Glycosylphosphatidylinositols (GPIs) anchor over 150 proteins as GPI-anchored proteins (GPI-APs) with crucial roles in diverse biological processes. The highly conserved biosynthesis of GPI-APs involves precise steps with at least 21 genes, categorized as PIG and PGAP genes. Pathogenic variants in these genes are linked to human diseases, highlighting the importance of each biosynthesis step. PGAP2 stands out among these genes due to its association with an expanded clinical spectrum of neurodevelopmental disorder (NDD) phenotypes with biallelic pathogenic variants. We present four patients from two families, one consanguineous and the other nonconsanguineous, each displaying distinct clinical presentations, including intellectual disability, hyperphosphatasia, hearing impairment, and epilepsy, as well as craniofacial and digital anomalies. Genetic analyses revealed homozygous and novel compound heterozygous missense variants in PGAP2 in four affected individuals, confirming the molecular diagnosis of hyperphosphatasia with impaired intellectual development syndrome 3 (HPMRS3). Importantly, the three amino acids affected by missense variants exhibit complete conservation in 10 vertebrate species, illuminating their crucial role in the gene’s functionality. Protein modeling provided additional evidence for the pathogenicity of the three substitutions, demonstrating their detrimental impact on protein folding and putative protein-protein interactions, ultimately leading to impaired protein function. The four patients in our study displayed common phenotypic features, such as brachydactyly, camptodactyly, and syndactyly, which have not been previously documented in individuals with PGAP2 variants. Notably, the occurrence of macrocephaly in two affected brothers from a consanguineous Pakistani family represents a novel finding. These previously unreported digital anomalies, along with macrocephaly and the identification of novel compound heterozygous variants, contribute to the expansion of the phenotypic and genotypic spectrum of HPMRS3 associated with PGAP2 variants.

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12. Our study comprises 34 novel mutations in ABCA12, expanding the mutational spectrum of ABCA12-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI.

Einleitung Ärztinnen und Ärzte verfügen im Vergleich zu nichtärztlichen Patientinnen und Patienten über ein umfangreicheres Fachwissen sowie einen erleichterten Zugang zu Leistungen des Gesundheitssystems. Im anglistischen Sprachraum existieren spezifische Empfehlungen für Ärztinnen und Ärzte zum Umgang mit eigener psychischer wie physischer Gesundheit und Krankheit. Derartige Empfehlungen liegen in Deutschland nicht vor.

We report on a young patient with a bicuspid aortic valve operated on for type A acute aortic dissection because of a blunt thoracic trauma. Aortic root replacement and ascending aortic and total arch repair together with the postoperative course were uneventful. Multigenerational genetic analyses revealed mutations in the NOTCH1 and ACTA2 genes in the patient and his father. The screening of his parents and children revealed no bicuspid aortic valve or aortic root dilation. This exceptionally rare case of double-hit mutations and the presence of blunt trauma reveals the complex etiology of aortic dissection in patients with a bicuspid aortic valve. (C) 2021 by The Society of Thoracic Surgeons

Concomitant Loeys-Dietz syndrome (LDS) and hematologic malignancies are exceptionally rare. This is the first report of a patient operated on for aortic root dilation who had been previously diagnosed with LDS and B-cell-lymphoma. After completion of chemotherapy and complete remission, an elective valve-sparing aortic root replacement (using the David-V method) was performed. Due to the positive family history, pre-operative genetic counseling was conducted, and revealed LDS with a TGFBR1 (transforming growth factor beta receptor type I) mutation in 6 probands of the family, albeit in 1 of them posthumously. This missense mutation has been previously described in relation to aortic dissection, but a causative relationship to malignancy has so far neither been proposed nor proven.

Objective The study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy. Methods Through diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding. Results Biallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype. Conclusions These data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling.

Variants in DONSON were recently identified as the cause of microcephaly, short stature, and limb abnormalities syndrome (MISSLA). The clinical spectra of MISSLA and Fanconi anaemia (FA) strongly overlap. For that reason, some MISSLA patients have been clinically diagnosed with FA. Here, we present the clinical data of siblings with MISSLA featuring a novel DONSON variant and summarize the current literature on MISSLA. Additionally, we perform computer-aided image analysis using the DeepGestalt technology to test how distinct the facial features of MISSLA and FA patients are. We show that MISSLA has a specific facial gestalt. Notably, we find that also FA patients feature facial characteristics recognizable by computer-aided image analysis. We conclude that computer-assisted image analysis improves diagnostic precision in both MISSLA and FA.

