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Contains fulltext : 305111.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 306427.pdf (Publisher’s version ) (Open Access), Precise regulation of gene expression is important for correct neurodevelopment. 9q34.3 deletions affecting the EHMT1 gene result in a syndromic neurodevelopmental disorder named Kleefstra syndrome. In contrast, duplications of the 9q34.3 locus encompassing EHMT1 have been suggested to cause developmental disorders, but only limited information has been available. We have identified 15 individuals from 10 unrelated families, with 9q34.3 duplications <1.5 Mb in size, encompassing EHMT1 entirely. Clinical features included mild developmental delay, mild intellectual disability or learning problems, autism spectrum disorder, and behavior problems. The individuals did not consistently display dysmorphic features, congenital anomalies, or growth abnormalities. DNA methylation analysis revealed a weak DNAm profile for the cases with 9q34.3 duplication encompassing EHMT1, which could segregate the majority of the affected cases from controls. This study shows that individuals with 9q34.3 duplications including EHMT1 gene present with mild non-syndromic neurodevelopmental disorders and DNA methylation changes different from Kleefstra syndrome., 01 juni 2024

Item does not contain fulltext, The neuronal SNARE complex drives synaptic vesicle exocytosis. Therefore, one of its core proteins syntaxin 1A (STX1A) has long been suspected to play a role in neurodevelopmental disorders. We assembled eight individuals harboring ultra rare variants in STX1A who present with a spectrum of intellectual disability, autism and epilepsy. Causative variants comprise a homozygous splice variant, three de novo missense variants and two inframe deletions of a single amino acid. We observed a phenotype mainly driven by epilepsy in the individuals with missense variants in contrast to intellectual disability and autistic behavior in individuals with single amino acid deletions and the splicing variant. In silico modeling of missense variants and single amino acid deletions show different impaired protein-protein interactions. We hypothesize the two phenotypic courses of affected individuals to be dependent on two different pathogenic mechanisms: (1) a weakened inhibitory STX1A-STXBP1 interaction due to missense variants results in an STX1A-related developmental epileptic encephalopathy and (2) a hampered SNARE complex formation due to inframe deletions causes an STX1A-related intellectual disability and autism phenotype. Our description of a STX1A-related neurodevelopmental disorder with or without epilepsy thus expands the group of rare diseases called SNAREopathies.

01 juli 2023, Item does not contain fulltext, Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

Contains fulltext : 296544.pdf (Publisher’s version ) (Open Access), BACKGROUND: Registries are important in rare disease research. The Anorectal Malformation Network (ARM-Net) registry is a well-established European patient registry collecting demographic, clinical, and functional outcome data. We assessed the quality of this registry through review of the structure, data elements, collected data, and user experience. MATERIAL AND METHODS: Design and data elements were assessed for completeness, consistency, usefulness, accuracy, validity, and comparability. An intra- and inter-user variability study was conducted through monitoring and re-registration of patients. User experience was assessed via a questionnaire on registration, design of registry, and satisfaction. RESULTS: We evaluated 119 data elements, of which 107 were utilized and comprised 42 string and 65 numeric elements. A minority (37.0%) of the 2278 included records had complete data, though this improved to 83.5% when follow-up elements were excluded. Intra-observer variability demonstrated 11.7% incongruence, while inter-observer variability was 14.7%. Users were predominantly pediatric surgeons and typically registered patients within 11-30 min. Users did not experience any significant difficulties with data entry and were generally satisfied with the registry, but preferred more longitudinal data and patient-reported outcomes. CONCLUSIONS: The ARM-Net registry presents one of the largest ARM cohorts. Although its collected data are valuable, they are susceptible to error and user variability. Continuous evaluations are required to maintain relevant and high-quality data and to achieve long-term sustainability. With the recommendations resulting from this study, we call for rare disease patient registries to take example and aim to continuously improve their data quality to enhance the small, but impactful, field of rare disease research. LEVEL OF EVIDENCE: V.

