A Novel Homozygous Variant in a Patient with a Glycosylphosphatidylinositol Biosynthesis Defect

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2023 Jul 29

PMID 37510348

Authors

Paolo Fontana

Alberto Budillon

Domenico Simeone

Francesca Del Vecchio Blanco

Martina Caiazza

Alessandra DAmico

Fortunato Lonardo

Vincenzo Nigro

Giuseppe Limongelli

Gioacchino Scarano

Affiliations

Soon will be listed here.

Abstract

Glycosylphosphatidylinositol biosynthesis defect 15 is a rare autosomal recessive disorder due to biallelic loss of function of GPAA1. At the moment, less than twenty patients have been reported, usually compound heterozygous for GPAA1 variants. The main clinical features are intellectual disability, hypotonia, seizures, and cerebellar atrophy. We describe a 4-year-old male with a novel, homozygous variant. The patient presents with typical features, such as developmental delay, hypotonia, seizures, and atypical features, such as macrocephaly, preauricular, and cheek appendages. When he was 15 months, the cerebellum was normal. When he was 33 months old, after the molecular diagnosis, magnetic resonance imaging was repeated, showing cerebellar atrophy. This case extends the clinical spectrum of the GPAA1-related disorder and helps to delineate phenotypic differences with defects of other subunits of the transamidase complex.

References

Kinoshita T . Biosynthesis and biology of mammalian GPI-anchored proteins. Open Biol. 2020; 10(3):190290. PMC: 7125958. DOI: 10.1098/rsob.190290. View

Nguyen T, Murakami Y, Sheridan E, Ehresmann S, Rousseau J, St-Denis A . Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia. Am J Hum Genet. 2017; 101(5):856-865. PMC: 5673666. DOI: 10.1016/j.ajhg.2017.09.020. View

Beleza-Meireles A, Hart R, Clayton-Smith J, Oliveira R, Falcao Reis C, Venancio M . Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients. Eur J Med Genet. 2015; 58(9):455-65. DOI: 10.1016/j.ejmg.2015.07.003. View

Nguyen T, Murakami Y, Wigby K, Baratang N, Rousseau J, St-Denis A . Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy. Am J Hum Genet. 2018; 103(4):602-611. PMC: 6174287. DOI: 10.1016/j.ajhg.2018.08.014. View

Efthymiou S, Dutra-Clarke M, Maroofian R, Kaiyrzhanov R, Scala M, Reza Alvi J . Expanding the phenotype of PIGS-associated early onset epileptic developmental encephalopathy. Epilepsia. 2021; 62(2):e35-e41. PMC: 7898547. DOI: 10.1111/epi.16801. View

Castle A, Salian S, Bassan H, Sofrin-Drucker E, Cusmai R, Herman K . Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in . Neurol Genet. 2021; 7(6):e631. PMC: 8532669. DOI: 10.1212/NXG.0000000000000631. View

Musacchia F, Ciolfi A, Mutarelli M, Bruselles A, Castello R, Pinelli M . VarGenius executes cohort-level DNA-seq variant calling and annotation and allows to manage the resulting data through a PostgreSQL database. BMC Bioinformatics. 2018; 19(1):477. PMC: 6291943. DOI: 10.1186/s12859-018-2532-4. View

Knaus A, Kortum F, Kleefstra T, Stray-Pedersen A, dukic D, Murakami Y . Mutations in PIGU Impair the Function of the GPI Transamidase Complex, Causing Severe Intellectual Disability, Epilepsy, and Brain Anomalies. Am J Hum Genet. 2019; 105(2):395-402. PMC: 6698879. DOI: 10.1016/j.ajhg.2019.06.009. View

Li Y, Yang L, Yang J, Shi J, Chai P, Ge S . A novel variant in GPAA1, encoding a GPI transamidase complex protein, causes inherited vascular anomalies with various phenotypes. Hum Genet. 2020; 139(12):1499-1511. DOI: 10.1007/s00439-020-02192-w. View

10.

Wu T, Yin F, Guang S, He F, Yang L, Peng J . The Glycosylphosphatidylinositol biosynthesis pathway in human diseases. Orphanet J Rare Dis. 2020; 15(1):129. PMC: 7254680. DOI: 10.1186/s13023-020-01401-z. View

11.

Kinoshita T . Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology: Introduction to a Thematic Review Series. J Lipid Res. 2015; 57(1):4-5. PMC: 4689333. DOI: 10.1194/jlr.E065417. View

12.

Chang I, He M, Lam C . Congenital disorders of glycosylation. Ann Transl Med. 2019; 6(24):477. PMC: 6331365. DOI: 10.21037/atm.2018.10.45. View

13.

Nguyen T, Murakami Y, Mobilio S, Niceta M, Zampino G, Philippe C . Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy. Am J Hum Genet. 2020; 106(4):484-495. PMC: 7118585. DOI: 10.1016/j.ajhg.2020.03.001. View

14.

Kvarnung M, Nilsson D, Lindstrand A, Korenke G, Chiang S, Blennow E . A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT. J Med Genet. 2013; 50(8):521-8. DOI: 10.1136/jmedgenet-2013-101654. View

15.

Vainauskas S, Maeda Y, Kurniawan H, Kinoshita T, Menon A . Structural requirements for the recruitment of Gaa1 into a functional glycosylphosphatidylinositol transamidase complex. J Biol Chem. 2002; 277(34):30535-42. DOI: 10.1074/jbc.M205402200. View

16.

Lukacs M, Blizzard L, Stottmann R . CNS glycosylphosphatidylinositol deficiency results in delayed white matter development, ataxia and premature death in a novel mouse model. Hum Mol Genet. 2020; 29(7):1205-1217. PMC: 7206848. DOI: 10.1093/hmg/ddaa046. View