We report 2 cases of girls with MECP2 gene variants who do not have typical clinical features of Rett syndrome except for intellectual disability and seizures. Both patients present with adipositas, macrocephalia, precocious puberty, and seizures. They have prominent eyebrows and a short neck as well as short and plump fingers. Sequencing by NGS revealed a novel variant c.1162_1172del; p.Pro388* in both patients.

INTRODUCTION:Next-generation sequencing in cases of hereditary neuromuscular disorders often yields multiple candidate gene variants. Here, we describe a case with mutations in two genes, lamin A/C (LMNA) and exostosin glycosyltransferase 2 (EXT2), which led to hereditary myopathy combined with multiple exostoses. CASE HISTORY:A 51-year-old German woman with a history of removal of multiple exostoses during childhood presented with proximal limb-girdle muscular dystrophy and a newly diagnosed cardiomyopathy with atrioventricular conduction block. Because her younger son had exostoses and her younger brother had died at age 44 after heart transplantation due to dilated cardiomyopathy, an autosomal dominant inheritance was suspected. RESULTS:Muscle biopsy revealed features of chronic myopathy associated with focal myofibrillar disintegration. Electron microscopy showed myonuclear, myofibrillar, and Z-disc alterations, accumulations of granulofilamentous material, and a large sporadic osmiophilic inclusion body reminiscent of a nemaline body. Mendeliome and Sanger sequencing detected both a c.1129>T LMNA mutation of known pathogenicity and a c.1101_1102delAG (E368Kfs*18) truncating EXT2 mutation in the patient and her affected son. DISCUSSION:The clinical, genetic, and muscle biopsy findings suggest that both mutations are pathogenic. The EXT2 mutation was most likely responsible for the multiple exostoses phenotype in mother and son, whereas the myopathy was probably caused by a combined effect of the LMNA and EXT2 mutations.

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 16, Issue 3 p. 348-350 Clinical Letter Buschke-Ollendorff-Syndrom mit einer neuartigen LEMD3-Mutation – Der Fall einer ungewöhnlichen Alopezie Susanne Darr-Foit, Corresponding Author Susanne Darr-Foit susanne.darr-foit@med.uni-jena.de Klinik für Hautkrankheiten, Universitätsklinikum Jena Korrespondenzanschrift Susanne Darr-Foit Klinik für Hautkrankheiten Universitätsklinikum Jena Erfurter Straße 35 07743 Jena E-mail: susanne.darr-foit@med.uni-jena.deSearch for more papers by this authorSibylle Schliemann, Sibylle Schliemann Klinik für Hautkrankheiten, Universitätsklinikum JenaSearch for more papers by this authorSolveig Schulz, Solveig Schulz Institut für Humangenetik, Universitätsklinikum JenaSearch for more papers by this authorPeter Elsner, Peter Elsner Klinik für Hautkrankheiten, Universitätsklinikum JenaSearch for more papers by this author Susanne Darr-Foit, Corresponding Author Susanne Darr-Foit susanne.darr-foit@med.uni-jena.de Klinik für Hautkrankheiten, Universitätsklinikum Jena Korrespondenzanschrift Susanne Darr-Foit Klinik für Hautkrankheiten Universitätsklinikum Jena Erfurter Straße 35 07743 Jena E-mail: susanne.darr-foit@med.uni-jena.deSearch for more papers by this authorSibylle Schliemann, Sibylle Schliemann Klinik für Hautkrankheiten, Universitätsklinikum JenaSearch for more papers by this authorSolveig Schulz, Solveig Schulz Institut für Humangenetik, Universitätsklinikum JenaSearch for more papers by this authorPeter Elsner, Peter Elsner Klinik für Hautkrankheiten, Universitätsklinikum JenaSearch for more papers by this author First published: 14 March 2018 https://doi.org/10.1111/ddg.13446_gAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume16, Issue3March 2018Pages 348-350 RelatedInformation

Recently, variants in DONSON have been reported to cause different disorders of the microcephalic primordial dwarfism spectrum. Using whole-exome sequencing, we identified two novel, compound heterozygous DONSON variants in a pair of siblings, one of whom was previously diagnosed with Fanconi anemia. This occurred because the present cases exhibited clinical findings in addition to those of the microcephalic primordial dwarfism disorder, including severe limb malformations. These findings suggest that the DONSON and Fanconi anemia proteins could have supplementary roles in developmental processes as they have in the maintenance of genomic integrity, resulting in related disease phenotypes.