Item does not contain fulltext, OBJECTIVE: We performed a 1-year evaluation of a novel strategy of simultaneously analyzing single nucleotide variants (SNVs), copy number variants (CNVs) and copy-number-neutral Absence-of-Heterozygosity from Whole Exome Sequencing (WES) data for prenatal diagnosis of fetuses with ultrasound (US) anomalies and a non-causative QF-PCR result. METHODS: After invasive diagnostics, whole exome parent-offspring trio-sequencing with exome-wide CNV analysis was performed in pregnancies with fetal US anomalies and a non-causative QF-PCR result (WES-CNV). On request, additional SNV-analysis, restricted to (the) requested gene panel(s) only (with the option of whole exome SNV-analysis afterward) was performed simultaneously (WES-CNV/SNV) or as rapid SNV-re-analysis, following a normal CNV analysis. RESULTS: In total, 415 prenatal samples were included. Following a non-causative QF-PCR result, WES-CNV analysis was initially requested for 74.3% of the chorionic villus (CV) samples and 45% of the amniotic fluid (AF) samples. In case WES-CNV analysis did not reveal a causative aberration, SNV-re-analysis was requested in 41.7% of the CV samples and 17.5% of the AF samples. All initial analyses could be finished within 2 weeks after sampling. For SNV-re-analysis during pregnancy, turn-around-times (TATs) varied between one and 8 days. CONCLUSION: We show a highly efficient all-in-one WES-based strategy, with short TATs, and the option of rapid SNV-re-analysis after a normal CNV result.

Contains fulltext : 294552.pdf (Publisher’s version ) (Open Access), PURPOSE: To characterize a novel neurodevelopmental syndrome due to loss-of-function (LoF) variants in Ankyrin 2 (ANK2), and to explore the effects on neuronal network dynamics and homeostatic plasticity in human-induced pluripotent stem cell-derived neurons. METHODS: We collected clinical and molecular data of 12 individuals with heterozygous de novo LoF variants in ANK2. We generated a heterozygous LoF allele of ANK2 using CRISPR/Cas9 in human-induced pluripotent stem cells (hiPSCs). HiPSCs were differentiated into excitatory neurons, and we measured their spontaneous electrophysiological responses using micro-electrode arrays (MEAs). We also characterized their somatodendritic morphology and axon initial segment (AIS) structure and plasticity. RESULTS: We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy. Using MEAs, we found that hiPSC-derived neurons with heterozygous LoF of ANK2 show a hyperactive and desynchronized neuronal network. ANK2-deficient neurons also showed increased somatodendritic structures and altered AIS structure of which its plasticity is impaired upon activity-dependent modulation. CONCLUSIONS: Phenotypic characterization of patients with de novo ANK2 LoF variants defines a novel NDD with early onset epilepsy. Our functional in vitro data of ANK2-deficient human neurons show a specific neuronal phenotype in which reduced ANKB expression leads to hyperactive and desynchronized neuronal network activity, increased somatodendritic complexity and AIS structure and impaired activity-dependent plasticity of the AIS.

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Contains fulltext : 284419.pdf (Publisher’s version ) (Open Access)

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Item does not contain fulltext, Anorectal malformation (ARM) is a relatively frequently occurring congenital anomaly of hindgut development with a prevalence of 1 in 3,000 live births. ARM may present as an isolated anomaly, but it can also be associated with other anomalies, sometimes as part of a recognizable syndrome. After birth, much medical attention is given to the treatment and restoring of bowel function in children with ARM. Effort should also be given to studying the etiology of the ARM in these patients. This information is important to both the medical community and the family, because it can help guide treatment and provides information on the long-term prognosis of the patient and recurrence risk in the family.In this article, we will review the current knowledge on the (genetic) etiology of (syndromic) ARM and provide guidelines for (family) history taking and clinical and genetic studies of ARM patients and their families, which is needed to study the causal factors in an ARM patient and for genetic counseling of the families.

