid myoclonia. Our comprehensive analysis of this large cohort of previously published and novel individuals with PIGT variants broadens the phenotypical spectrum and shows that both Asn527Ser and Val528Met are associated with a milder phenotype and less severe outcome. Our data show that PIGT is a new candidate gene for myoclonic atonic epilepsy. Our genotype-phenotype correlation will be useful for future genetic counseling. Natural history studies of this mild spectrum of PIGT-related disorder may shed light on hitherto unknown aspects of this rare disorder.

【 授权许可】

Unknown