Interstitial 2q24.2q24.3 Microdeletion: Two New Cases with Similar Clinical Features with the Exception of Profound Deafness.

Interstitial 2q24.2q24.3 microdeletions are rare cytogenetic aberrations associated with heterogeneous clinical features depending on the size of the deletion. Here, we describe 2 patients with overlapping de novo 2q24.2q24.3 deletions, characterized by array-CGH. This is the smallest 2q24.2q24.3 region of overlap described in the literature encompassing only 9 genes (SLC4A10, DPP4, GCG, FAP, IFIH1, GCA, KCNH7, FIGN, GRB14). We focused our attention on SLC4A10, DPP4, and KCNH7, genes associated with neurological features. Our patients presented similar features: intellectual disability, developmental and language delay, hypotonia, joint laxity, and dysmorphic features. Only patient 2 showed profound deafness and also carried a heterozygous mutation of the GJB2 gene responsible for autosomal recessive deafness 1A (DFNB1A: OMIM 220290). Could the disruption of a gene present in the 2q24.2q24.3 deleted region be responsible for her profound hearing loss?

Alcohol septal ablation for left ventricular outflow tract obstruction in cardiac amyloidosis: New indication for an established therapy.

Cardiac amyloidosis can occasionally demonstrate an atypical pattern of infiltration, causing asymmetric septal thickening and a left ventricular outflow tract (LVOT) gradient with systolic anterior motion (SAM) of the mitral valve resembling obstructive hypertrophic cardiomyopathy. We present a case of a 70-year-old man with cardiac light-chain amyloidosis and LVOT obstruction successfully treated with alcohol septal ablation (ASA). Following the procedure, he reported significant improvement in his heart failure symptoms as well as improvement in LVOT gradient and SAM of the mitral valve. This case demonstrates that ASA is a technically feasible and effective procedure for relieving LVOT obstruction in cardiac amyloidosis and can be considered as a treatment option in patients whose symptoms are refractory to medical therapy.

The impact of increased pulmonary arterial pressure on outcomes after transcatheter aortic valve replacement.

OBJECTIVE: To evaluate the impact of increased pulmonary artery systolic pressure (PASP) on outcomes after transcatheter aortic valve replacement (TAVR). METHODS: A total of 242 patients who underwent TAVR were retrospectively reviewed. Transthoracic echocardiography estimated PASP. The cohorts were divided into three groups according to the numerical change of PASP; Increased (post-TAVR PASP at 1 month minus pre-TAVR PASP, ≥ + 5 mmHg; n = 52), No change (-5 to +5 mmHg; n = 86) and Decreased (≤ -5 mmHg; n = 104). Patient demographics and clinical outcomes until 1 year were evaluated. Logistic regression model was used for multivariate risk analysis. RESULTS: At 1 year, the Increased group showed higher mortality (21 ± 6%) than the No change group (5 ± 2%) (hazard ratio [HR]: 4.8, 95% confidence interval [CI]: 1.7-13.5; p < .01) and the Decreased group (8 ± 3%) (HR: 2.8, 95% CI: 1.1-6.7; p = .02). Rehospitalization rate for valve-related or heart failure was also higher in the Increased group (21 ± 6%) than the No change group (10 ± 3%) (HR: 2.4, 95% CI: 1.1-6.0; p = .04). Predictors of PASP deterioration were hypertension (odds ratio [OR]: 3.9, 95% CI: 1.1-13.8; p = .04) and left ventricular end-diastolic diameter >50 mm (OR: 2.2, 95% CI: 1.1-4.6; p = .04), and the increased PASP remained an independent predictor of 1-year all-cause mortality (HR; 2.7, 95% CI: 1.0-6.8; p = .04). CONCLUSIONS: Regardless of the baseline PASP, patients with increased PASP at 1 month after successful TAVR were at higher risk of mortality and rehospitalization within 1 year. Strict medical management should be considered for patients who showed dilated left ventricle preoperatively.

DNA Methylation Profiling of Uniparental Disomy Subjects Provides a Map of Parental Epigenetic Bias in the Human Genome.

Genomic imprinting is a mechanism in which gene expression varies depending on parental origin. Imprinting occurs through differential epigenetic marks on the two parental alleles, with most imprinted loci marked by the presence of differentially methylated regions (DMRs). To identify sites of parental epigenetic bias, here we have profiled DNA methylation patterns in a cohort of 57 individuals with uniparental disomy (UPD) for 19 different chromosomes, defining imprinted DMRs as sites where the maternal and paternal methylation levels diverge significantly from the biparental mean. Using this approach we identified 77 DMRs, including nearly all those described in previous studies, in addition to 34 DMRs not previously reported. These include a DMR at TUBGCP5 within the recurrent 15q11.2 microdeletion region, suggesting potential parent-of-origin effects associated with this genomic disorder. We also observed a modest parental bias in DNA methylation levels at every CpG analyzed across ∼1.9 Mb of the 15q11-q13 Prader-Willi/Angelman syndrome region, demonstrating that the influence of imprinting is not limited to individual regulatory elements such as CpG islands, but can extend across entire chromosomal domains. Using RNA-seq data, we detected signatures consistent with imprinted expression associated with nine novel DMRs. Finally, using a population sample of 4,004 blood methylomes, we define patterns of epigenetic variation at DMRs, identifying rare individuals with global gain or loss of methylation across multiple imprinted loci. Our data provide a detailed map of parental epigenetic bias in the human genome, providing insights into potential parent-of-origin effects.