Contains fulltext : 237970.pdf (Publisher’s version ) (Open Access), The CEP83 protein is an essential part in the first steps of ciliogenesis, causing a ciliopathy if deficient. As a core component of the distal appendages of the centriole, CEP83 is located in almost all cell types and is involved in the primary cilium assembly. Previously reported CEP83 deficient patients all presented with nephronophthisis and kidney dysfunction. Despite retinal degeneration being a common feature in ciliopathies, only one patient also had retinitis. Here, we present two unrelated patients, who both presented with retinitis pigmentosa, without nephronophthisis or any form of kidney dysfunction. Both patients harbor bi-allelic variants in CEP83. This report expands the current clinical spectrum of CEP83 deficiency. For timely diagnosis of CEP83 deficiency, we advocate that CEP83 should be included in gene panels for inherited retinal diseases.

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Contains fulltext : 229275.pdf (Publisher’s version ) (Open Access), BACKGROUND: The VACTERL association (VACTERL) includes at least three of these congenital anomalies: vertebral, anal, cardiac, trachea-esophageal, renal, and limb anomalies. Assisted reproductive techniques (ART), pregestational diabetes mellitus, and chronic lower obstructive pulmonary disorders (CLOPD) have been associated with VACTERL. We aimed to replicate these findings and were interested in additional maternal risk factors. METHODS: A case-control study using self-administered questionnaires was performed including 142 VACTERL cases and 2,135 population-based healthy controls. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). RESULTS: Parents who used invasive ART had an increased risk of VACTERL in offspring (aOR 4.4 [95%CI 2.1-8.8]), whereas the increased risk for mothers with CLOPD could not be replicated. None of the case mothers had pregestational diabetes mellitus. Primiparity (1.5 [1.1-2.1]) and maternal pregestational overweight and obesity (1.8 [1.2-2.8] and 1.8 [1.0-3.4]) were associated with VACTERL. Consistent folic acid supplement use during the advised periconceptional period may reduce the risk of VACTERL (0.5 [0.3-1.0]). Maternal smoking resulted in an almost twofold increased risk of VACTERL. CONCLUSION: We identified invasive ART, primiparity, pregestational overweight and obesity, lack of folic acid supplement use, and smoking as risk factors for VACTERL.

Background: The VACTERL association (VACTERL) includes at least three of these congenital anomalies: vertebral, anal, cardiac, trachea-esophageal, renal, and limb anomalies. Assisted reproductive techniques (ART), pregestational diabetes mellitus, and chronic lower obstructive pulmonary disorders (CLOPD) have been associated with VACTERL. We aimed to replicate these findings an

Background: The VATER/VACTERL association (VACTERL) is defined as the non-random occurrence of the following congenital anomalies: Vertebral, Anal, Cardiac, Tracheal-Esophageal, Renal, and Limb anomalies. As no unequivocal candidate gene has been identified yet, patients are diagnosed phenotypically. The aims of this study were to identify patients with monogenic disorders using a genetics-first approach, and to study whether variants in candidate genes are involved in the etiology of VACTERL or the individual features of VACTERL: Anorectal malformation (ARM) or esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Methods: Using molecular inversion probes, a candidate gene panel of 56 genes was sequenced in three patient groups: VACTERL (n = 211), ARM (n = 204), and EA/TEF (n = 95). Loss-of-function (LoF) and additional likely pathogenic missense variants, were prioritized and validated using Sanger sequencing. Validated variants were tested for segregation and patients were clinically re-evaluated. Results: In 7 out of the 510 patients (1.4%), pathogenic or likely pathogenic variants were identified in SALL1, SALL4, and MID1, genes that are associated with Townes-Brocks, Duane-radial-ray, and Opitz-G/BBB syndrome. These syndromes always include ARM or EA/TEF, in combination with at least two other VACTERL features. We did not identify LoF variants in the remaining candidate genes. Conclusions: None of the other candidate genes were identified as novel unequivocal disease genes for VACTERL. However, a genetics-first approach allowed refinement of the clinical diagnosis in seven patients, in whom an alternative molecular-based diagnosis was found with important implications for the counseling of the families.