Buschke-Ollendorff syndrome (BOS) (OMIM 166700) is an autosomal dominant connective tissue disorder that was first described in 1928 by Abraham Buschke and Helene Ollendorff-Curth. It is defined by the coexistence of connective tissue nevi and osteopoikilosis with a good prognosis. Skin and skeletal lesions may occur independently [1–3] since affected persons may not express the full phenotype. Here we describe the unusual case of a 60-year-old woman with isolated nevus elasticus and a mutation in the LEMD3 (LEM Domain Containing 3) gene. The patient presented after years of failed topical treatment with external corticosteroids. She reported a hairless area at the occiput with a history of 25 years, and a second lesion nearby that appeared two years ago. The lesions were asymptomatic but she noticed a slight increase in the size of both areas. She also reported bone pain in the large joints and the lower legs. Her first-degree relatives did not report a history of similar lesions or bone diseases. Physical examination showed a triangular, completely hairless yellowish atrophic plaque with a diameter of 10 cm (Figure 1) at the occiput and a similar lesion nearby with a diameter of 4 cm. The lesions had no hair follicle apertures or signs of inflammation, even at the margins. There were no other conspicuous findings at the time of examination. Several causes for scarring alopecia were considered in the differential diagnosis, including lupus erythematosus, scleroderma, lichen planopilaris, pseudopelade of Brocq, skin tumors, nevus elasticus and nevus mucinosus. The antinuclear antibody titer was positive (1 : 500, homogenous and nucleolar pattern, IgG), but test results were negative for autoantibody detection using FEIA (fluorescence enzyme immunoassay) (Scl70, CENP, ds-DNA, CCP) as well as Borrelia serology and the blood glucose profile. Histological workup of two skin biopsies (center and margin) of the more recent lesion stained with hematoxylin-eosin, resorcin-fuchsin and alcian blue showed orthokeratosis and pseudopelade without inflammatory changes, but clearly increased and coarsened elastic fibers in the dermis without evidence of mucin (Figure 2). The biopsy from the margin showed a decreased quantity of hair follicles with perifollicular fibrosis, but no hair follicles were seen in the center. Computed tomography revealed a missing external lamina of the occipital bone underlying the affected skin. Recent radiographs of the spine, hands and feet revealed no foci of fibrosis or sclerosis but evidence of degenerative changes. Based on these findings we suspected Buschke-Ollendorff syndrome (BOS). BOS lesions may have predominantly elastic-type nevi (juvenile elastoma) or predominantly collagen-type nevi (dermatofibrosis lenticularis disseminata) [4–6]. Patients present with skin-colored or yellowish papules, nodules or plaques, which may appear in symmetrical or asymmetrical configurations at any age, but in childhood in the majority of cases [5]. In this context, studies have reported loss of function mutations in the LEMD3 gene [6], which expresses inner Figure 1 Triangular, completely hairless yellowish plaque with a diameter of 10 cm on the occiput of a 60-year-old woman.

We report on a patient operated on for degenerative myxomatous mitral and tricuspid valve disease (Barlow's disease) and aortic root dilatation. A valve repair operation and the postoperative course were uneventful. Multigenerational genetic analyses revealed two different mutations in the transforming growth factor beta-2 gene in the same patient. The two mutations in different exons were inherited from both parents each. None of the parents presented with either valve dysfunction or aortic root dilatation. This rare case illustrates potentially common genetic and signaling pathways of concomitant myxomatous valve disease and aortic root dilatation.

