Two Novel Cases with PIGQ-CDG: Expansion of the Genotype-Phenotype Spectrum and Evaluation of GestaltMatcher as a Diagnostic Tool

Katarína Kušíková^1*Tzung-Chien Hsieh²Mateja Pfeifer³Christine Fauth⁴Yoshiko Murakami⁵Franco Laccone³Daniela Karall⁶Walter Bonfig⁷Helen Stewart⁸Denisa Weis⁹

• ¹Department of Pediatric Neurology, Medical School, Comenius University and National Institute of Children's Diseases, Bratislava, Slovakia, Bratislava, Slovakia
• ²Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-University Bonn, Germany, Bonn, Germany
• ³Institute of Medical Genetics, Medical University of Vienna, Austria, Vienna, Austria
• ⁴Institute of Human Genetics, Medical University of Innsbruck, Austria, Innsbruck, Austria
• ⁵Laboratory of Immunoglycobiology, Research Institute for microbial diseases, Osaka University, Japan, Osaka, Japan
• ⁶Department of Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Austria, Innsbruck, Austria
• ⁷Department of Pediatrics, Klinikum Wels-Grieskirchen, Wels, Austria, Wels, Austria
• ⁸Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, UK, Oxford, United Kingdom
• ⁹Department of Medical Genetics, Kepler University Hospital, School of Medicine, Johannes Kepler University, Linz, Austria, Linz, Austria

Introduction: The glycosylphosphatidylinositol (GPI)-anchor is a glycolipid that anchors proteins to the eucaryotic cell surface. An anchoring process is a posttranslational modification of at least 150 molecules with various functions. Biallelic causal variants in the PIGQ gene (OMIM: * 605754) are associated with the type of disorder of glycosylphosphatidylinositol biosynthesis PIGQ-CDG, called also Multiple congenital anomalies-hypotonia-seizures syndrome 4 (MCAHS4, OMIM: # 618548). Only 11 patients with this condition have been published so far. Methods: We present two novel cases of MCAHS4 with one novel and one already known variant in the PIGQ gene, detailed phenotyping, and a review of all published cases so far. For deep gestalt analysis, we used GestaltMatcher and investigated its potential use in diagnosing MCAHS4 patients. Results: In the PIGQ gene, we found one novel frameshift variant c.1092dupC, p.(Phe365LeufsTer78) and one missense c.1370T>G, p.(Leu457Arg) already listed in the ClinVar database as a VUS, which pathogenicity we proved by a functional study on Chinese hamster ovarian cells. After reviewing all 13 already diagnosed MCAHS4 patients, we found that attacks of rhabdomyolysis induced by a febrile infection were documented only in our patient. Facial dysmorphism (coarse features, anteverted nares, and open mouth) seen in all analyzed MCAHS4 patients seems to be specific. Moreover, GestaltMatcher proved that MCAHS4 patients shared a similar facial phenotype. Discussion: The present work expands the genotype spectrum by describing a novel causal PIGQ variant and validation of pathogenicity of an already-known VUS variant. Because of their life-threatening complications, attacks of rhabdomyolysis should be considered in MCAHS4 patients. GestaltMatcher can be an effective tool in the diagnostic setting of MCAHS4.