BACKGROUND: Antipsychotic medication is effective for symptomatic treatment in schizophrenia-spectrum disorders. After symptom remission, continuation of antipsychotic treatment is associated with lower relapse rates and lower symptom severity compared to dose reduction/discontinuation. Therefore, most guidelines recommend continuation of treatment with antipsychotic medication for at least 1 year. Recently, however, these guidelines have been questioned as one study has shown that more patients achieved long-term functional remission in an early discontinuation condition-a finding that was not replicated in another recently published long-term study. METHODS/DESIGN: The HAMLETT (Handling Antipsychotic Medication Long-term Evaluation of Targeted Treatment) study is a multicenter pragmatic single-blind randomized controlled trial in two parallel conditions (1:1) investigating the effects of continuation versus dose-reduction/discontinuation of antipsychotic medication after remission of a first episode of psychosis (FEP) on personal and social functioning, psychotic symptom severity, and health-related quality of life. In total 512 participants will be included, aged between 16 and 60 years, in symptomatic remission from a FEP for 3-6 months, and for whom psychosis was not associated with severe or life-threatening self-harm or violence. Recruitment will take place at 24 Dutch sites. Patients are randomized (1:1) to: continuation of antipsychotic medication until at least 1 year after remission (original dose allowing a maximum reduction of 25%, or another antipsychotic drug in similar dose range); or gradual dose reduction till eventual discontinuation of antipsychotics according to a tapering schedule. If signs of relapse occur in this arm, medication dose can be increased again. Measurements are conducted at baseline, at 3, and 6 months post-baseline, and yearly during a follow-up period of 4 years. DISCUSSION: The HAMLETT study will offer evidence to guide patien

Contains fulltext : 220449.pdf (Publisher’s version ) (Open Access), BACKGROUND: The VACTERL association (VACTERL) is the nonrandom occurrence of at least three of these congenital anomalies: vertebral, anal, cardiac, tracheoesophageal, renal, and limb anomalies. Despite suggestions for involvement of several genes and nongenetic risk factors from small studies, the etiology of VACTERL remains largely unknown. OBJECTIVE: To identify maternal risk factors for VACTERL in offspring in a large European study. METHODS: A case-control study was performed using data from 28 EUROCAT registries over the period 1997-2015 with case and control ascertainment through hospital records, birth and death certificates, questionnaires, and/or postmortem examinations. Cases were diagnosed with VACTERL, while controls had a genetic syndrome and/or chromosomal abnormality. Data collected included type of birth defect and maternal characteristics, such as age, use of assisted reproductive techniques (ART), and chronic illnesses. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) with 95% confidence intervals (95% CI). RESULTS: The study population consisted of 329 VACTERL cases and 49,724 controls with recognized syndromes or chromosomal abnormality. For couples who conceived through ART, we found an increased risk of VACTERL (aOR 2.3 [95% CI 1.3, 3.9]) in offspring. Pregestational diabetes (aOR 3.1 [95% CI 1.1, 8.6]) and chronic lower obstructive pulmonary diseases (aOR 3.9 [95% CI 2.2, 6.7]) also increased the risk of having a child with VACTERL. Twin pregnancies were not associated with VACTERL (aOR 0.6 [95% CI 0.3, 1.4]). CONCLUSION: We identified several maternal risk factors for VACTERL in offspring befitting a multifactorial etiology.

Contains fulltext : 205341.pdf (publisher's version ) (Open Access)

Contains fulltext : 206572.pdf (publisher's version ) (Open Access), We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Contains fulltext : 196255.pdf (publisher's version ) (Open Access), In nonhigh risk patients with hypertrophic cardiomyopathy (HC), the presence of extensive late gadolinium enhancement (LGEext) at cardiovascular magnetic resonance (CMR) imaging has been proposed as a risk modifier in the decision process for implantable cardioverter defibrillator implantation. With a pretest risk of about 10%, a strategy that alters the likelihood of LGEext could markedly affect efficacious CMR imaging. Our aim was to study the potential of clinical variables and biomarkers to predict LGEext. In 98 HC patients without any clear indication for implantable cardioverter defibrillator implantation, we determined the discriminative values of a set of clinical variables and a panel of biomarkers (hs-cTnT, NTproBNP, GDF-15, and Gal-3, CICP) for LGEext, that is, LGE >/=15% of the left ventricular mass. LGEext was present in 10% (10/98) of patients. The clinical prediction model contained a history of nonsustained ventricular tachycardia, maximal wall thickness and reduced systolic function (c-statistic: 0.868, p <0.001). Of all biomarkers, only hs-cTnT was associated with LGEext, in addition to the improved clinical model of diagnostic accuracy (p=0.04). A biomarker-only strategy allowed the exclusion of LGEext in half of the cohort, in case of a hs-cTnT concentration less than the optimal cutoff (Youden index; 8 ng/L-sensitivity 100%, specificity 54%). In conclusion, in this nonhigh risk HC cohort, the pretest likelihood of LGEext can be altered using clinical variables and the addition of hs-cTnT. The promising findings with the use of hs-cTnT only call for new initiatives to study its impact on efficacious CMR imaging in a larger HC population, either with or without additional use of clinical variables.