We present a case of a 26-year-old female patient with bloating, post-prandial nausea and recurrent vomiting after solid food intake. A gastric emptying scintigraphy showed a delayed gastric emptying, defining gastroparesis. Because of her past medical history of short stature and pulmonary stenosis, we initiated genetic counseling where the diagnosis of Noonan syndrome was made. Dietary therapy and medication with domperidone quickly led to relief of the discomfort due to gastroparesis. However, prokinetics are not indicated for long-term therapy, as cardiac arrhythmia may occur. A risk-benefit assessment should be done. There are several novel approaches which need to be further investigated.

OBJECTIVES Genetic defects associated with bicuspid aortopathy have been infrequently analysed. Our goal was to examine the prevalence of rare genetic variants in patients with a bicuspid aortic valve (BAV) with a root phenotype using next-generation sequencing technology. METHODS We investigated a total of 124 patients with BAV with a root dilatation phenotype who underwent aortic valve ± proximal aortic surgery at a single institution (BAV database, n  = 812) during a 20-year period (1995-2015). Cross-sectional follow-up revealed 63 (51%) patients who were still alive and willing to participate. Systematic follow-up visits were scheduled from March to December 2015 and included aortic imaging as well as peripheral blood sampling for genetic testing. Next-generation sequencing libraries were prepared using a custom-made HaloPlex HS gene panel and included 20 candidate genes known to be associated with aortopathy and BAV. The primary end-point was the prevalence of genetic defects in our study cohort. RESULTS A total of 63 patients (mean age 46 ± 10 years, 92% men) with BAV root phenotype and mean post-aortic valve replacement follow-up of 10.3 ± 4.9 years were included. Our genetic analysis yielded a wide spectrum of rare, potentially or likely pathogenic variants in 19 (30%) patients, with NOTCH1 variants being the most common ( n  = 6). Moreover, deleterious variants were revealed in AXIN1 ( n  = 3), NOS3 ( n  = 3), ELN ( n  = 2), FBN1 ( n  = 2) , FN1 ( n  = 2) and rarely in other candidate genes. CONCLUSIONS Our preliminary study demonstrates a high prevalence and a wide spectrum of rare genetic variants in patients with the BAV root phenotype, indicative of the potentially congenital origin of associated aortopathy in this specific BAV cohort.

Einleitung: Das Fryns Syndrom, Erstbeschreibung 1979, ist eine seltene Differentialdiagnose des Pallister-Kilian-Syndroms (sporadische Mosaiktetrasomie Chr. 12 p), dessen Leitsymptom die Zwerchfellhernie (meist als Bochdalek-Hernie links) in wechselnder Kombination mit weiteren, schweren Fehlbildungen aller Organsysteme ist. Das familiäre Auftreten legt ein autosomal-rezessives Erbmuster nahe, während die exakte genetische Ursache bisher nicht bekannt ist. Insgesamt sind in der Literatur knapp > 110 Fälle beschrieben, wobei etwas mehr als 80 3 von 5 der zusätzlichen Kerncharakteristika aufwiesen: kraniofaziale Dysmorphien, LKGS, Lungenhypoplasie mit fehlender Lobulierung, zystische Nierendysplasien und andere Organfehlbildungen, z.B. Herz, Gehirn, und distale Extremitätenfehlbildungen.

X-linked intellectual disability (XLID) is a genetically heterogeneous disorder with more than 100 genes known to date. Most genes are responsible for a small proportion of patients only, which has hitherto hampered the systematic screening of large patient cohorts. We performed targeted enrichment and next-generation sequencing of 107 XLID genes in a cohort of 150 male patients. Hundred patients had sporadic intellectual disability, and 50 patients had a family history suggestive of XLID. We also analysed a sporadic female patient with severe ID and epilepsy because she had strongly skewed X-inactivation. Target enrichment and high parallel sequencing allowed a diagnostic coverage of >10 reads for ~96% of all coding bases of the XLID genes at a mean coverage of 124 reads. We found 18 pathogenic variants in 13 XLID genes ( AP1S2 , ATRX, CUL4B, DLG3 , IQSEC2 , KDM5C , MED12 , OPHN1 , SLC9A6 , SMC1A, UBE2A, UPF3B and ZDHHC9 ) among the 150 male patients. Thirteen pathogenic variants were present in the group of 50 familial patients (26%), and 5 pathogenic variants among the 100 sporadic patients (5%). Systematic gene dosage analysis for low coverage exons detected one pathogenic hemizygous deletion. An IQSEC2 nonsense variant was detected in the female ID patient, providing further evidence for a role of this gene in encephalopathy in females. Skewed X-inactivation was more frequently observed in mothers with pathogenic variants compared with those without known X-linked defects. The mutation rate in the cohort of sporadic patients corroborates previous estimates of 5–10% for X-chromosomal defects in male ID patients.

