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PIGH deficiency can be associated with severe neurodevelopmental and skeletal manifestations
Author(s) -
TremblayLaganière Camille,
Kaiyrzhanov Rauan,
Maroofian Reza,
Nguyen Thi Tuyet Mai,
Salayev Kamran,
Chilton Ilana T.,
Chung Wendy K.,
Madden Jill A.,
Phornphutkul Chanika,
Agrawal Pankaj B.,
Houlden Henry,
Campeau Philippe M.
Publication year - 2021
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13877
Subject(s) - microcephaly , hypotonia , autism spectrum disorder , phenotype , speech delay , dysarthria , intellectual disability , hearing loss , global developmental delay , medicine , language delay , apraxia , psychomotor retardation , autism , neurodevelopmental disorder , genetics , pediatrics , biology , pathology , psychology , audiology , gene , language development , psychiatry , developmental psychology , alternative medicine , aphasia
Phosphatidylinositol Glycan Anchor Biosynthesis class H (PIGH) is an essential player in the glycosylphosphatidylinositol (GPI) synthesis, an anchor for numerous cell membrane‐bound proteins. PIGH deficiency is a newly described and rare disorder associated with developmental delay, seizures and behavioral difficulties. Herein, we report three new unrelated families with two different bi‐allelic PIGH variants, including one new variant p.(Arg163Trp) which seems associated with a more severe phenotype. The common clinical features in all affected individuals are developmental delay/intellectual disability and hypotonia. Variable clinical features include seizures, autism spectrum disorder, apraxia, severe language delay, dysarthria, feeding difficulties, facial dysmorphisms, microcephaly, strabismus, and musculoskeletal anomalies. The two siblings homozygous for the p.(Arg163Trp) variant have severe symptoms including profound psychomotor retardation, intractable seizures, multiple bone fractures, scoliosis, loss of independent ambulation, and delayed myelination on brain MRI. Serum iron levels were significantly elevated in one individual. All tested individuals with PIGH deficiency had normal alkaline phosphatase and CD16, a GPI‐anchored protein (GPI‐AP), was found to be decreased by 60% on granulocytes from one individual. This study expands the PIGH deficiency phenotype range toward the severe end of the spectrum with the identification of a novel pathogenic variant.