Contains fulltext : 183873.pdf (publisher's version ) (Open Access)

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive web-based survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

In nonhigh risk patients with hypertrophic cardiomyopathy (HC), the presence of extensive late gadolinium enhancement (LGEext) at cardiovascular magnetic resonance (CMR) imaging has been proposed as a risk modifier in the decision process for implantable cardioverter defibrillator implantation. With a pretest risk of about 10%, a strategy that alters the likelihood of LGEext could markedly affect efficacious CMR imaging. Our aim was to study the potential of clinical variables and biomarkers to predict LGEext. In 98 HC patients without any clear indication for implantable cardioverter defibrillator implantation, we determined the discriminative values of a set of clinical variables and a panel of biomarkers (hs-cTnT, NTproBNP, GDF-15, and Gal-3, CICP) for LGEext, that is, LGE ≥15% of the left ventricular mass. LGEext was present in 10% (10/98) of patients. The clinical prediction model contained a history of nonsustained ventricular tachycardia, maximal wall thickness and reduced systolic function (c-statistic: 0.868, p <0.001). Of all biomarkers, only hs-cTnT was associated with LGEext, in addition to the improved clinical model of diagnostic accuracy (p = 0.04). A biomarker-only strategy allowed the exclusion of LGEext in half of the cohort, in case of a hs-cTnT concentration less than the optimal cutoff

Item does not contain fulltext, STUDY QUESTION: Are anorectal malformations (ARMs) associated with previous miscarriages or single nucleotide polymorphisms (SNPs) in the Bone Morphogenetic Protein 4 (BMP4) and GLI family zinc finger 2 (GLI2) genes? SUMMARY ANSWER: The SNP rs3738880 in GLI2 and miscarriages were associated with ARM, especially in patients with multiple congenital anomalies (MCA). WHAT IS KNOWN ALREADY: ARM are one of the most common birth defects of the gastrointestinal tract. The etiology is likely to be multifactorial, involving both environmental and genetic factors. SNPs in BMP4 and GLI2 genes were associated with ARM in non-Caucasian populations. During a patient information day, several mothers of ARM patients reported their concerns about previous miscarriages. STUDY DESIGN, SIZE, DURATION: A case-control study was performed among 427 ARM patients and 663 population-based controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: We examined the associations of ARM with SNPs in GLI2 and BMP4 using DNA samples of the children and associations with previous miscarriages using parental questionnaires. In addition, gene-gene and gene-environment interaction analyses were performed. MAIN RESULTS AND THE ROLE OF CHANCE: The SNP rs3738880 in GLI2 was associated with ARM, especially in patients with MCA (homozygous GG-genotype: odds ratio (OR): 2.1; 95% CI: 1.2, 3.7). We identified previous miscarriages as a new risk factor for ARM, especially when occurring in the pregnancy directly preceding the index pregnancy and in patients with MCA (OR: 2.1; 95% CI: 1.3, 3.5). No association with rs17563 in BMP4, nor gene-gene or gene-environment interactions were found. LIMITATIONS, REASONS FOR CAUTION: The possibility of recall errors for previous miscarriage, but we expect these errors to be limited, as a miscarriage is a major life event. In addition, potential misclassification regarding miscarriages and stillbirth, but sensitivity analyses showed that this did not influence our results. WIDER I