Recent studies on the pathogenic mechanisms of recessive hyperekplexia indicate disturbances in glycine receptor (GlyR) α1 biogenesis. Here, we examine the properties of a range of novel glycine receptor mutants identified in human hyperekplexia patients using expression in transfected cell lines and primary neurons. All of the novel mutants localized in the large extracellular domain of the GlyR α1 have reduced cell surface expression with a high proportion of receptors being retained in the ER, although there is forward trafficking of glycosylated subpopulations into the ER-Golgi intermediate compartment and cis-Golgi compartment. CD spectroscopy revealed that the mutant receptors have proportions of secondary structural elements similar to wild-type receptors. Two mutants in loop B (G160R, T162M) were functional, but none of those in loop D/β2-3 were. One nonfunctional truncated mutant (R316X) could be rescued by coexpression with the lacking C-terminal domain. We conclude that a proportion of GlyR α1 mutants can be transported to the plasma membrane but do not necessarily form functional ion channels. We suggest that loop D/β2-3 is an important determinant for GlyR trafficking and functionality, whereas alterations to loop B alter agonist potencies, indicating that residues here are critical elements in ligand binding.

Prenatal DiagnosisVolume 32, Issue 10 p. 1016-1018 Research Letter Prenatal diagnosis of hypoplastic left heart syndrome associated with Noonan Syndrome and de novo RAF1 mutation Solveig Schulz, Corresponding Author Solveig Schulz Center for Human Genetics, Jena University Hospital, Jena, Germany Solveig Schulz. E-mail: [email protected]Search for more papers by this authorRosemarie Fröber, Rosemarie Fröber Institute of Anatomy, Jena University Hospital, Jena, GermanySearch for more papers by this authorCornelia Kraus, Cornelia Kraus Institute of Human Genetics, University Erlangen, GermanySearch for more papers by this authorUwe Schneider, Uwe Schneider Clinic of Obstetrics and Gynecology, Jena University Hospital, Jena, GermanySearch for more papers by this author Solveig Schulz, Corresponding Author Solveig Schulz Center for Human Genetics, Jena University Hospital, Jena, Germany Solveig Schulz. E-mail: [email protected]Search for more papers by this authorRosemarie Fröber, Rosemarie Fröber Institute of Anatomy, Jena University Hospital, Jena, GermanySearch for more papers by this authorCornelia Kraus, Cornelia Kraus Institute of Human Genetics, University Erlangen, GermanySearch for more papers by this authorUwe Schneider, Uwe Schneider Clinic of Obstetrics and Gynecology, Jena University Hospital, Jena, GermanySearch for more papers by this author First published: 23 July 2012 https://doi.org/10.1002/pd.3938Citations: 9 Funding sources: None Conflicts of interest: None declared Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1 Allen RH, Benson CB, Haug LW. Pregnancy outcome of fetuses with a diagnosis of hypoplastic left ventricle on prenatal sonography. J Ultrasound Med 2005; 24(9): 1199–203. 2 Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 2010; 126(4): 746–59. 3 Lee BH, Kim JM, Jin HY, Kim GH, Choi JH, Yoo HW. Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. J Pediatr 2011; 159(6): 1029–35. 4 Bakker M, Pajkrt E, Mathijssen IB, Bilardo CM. Targeted ultrasound examination and DNA testing for Noonan syndrome, in fetuses with increased nuchal translucency and normal karyotype. Prenat Diagn 2011; 31: 833–40. 5 Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 2007; 39(8): 1007–12. 6 Antonelli D, Antonelli J, Rosenfeld T. Noonan's syndrome associated with hypoplastic left heart. Cardiology 1990; 77(1): 62–5. 7 Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet 2007; 39(8): 1013–7. Citing Literature Volume32, Issue10October 2012Pages 1016-1018 ReferencesRelatedInformation