Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors.
PIGT-CDG, an autosomal recessive syndromic intellectual disability disorder of glycosylphosphatidylinositol (GPI) anchors, was recently described in two independent kindreds [Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3 (OMIM, #615398)]. PIGT encodes phosphatidylinositol-glycan biosynthesis class T, a subunit of the heteropentameric transamidase complex that facilitates the transfer of GPI to proteins. GPI facilitates attachment (anchoring) of proteins to cell membranes. We describe, at ages 7 and 6 years, two children of non-consanguineous parents; they had hypotonia, severe global developmental delay, and intractable seizures along with endocrine, ophthalmologic, skeletal, hearing, and cardiac anomalies. Exome sequencing revealed that both siblings had compound heterozygous variants in PIGT (NM_015937.5), i.e., c.918dupC, a novel duplication leading to a frameshift, and c.1342C > T encoding a previously described missense variant. Flow cytometry studies showed decreased surface expression of GPI-anchored proteins on granulocytes, consistent with findings in previous cases. These siblings further delineate the clinical spectrum of PIGT-CDG, reemphasize the neuro-ophthalmologic presentation, clarify the endocrine features, and add hypermobility, low CSF albumin quotient, and hearing loss to the phenotypic spectrum. Our results emphasize that GPI anchor-related congenital disorders of glycosylation (CDGs) should be considered in subjects with early onset severe seizure disorders and dysmorphic facial features, even in the presence of a normal carbohydrate-deficient transferrin pattern and N-glycan profiling. Currently available screening for CDGs will not reliably detect this family of disorders, and our case reaffirms that the use of flow cytometry and genetic testing is essential for diagnosis in this group of disorders.
Medical Genetics and Genomic Medicine Training Program, Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, USA. Electronic address: lamct@mail.nih.gov.
Christina
C
Lam
Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, USA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA.
Gretchen A
GA
Golas
Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, USA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA.
Mariska
M
Davids
Human Biochemical Genetics Section, Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, USA.
Marjan
M
Huizing
Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, USA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA.
Megan S
MS
Kane
Division of Genetics and Developmental Biology, NIGMS, NIH, Bethesda, MD, USA.
Donna M
DM
Krasnewich
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA; Human Biochemical Genetics Section, Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, USA.
May Christine V
MCV
Malicdan
Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, USA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA; Human Biochemical Genetics Section, Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, USA.
David R
DR
Adams
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA; Human Biochemical Genetics Section, Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, USA.
Thomas C
TC
Markello
Ophthalmic Genetics and Visual Function Branch, NEI, NIH, Bethesda, MD, USA.
Wadih M
WM
Zein
Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, USA.
Andrea L
AL
Gropman
Heritable Disorders Branch, NICHD, NIH, Bethesda, MD, USA.
Maya B
MB
Lodish
Section on Endocrinology & Genetics, NICHD, NIH, Bethesda, MD, USA.
Constantine A
CA
Stratakis
Hematology Service, Clinical Center, NIH, Bethesda, MD, USA.
Irina
I
Maric
Immunology Service, Clinical Center, NIH, Bethesda, MD, USA.
Sergio D
SD
Rosenzweig
Department of Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD, USA.
Eva H
EH
Baker
Medical Genetics and Genomic Medicine Training Program, Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, USA.
Carlos R
CR
Ferreira
Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR, USA.
Noelle R
NR
Danylchuk
Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR, USA.
Stephen
S
Kahler
Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR, USA.
Adolfo D
AD
Garnica
Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR, USA.
G
G
Bradley Schaefer
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA.
Cornelius F
CF
Boerkoel
Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, USA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA; Human Biochemical Genetics Section, Medical Genetics Branch, NHGRI, NIH, Bethesda, MD, USA.
William A
WA
Gahl
Office of the Clinical Director, NHGRI, NIH, Bethesda, MD, USA; NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA.
Lynne A
LA
Wolfe
D000217:Acyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002658:Developmental Disabilities / Q000378:metabolism; D005347:Fibroblasts; D016368:Frameshift Mutation; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D009123:Muscle Hypotonia / Q000378:metabolism; D020125:Mutation, Missense; D012867:Skin / Q000166:cytology
D017261:Glycosylphosphatidylinositols; D000217:Acyltransferases; C081007:COOH-terminal signal transamidase
Congenital disorder of glycosylation; Exome; Flow cytometry; Glycosylphosphatidylinositol anchor; PIGT-CDG; Phenotype