Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects

Background: Goltz syndrome (GS) is a X-linked disorder defined by defects of mesodermal- and ectodermal-derived structures and caused by PORCN mutations. Features include striated skin-pigmentation, ocular and skeletal malformations and supernumerary or hypoplastic nipples. Generally, GS is associated with in utero lethality in males and most of the reported male patients show mosaicism (only three non-mosaic surviving males have been described so far). Also, precise descriptions of neurological deficits in GS are rare and less severe phenotypes might not only be caused by mosaicism but also by less pathogenic mutations suggesting the need of a molecular genetics and functional work-up of these rare variants. Results: We report two cases: one girl suffering from typical skin and skeletal abnormalities, developmental delay, microcephaly, thin corpus callosum, periventricular gliosis and drug-resistant epilepsy caused by a PORCN nonsense-mutation (c.283C > T, p.Arg95Ter). Presence of these combined neurological features indicates that CNS-vulnerability might be a guiding symptom in the diagnosis of GS patients. The other patient is a boy with a supernumerary nipple and skeletal anomalies but also, developmental delay, microcephaly, cerebral atrophy with delayed myelination and drug-resistant epilepsy as predominant features. Skin abnormalities were not observed. Genotyping revealed a novel PORCN missense-mutation (c.847G > C, p.Asp283His) absent in the Genome Aggregation Database (gnomAD) but also identified in his asymptomatic mother. Given that non-random X-chromosome inactivation was excluded in the mother, fibroblasts of the index had been analyzed for PORCN protein-abundance and -distribution, vulnerability against additional ER-stress burden as well as for protein secretion revealing changes. Conclusions: Our combined findings may suggest incomplete penetrance for the p.Asp283His variant and provide novel insights into the molecular etiology of GS by adding impaired ER-function and altered protein secretion to the list of pathophysiological processes resulting in the clinical manifestation of GS.Open Access funding enabled and organized by Projekt DEAL. We gratefully acknowledge the financial support by the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen and the Bundesministerium für Bildung und Forschung. This work was also supported by a Grant of the French Muscular Dystrophy Association (AFM-Téléthon) (#21466) to AR. Parts of this study were financed in the framework of the NME-GPS project by the European Regional Development Fund (ERDF). The project is supported by TUBITAK (The Scientific and Technological Research Council of Turkey) Project No. 216S771. RH was supported by the European Research Council [309548], the Wellcome Investigator Award [109915/Z/15/Z]. The Medical Research Council (UK) [MR/N025431/1]; the Wellcome Trust Pathfinder Scheme [201064/Z/16/Z], the Newton Fund [UK/Turkey, MR/N027302/1], the Lily Foundation and the Evelyn Trust. Sequencing and analysis of patient 2 were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute Grant UM1 HG008900 and in part by National Human Genome Research Institute Grant R01 HG009141. Sequencing of patient 1 was carried out through the Biobanking and Biomedical Resources Research Infrastructure ‐ large prospective cohorts (BBMRI‐LPC) 2016 access call for Whole Exome Sequencing (FP7/2007‐2013), Grant Number: 313010. Data was analyzed using the RD‐Connect Genome‐Phenome Analysis platform developed under FP7/2007‐2013 funded project, Grant Number: 305444. HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). The study was further supported by the Horizon 2020 research and innovation program via Grant 779257 “Solve-RD” (RH and HL). USS, RH and HL are members of the European Reference Network for Rare Neuromuscular Diseases (EURO-NMD). YO is supported by the Turkish Academy of Sciences’ Young Investigator Award (TÜBA-GEBIP)