Contains fulltext : 169855.pdf (publisher's version ) (Closed access)

Contains fulltext : 169685.pdf (publisher's version ) (Closed access), OBJECTIVE: Areas of high signal intensity (HighT2) on T2-weighted cardiovascular magnetic resonance (CMR) imaging have been demonstrated in hypertrophic cardiomyopathy (HCM). It has been hypothesised that HighT2 may indicate active tissue injury in HCM. In this context, we studied HighT2 in relation to cardiac troponin. METHODS: Outpatient HCM patients without a history of coronary artery disease underwent CMR imaging at 1.5 T using T2-weighted, cine and late gadolinium enhancement (LGE) imaging to assess HighT2, left ventricular (LV) function, LV mass and the presence and extent of LGE. Highly sensitive cardiac troponin T (hs-cTnT) was assessed as a marker of injury, with hs-cTnT >/=14 and >3 ng/L defined as an elevated and detectable troponin. RESULTS: HighT2 was present in 28% of patients (28/101). An elevated hs-cTnT was present in 54% of patients with HighT2 (15/28) compared with 14% of patients without HighT2 (10/73) (p<0.001). Hs-cTnT was detectable in 96% of patients with HighT2 (27/28) compared with 66% of patients without HighT2 (48/73) (p=0.002). In case of an undetectable hs-cTnT, HighT2 was only seen in 4% (1/26). In addition, the extent of HighT2 was related with increasing hs-cTnT concentrations (Spearman's rho: 0.42, p<0.001). CONCLUSIONS: In this CMR study of patients with HCM, we observed HighT2 in a quarter of patients, and demonstrated that HighT2 was associated with an elevated hs-cTnT. This observation, combined with the very high negative predictive value of an undetectable hs-cTnT for HighT2, provides supportive evidence for the hypothesis that HighT2 is indicative of recently sustained myocyte injury.

Item does not contain fulltext, BACKGROUND: Interpretation of missense variants can be especially difficult when the variant is also found in control populations. This is what we encountered for the LMNA c.992G>A (p.(Arg331Gln)) variant. Therefore, to evaluate the effect of this variant, we combined an evaluation of clinical data with functional experiments and morphological studies. METHODS AND RESULTS: Clinical data of 23 probands and 35 family members carrying this variant were retrospectively collected. A time-to-event analysis was performed to compare the course of the disease with carriers of other LMNA mutations. Myocardial biopsies were studied with electron microscopy and by measuring force development of the sarcomeres. Morphology of the nuclear envelope was assessed with immunofluorescence on cultured fibroblasts. The phenotype in probands and family members was characterized by atrioventricular conduction disturbances (61% and 44%, respectively), supraventricular arrhythmias (69% and 52%, respectively), and dilated cardiomyopathy (74% and 14%, respectively). LMNA p.(Arg331Gln) carriers had a significantly better outcome regarding the composite end point (malignant ventricular arrhythmias, end-stage heart failure, or death) compared with carriers of other pathogenic LMNA mutations. A shared haplotype of 1 Mb around LMNA suggested a common founder. The combined logarithm of the odds score was 3.46. Force development in membrane-permeabilized cardiomyocytes was reduced because of decreased myofibril density. Structural nuclear LMNA-associated envelope abnormalities, that is, blebs, were confirmed by electron microscopy and immunofluorescence microscopy. CONCLUSIONS: Clinical, morphological, functional, haplotype, and segregation data all indicate that LMNA p.(Arg331Gln) is a pathogenic founder mutation with a phenotype reminiscent of other LMNA mutations but with a more benign course.

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA br

RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between −2.5 to −5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.

