Data Sheet 1_Two novel cases with PIGQ-CDG: expansion of the genotype–phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool.docx

IntroductionThe glycosylphosphatidylinositol (GPI) anchor is a glycolipid that anchors proteins to the eukaryotic 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 a type of disorder of glycosylphosphatidylinositol biosynthesis (PIGQ-congenital disorders of glycosylation (CDGs), also called multiple congenital anomalies-hypotonia-seizures syndrome 4 (MCAHS4, OMIM: # 618548). Only 11 patients with this condition have been reported to date.
MethodsWe 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. We used GestaltMatcher for deep gestalt analysis and investigated its potential use in diagnosing MCAHS4 patients.
ResultsIn 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 variant of uncertain significance (VUS), whose 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.
DiscussionThe present work expands the genotype spectrum by describing a novel causal PIGQ variant and validating the 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.

引言：糖基磷脂酰肌醇（glycosylphosphatidylinositol, GPI）锚是一种糖脂，可将蛋白质锚定在真核细胞表面。该锚定过程是对至少150种具有不同功能的分子进行的翻译后修饰。PIGQ基因（OMIM: *605754）的双等位致病变异与一类糖基磷脂酰肌醇生物合成障碍相关，即PIGQ相关性先天性糖基化障碍（PIGQ-congenital disorders of glycosylation, CDGs），也被称为多发性先天异常-肌张力低下-癫痫综合征4型（multiple congenital anomalies-hypotonia-seizures syndrome 4, MCAHS4, OMIM: #618548）。截至目前，全球仅报道过11例该疾病患者。
方法：本研究报道2例MCAHS4患者，其PIGQ基因分别携带1个新发变异与1个已知变异，同时对患者开展了详细的表型分析，并回顾了迄今已发表的所有相关病例。本研究使用GestaltMatcher进行深度面容表型分析，并探讨了其在MCAHS4患者诊断中的应用潜力。
结果：本研究在PIGQ基因中检出1个新发移码变异c.1092dupC，p.(Phe365LeufsTer78)，以及1个已在ClinVar数据库中登记为意义未明变异（variant of uncertain significance, VUS）的错义变异c.1370T>G，p.(Leu457Arg)；并通过中国仓鼠卵巢细胞功能实验证实了该错义变异的致病性。回顾全部13例已确诊的MCAHS4患者后发现，仅本研究的2例患者中出现了发热感染诱发的横纹肌溶解发作。所有纳入分析的MCAHS4患者均存在的面部畸形（面容粗糙、鼻孔前倾、张口状态）具有特异性。此外，GestaltMatcher分析证实MCAHS4患者具有相似的面容表型。
讨论：本研究通过报道1个新发PIGQ致病变异，并验证了1个已知意义未明变异的致病性，拓展了该疾病的基因型谱。鉴于横纹肌溶解发作可危及生命，临床对MCAHS4患者需警惕此类并发症。GestaltMatcher可作为MCAHS4临床诊断的有效辅助工具。