Haploinsufficiency of TRIP12 causes a neurodevelopmental disorder characterized by intellectual disability associated with epilepsy, autism spectrum disorder and dysmorphic features, also named... Show moreHaploinsufficiency of TRIP12 causes a neurodevelopmental disorder characterized by intellectual disability associated with epilepsy, autism spectrum disorder and dysmorphic features, also named Clark-Baraitser syndrome. Only a limited number of cases have been reported to date. We aimed to further delineate the TRIP12-associated phenotype and objectify characteristic facial traits through GestaltMatcher image analysis based on deep-learning algorithms in order to establish a TRIP12 gestalt. 38 individuals between 3 and 66 years (F = 20, M = 18) - 1 previously published and 37 novel individuals - were recruited through an ERN ITHACA call for collaboration. 35 TRIP12 variants were identified, including frameshift (n = 15) and nonsense (n = 6) variants, as well as missense (n = 5) and splice (n = 3) variants, intragenic deletions (n = 4) and two multigene deletions disrupting TRIP12. Though variable in severity, global developmental delay was noted in all individuals, with language deficit most pronounced. About half showed autistic features and susceptibility to obesity seemed inherent to this disorder. A more severe expression was noted in individuals with a missense variant. Facial analysis showed a clear gestalt including deep-set eyes with narrow palpebral fissures and fullness of the upper eyelids, downturned corners of the mouth and large, often low-set ears with prominent earlobes. We report the largest cohort to date of individuals with TRIP12 variants, further delineating the associated phenotype and introducing a facial gestalt. These findings will improve future counseling and patient guidance. Show less
Importance Healthcare concepts for chronic diseases based on tele-monitoring have become increasingly important during COVID-19 pandemic.Objective To study the effectiveness of a novel integrated... Show moreImportance Healthcare concepts for chronic diseases based on tele-monitoring have become increasingly important during COVID-19 pandemic.Objective To study the effectiveness of a novel integrated care concept (NICC) that combines tele-monitoring with the support of a call centre in addition to guideline therapy for patients with atrial fibrillation, heart failure, or treatment-resistant hypertension.Design A prospective, parallel-group, open-label, randomized, controlled trial.Setting Between December 2017 and August 2019 at the Rostock University Medical Center (Germany).Participants Including 960 patients with either atrial fibrillation, heart failure, or treatment-resistant hypertension.Interventions Patients were randomized to either NICC (n = 478) or standard-of-care (SoC) (n = 482) in a 1:1 ratio. Patients in the NICC group received a combination of tele-monitoring and intensive follow-up and care through a call centre.Main outcomes and measures Three primary endpoints were formulated: (1) composite of all-cause mortality, stroke, and myocardial infarction; (2) number of inpatient days; (3) the first plus cardiac decompensation, all measured at 12-months follow-up. Superiority was evaluated using a hierarchical multiple testing strategy for the 3 primary endpoints, where the first step is to test the second primary endpoint (hospitalization) at two-sided 5%-significance level. In case of a non-significant difference between the groups for the rate of hospitalization, the superiority of NICC over SoC is not shown.Results The first primary endpoint occurred in 1.5% of NICC and 5.2% of SoC patients (OR: 3.3 [95%CI 1.4-8.3], p = 0.009). The number of inpatient treatment days did not differ significantly between both groups (p = 0.122). The third primary endpoint occurred in 3.6% of NICC and 8.1% of SoC patients (OR: 2.2 [95%CI 1.2-4.2], p = 0.016). Four patients died of all-cause death in the NICC and 23 in the SoC groups (OR: 4.4 [95%CI 1.6-12.6], p = 0.006). Based on the prespecified hierarchical statistical analysis protocol for multiple testing, the trial did not meet its primary outcome measure.Conclusions and relevance Among patients with atrial fibrillation, heart failure, or treatment-resistant hypertension, the NICC approach was not superior over SoC, despite a significant reduction in all-cause mortality, stroke, myocardial infarction and cardiac decompensation. Show less
Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important... Show moreLoss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different PHF8 predicted loss-of-function variants in eight individuals. Features of PHF8-XLID include ID and craniofacial dysmorphology. In this report we present 16 additional individuals with PHF8-XLID from 11 different families of diverse ancestry. We also present five individuals from four different families who have ID and a variant of unknown significance in PHF8 with no other explanatory variant in another gene. All affected individuals exhibited developmental delay and all but two had borderline to severe ID. Of the two who did not have ID, one had dyscalculia and the other had mild learning difficulties. Craniofacial findings such as hypertelorism, microcephaly, elongated face, ptosis, and mild facial asymmetry were found in some affected individuals. Orofacial clefting was seen in three individuals from our cohort, suggesting that this feature is less common than previously reported. Autism spectrum disorder and attention deficit hyperactivity disorder, which were not previously emphasized in PHF8-XLID, were frequently observed in affected individuals. This series expands the clinical phenotype of this rare ID syndrome caused by loss of PHF8 function. Show less
Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important... Show moreLoss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different PHF8 predicted loss-of-function variants in eight individuals. Features of PHF8-XLID include ID and craniofacial dysmorphology. In this report we present 16 additional individuals with PHF8-XLID from 11 different families of diverse ancestry. We also present five individuals from four different families who have ID and a variant of unknown significance in PHF8 with no other explanatory variant in another gene. All affected individuals exhibited developmental delay and all but two had borderline to severe ID. Of the two who did not have ID, one had dyscalculia and the other had mild learning difficulties. Craniofacial findings such as hypertelorism, microcephaly, elongated face, ptosis, and mild facial asymmetry were found in some affected individuals. Orofacial clefting was seen in three individuals from our cohort, suggesting that this feature is less common than previously reported. Autism spectrum disorder and attention deficit hyperactivity disorder, which were not previously emphasized in PHF8-XLID, were frequently observed in affected individuals. This series expands the clinical phenotype of this rare ID syndrome caused by loss of PHF8 function. Show less
Bassani, S.; Beelen, E. van; Rossel, M.; Voisin, N.; Morgan, A.; Arribat, Y.; ... ; Reymond, A. 2021
Non-Syndromic Hereditary Hearing Loss (NSHHL) is a genetically heterogeneous sensory disorder with about 120 genes already associated. Through exome sequencing (ES) and data aggregation, we... Show moreNon-Syndromic Hereditary Hearing Loss (NSHHL) is a genetically heterogeneous sensory disorder with about 120 genes already associated. Through exome sequencing (ES) and data aggregation, we identified a family with six affected individuals and one unrelated NSHHL patient with predicted-to-be deleterious missense variants in USP48. We also uncovered an eighth patient presenting unilateral cochlear nerve aplasia and a de novo splice variant in the same gene. USP48 encodes a ubiquitin carboxyl-terminal hydrolase under evolutionary constraint. Pathogenicity of the variants is supported by in vitro assays that showed that the mutated proteins are unable to hydrolyze tetra-ubiquitin. Correspondingly, three-dimensional representation of the protein containing the familial missense variant is situated in a loop that might influence the binding to ubiquitin. Consistent with a contribution of USP48 to auditory function, immunohistology showed that the encoded protein is expressed in the developing human inner ear, specifically in the spiral ganglion neurons, outer sulcus, interdental cells of the spiral limbus, stria vascularis, Reissner's membrane and in the transient Kolliker's organ that is essential for auditory development. Engineered zebrafish knocked-down for usp48, the USP48 ortholog, presented with a delayed development of primary motor neurons, less developed statoacoustic neurons innervating the ears, decreased swimming velocity and circling swimming behavior indicative of vestibular dysfunction and hearing impairment. Corroboratingly, acoustic startle response assays revealed a significant decrease of auditory response of zebrafish lacking usp48 at 600 and 800 Hz wavelengths. In conclusion, we describe a novel autosomal dominant NSHHL gene through a multipronged approach combining ES, animal modeling, immunohistology and molecular assays. Show less
Many biomarkers that could be used to assess ejection fraction, heart failure, or myocardial infarction fail to translate into clinical practice because they lack essential performance... Show moreMany biomarkers that could be used to assess ejection fraction, heart failure, or myocardial infarction fail to translate into clinical practice because they lack essential performance characteristics or fail to meet regulatory standards for approval. Despite their potential, new technologies have added to the complexities of successful translation into clinical practice. Biomarker discovery and implementation require a standardized approach that includes: identification of a clinical need; identification of a valid surrogate biomarker, stepwise assay refinement, demonstration of superiority over current standard-of-care; development and understanding of a clinical pathway; and demonstration of real-world performance. Successful biomarkers should improve efficacy or safety of treatment, while being practical at a realistic cost. Everyone involved in cardiovascular healthcare, including researchers, clinicians, and industry partners, are important stakeholders in facilitating the development and implementation of biomarkers. This article provides suggestions for a development pathway for new biomarkers, discusses regulatory issues and challenges, and suggestions for accelerating the pathway to improve patient outcomes. Real-life examples of successful biomarkers-high-sensitivity cardiac troponin, T2* cardiovascular magnetic resonance imaging, and echocardiography are used to illustrate the value of a standardized development pathway in the translation of concepts into routine clinical practice. Show less
Purpose Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical... Show morePurpose Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. Methods We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. Results The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. Conclusion The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans. Show less
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between... Show moreObesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation. Show less
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have... Show moreMost common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits(1), but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait(2,3). The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways. Show less