Item does not contain fulltext, PURPOSE: The goal of this study was to determine the degree of consensus in the management of spinal cord tethering (TC) in patients with anorectal malformation (ARM) in a large cohort of European pediatric centers. METHODS: A survey was sent to pediatric surgeons (one per center) members of the ARM-Net Consortium. RESULTS: Twenty-four (86%) from ten different countries completed the survey. Overall prevalence of TC was: 21% unknown, 46% below 15, and 29% between 15 and 30%. Ninety-six agreed on screening all patients for TC regardless the type of ARM and 79% start screening at birth. Responses varied in TC definition and diagnostic tools. Fifty percent of respondents prefer ultrasound (US), 21% indicate either US or magnetic resonance (MRI) based on a pre-defined risk of presenting TC, and 21% perform both. Discrepancy exists in complementary test: 82% carry out urodynamic studies (UDS) and only 37% perform somatosensory-evoked potentials (SSEP). Prophylactic untethering is performed in only two centers (8%). CONCLUSIONS: Survey results support TC screening in all patients with ARM and conservative management of TC. There is discrepancy in the definition of TC, screening tools, and complementary test. Protocols should be developed to avoid such variability in management.

Item does not contain fulltext, A recent outbreak of Zika virus in Brazil has led to a simultaneous increase in reports of neonatal microcephaly. Zika targets cerebral neural precursors, a cell population essential for cortical development, but the cause of this neurotropism remains obscure. Here we report that the neural RNA-binding protein Musashi-1 (MSI1) interacts with the Zika genome and enables viral replication. Zika infection disrupts the binding of MSI1 to its endogenous targets, thereby deregulating expression of factors implicated in neural stem cell function. We further show that MSI1 is highly expressed in neural progenitors of the human embryonic brain and is mutated in individuals with autosomal recessive primary microcephaly. Selective MSI1 expression in neural precursors could therefore explain the exceptional vulnerability of these cells to Zika infection.

Item does not contain fulltext, AIMS: Phenotypic heterogeneity and incomplete penetrance are common in patients with hypertrophic cardiomyopathy (HCM). We aim to improve the understanding in genotype-phenotype correlations in HCM, particularly the contribution of an MYL2 founder mutation and risk factors to left ventricular hypertrophic remodelling. METHODS AND RESULTS: We analysed 14 HCM families of whom 38 family members share the MYL2 c.64G > A [p.(Glu22Lys)] mutation and a common founder haplotype. In this unique cohort, we investigated factors influencing phenotypic outcome in addition to the primary mutation. The mutation alone showed benign disease manifestation with low penetrance. The co-presence of additional risk factors for hypertrophy such as hypertension, obesity, or other sarcomeric gene mutation increased disease penetrance substantially and caused HCM in 89% of MYL2 mutation carriers (P = 0.0005). The most prominent risk factor was hypertension, observed in 71% of mutation carriers with HCM and an additional risk factor. CONCLUSION: The MYL2 mutation c.64G > A on its own is incapable of triggering clinical HCM in most carriers. However, the presence of an additional risk factor for hypertrophy, particularly hypertension, adds to the development of HCM. Early diagnosis of risk factors is important for early treatment of MYL2 mutation carriers and close monitoring should be guaranteed in this case. Our findings also suggest that the presence of hypertension or another risk factor for hypertrophy should not be an exclusion criterion for genetic studies.

Contains fulltext : 158967.pdf (publisher's version ) (Open Access), Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine.

Contains fulltext : 172059.pdf (publisher's version ) (Open Access), BACKGROUND: The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the congenital uro-rectal malformation spectrum. Initial studies have implicated rare copy number variations (CNVs), including recurrent duplications of chromosomal region 22q11.21, in BEEC etiology. METHODS: To detect further CNVs, array analysis was performed in 169 BEEC patients. Prior to inclusion, 22q11.21 duplications were excluded using multiplex ligation-dependent probe amplification. RESULTS: Following the application of stringent filter criteria, seven rare CNVs were identified: n = 4, not present in 1307 in-house controls; n = 3, frequency of <0.002 in controls. These CNVs ranged from 1 to 6.08 Mb in size. To identify smaller CNVs, relaxed filter criteria used in the detection of previously reported BEEC associated chromosomal regions were applied. This resulted in the identification of six additional rare CNVs: n = 4, not present in 1307 in-house controls; n = 2, frequency <0.0008 in controls. These CNVs ranged from 0.03-0.08 Mb in size. For 10 of these 13 CNVs, confirmation and segregation analyses were performed (5 of maternal origin; 5 of paternal origin). Interestingly, one female with classic bladder extrophy carried a 1.18 Mb duplication of 22q11.1, a chromosomal region that is associated with cat eye syndrome. CONCLUSIONS: A number of rare CNVs were identified in BEEC patients, and these represent candidates for further evaluation. Rare inherited CNVs may constitute modifiers of, or contributors to, multifactorial BEEC phenotypes.

