Inherited glycophosphatidylinositol deficiency variant database and analysis of pathogenic variants

Abstract

Background Glycophosphatidylinositol‐anchored proteins (GPI‐APs) mediate several physiological processes such as embryogenesis and neurogenesis. Germline variants in genes involved in their synthesis can disrupt normal development and result in a variety of clinical phenotypes. With the advent of new sequencing technologies, more cases are identified, leading to a rapidly growing number of reported genetic variants. With this number expected to rise with increased accessibility to molecular tests, an accurate and up‐to‐date database is needed to keep track of the information and help interpret results. Methods We therefore developed an online resource ( www.gpibiosynthesis.org ) which compiles all published pathogenic variants in GPI biosynthesis genes which are deposited in the LOVD database. It contains 276 individuals and 192 unique public variants; 92% of which are predicted as damaging by bioinformatics tools. Results A significant proportion of recorded variants was substitution variants (81%) and resulted mainly in missense and frameshift alterations. Interestingly, five patients (2%) had deleterious mutations in untranslated regions. CADD score analysis placed 97% of variants in the top 1% of deleterious variants in the human genome. In genome aggregation database, the gene with the highest frequency of reported pathogenic variants is PIGL , with a carrier rate of 1/937. Conclusion We thus present the GPI biosynthesis database and review the molecular genetics of published variants in GPI‐anchor biosynthesis genes.

Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations

“…Dyskinetic movements have been reported in a subset of patients with mutations of PIGA, PIGN, PGAP1, and PGAP3 19-22 but do not appear as a frequent finding in IGDs, according to the GPI biosynthesis disorder database. 23 In our patients, dyskinetic movements became apparent in the first months of life and progressed to spastic quadriplegia since the third year of life in the 2 patients who grew older than that age (patients 1 and 4).…”

Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature

“…Compared to other IGDs, there are more often bi-allelic nonsense and/or frameshift variants in PIGQ, but there is also increased mortality. 22 This might be because bi-allelic loss-of-function mutations in other GPI-biosynthesis genes lead to embryonic lethality, while it does not for PIGQ.…”

“…Analysis of further affected individuals may reveal a genotype‐phenotype correlation, and given that PIGQ is part of the N‐acetylglucosamine complex, the protein location of the disease‐causing variants may result in differential impact for the binding of other enzymes in the complex. Compared to other IGDs, there are more often bi‐allelic nonsense and/or frameshift variants in PIGQ , but there is also increased mortality 22 . This might be because bi‐allelic loss‐of‐function mutations in other GPI‐biosynthesis genes lead to embryonic lethality, while it does not for PIGQ .…”

Prenatal ultrasound findings associated with PIGW variants: One more piece in the FRYNS syndrome puzzle? PIGW‐related prenatal findings

“…5 Pathogenic variants in PIG/PGAP genes cause a group of clinically and genetically heterogeneous conditions, collectively known as GPI biosynthesis defects (GPIBDs), associated with a broad clinical spectrum, including ID/developmental delay, epilepsy, dysmorphic features and congenital anomalies (multiple congenital anomalies (MCA)). 6,7 In particular, biallelic variants in PIGW have been associated with GPIBD11 (OMIM #616025), an autosomal recessive disorder mainly characterized by ID, epileptic seizures and facial dysmorphisms (broad nasal bridge, anteverted nares, tented upper lip). Neonatal hypotonia, brain abnormalities (such as subarachnoid spaces enlargement and Dandy Walker malformation), behavioral disorders, recurrent infection and hyperphosphatasia have also been occasionally associated with PIGW variants [7][8][9][10] .…”