The objective of this study was to compare the prevalence of genetic disorders in anorectal malformation (ARM) patients with upper limb anomalies to that in ARM patients with other associated anomalies. A retrospective case study was performed in two pediatric surgery centers. All patients born between 1990 and 2012 were included. VACTERL (vertebral defects (V), anal atresia (A), cardiac malformations (C), tracheoesophageal fistula with esophageal atresia (TE), renal dysplasia (R), and limb anomalies (L)) was defined as at least three components present. We included 700 ARM patients: 219 patients (31 %) had isolated ARM, 43 patients (6 %) had a major upper limb anomaly, and 438 patients (63 %) had other associated anomalies. The most prevalent upper limb anomalies were radial dysplasia (n = 12) and hypoplastic thumb (n = 11). Ten of the 43 patients (23 %) with an upper limb anomaly were diagnosed with a genetic disorder—nine also met the VACTERL criteria—vs. 9 % of ARM patients with other anomalies (p = 0.004, chi-squared test). Conclusion: Genetic disorders are twice as frequently diagnosed in ARM patients with upper limb anomalies than in those with other anomalies. As they also frequently meet the VACTERL criteria, it is important to consider VACTERL as a diagnosis per exclusionem. Genetic counseling is certainly warranted in these patients.What is Known:• Anorectal malformations (ARMs) often co-occur with other congenital anomalies, including upper limb anomalies, mainly of pre-axial origin.• Co-occurrence of ARMs and upper limb anomalies is seen in disorders such as Townes-Brocks syndrome, Fanconi anemia, and VACTERL association.What is New:• ARM patients with a major upper limb anomaly—with or without other congenital anomalies—have a twofold greater chance of a genetic disorder than have non-isolated ARM patients without upper limb anomalies.• Not all upper limb anomalies in ARM patients are part of the VACTERL association; a workup for genetic evaluation is

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Item does not contain fulltext, This is the second report of a family with a recurrence of a CDKL5 mutation (c. 283-3_290del) in 2 sisters. Both parents tested negative for the mutation in all tissues, but germline mosaicism is likely. Clinically CDKL5 patients resemble those with Rett syndrome, caused by a MECP2 mutation, who experience a regression, after an initial normal development. Even though both siblings showed a typical CDKL5 phenotype, their presentation is different. From birth, the oldest daughter had a severe developmental delay, feeding problems, and hypotonia and experienced daily refractory seizures. The youngest daughter appeared to be normal until age 3 months. At that age seizures started, deterioration and regression became evident, and an epileptic encephalopathy developed. This report of familial recurrence, with suspected germline mosaicism in a healthy parent, has important consequences for genetic counseling. Although it is not possible to predict an exact recurrence risk, it is likely to be increased.

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Contains fulltext : 153944.pdf (publisher's version ) (Closed access), Anorectal malformations (ARM) are rare congenital malformations of the gastrointestinal tract. Approximately 60% of the patients have additional congenital malformations, such as hypospadias. A recently published article showed that deletion of one single gene, dickkopf WNT signaling pathway inhibitor-1 (Dkk1), resulted in an imperforate anus with rectourinary fistula and preputial hypospadias in mice. To determine whether DKK1 also plays a role in the etiology of ARM and hypospadias in humans, we sequenced the four exons of the DKK1 gene in 17 patients affected with both ARM and hypospadias. No new potential disease-causing variant was identified. However, we detected a known non-synonymous variant in one patient, which was predicted in silico to be damaging, and the corresponding unaffected amino acid is highly conserved. CONCLUSION: In this human study, a potential interesting non-synonymous variant was found in the DKK1 gene. Whether this variant plays a contributory role in the genesis of ARM or hypospadias would require a much larger study.