Clinical and Molecular Characterization of Two Patients with CNTN6 Copy Number Variations.

Submicroscopic chromosomal alterations usually involve different protein-coding genes and regulatory elements that are responsible for rare contiguous gene disorders, which complicate the understanding of genotype-phenotype correlations. Chromosome band 3p26.3 contains 3 genes encoding neuronal cell adhesion molecules: CHL1, CNTN6, and CNTN4. We describe 2 boys aged 8 years and 11 years mainly affected by intellectual disability and autism spectrum disorder, who harbor a paternally inherited 3p26.3 microdeletion and a 3p26.3 microduplication, respectively. Both anomalies involved only the CNTN6 gene, which encodes contactin 6, a member of the contactin family (MIM 607220). Contactins show pronounced brain expression and function. Interestingly, phenotypes in reciprocal microdeletions and microduplications of CNTN6 are very similar. In conclusion, our data, added to those reported in the literature, are particularly significant for understanding the pathogenic effect of single gene dosage alterations. As for other recurrent syndromes with variable phenotype, these findings are challenging in genetic counselling because of an evident variable penetrance.

Intragenic Microdeletion of ULK4 and Partial Microduplication of BRWD3 in Siblings with Neuropsychiatric Features and Obesity.

ULK4 and BRWD3 deletions have been identified in patients with developmental/language delay and intellectual disability. Both genes play pivotal roles in brain development. In particular, ULK4 encodes serine/threonine kinases that are critical for the development and function of the nervous system, while BRWD3 plays a crucial role in ubiquitination, as part of the ubiquitin/proteasome system. We report on 2 brothers, aged 7.6 and 20 years, presenting with cognitive impairment, epilepsy, autistic features, hearing loss, and obesity. Array-CGH analysis demonstrated 2 rare CNVs in both siblings: a paternally inherited microdeletion of ∼145 kb at 3p22.1, disrupting the ULK4 gene, and a maternally inherited microduplication of ∼117 kb at Xq21.1 including only the BRWD3 gene. As already described for other recurrent syndromes with variable phenotype, these findings are challenging in genetic counseling because of an evident variable penetrance. We discuss the possible correlations between the clinical phenotype of our patients and the function of the genes involved in these microrearrangements.

Characterization of the Phenotype Associated with Microduplication Reciprocal to NF1 Microdeletion Syndrome.

17q11.2 microduplication syndrome is a recently described relatively rare condition associated with a nonspecific phenotype. Intellectual disability, developmental delay, and dysmorphisms are the only clinical features common to a majority of cases. Seventeen patients have been reported so far. Here, we present another patient with 17q11.2 duplication and no signs of neurofibromatosis type 1, identified by array-CGH. We compared clinical features and genetic data with those of previously reported patients with 17q11.2 microduplications. We also analyzed the gene content of the duplicated region in order to investigate the possible role of specific genes in the clinical phenotype of our patient.

Hypogonadotropic hypogonadism in a trisomy X carrier: phenotype description and genotype correlation.

We report on a 31-year old female who presented at genetic counseling for a small uterus, secondary amenorrhea and sterility. Gonadotropic hormone levels were low, suggesting a Hypogonadotropic Hypogonadism (HH) condition. Cytogenetic analysis demonstrated the presence of Trisomy X associated to an interstitial deletion of chromosome 4q13.2, resulting in the complete loss of a copy of the GNRHR gene. As GNRHR is known to be responsible for an autosomal recessive form of HH, we checked the status of the undeleted allele and we found the Q106R substitution. In conclusion, the results of our cytogenetic and molecular analyses have allowed us to clarify the etiology of the patient's condition.

Clinical and Molecular Cytogenetic Characterization of a de novo Interstitial 1p31.1p31.3 Deletion in a Boy with Moderate Intellectual Disability and Severe Language Impairment.

Interstitial 1p deletions are rare events. Very few cases of 1p31.1p31.3 deletions characterized by variable phenotypes have been reported. No clear genotype-phenotype correlation has been determined yet. We present a child with a de novo interstitial 1p31.1p31.3 deletion, identified by array CGH, associated with intellectual disability and severe language impairment. The deleted region contains 20 OMIM genes, but we focused on GADD45A (MIM 126335; growth arrest- and DNA damage-inducible gene), LRRC7 (MIM 614453; leucine-rich repeat-containing protein 7), and NEGR1 (MIM 613173; neuronal growth regulator 1). We discuss whether these genes play a role in determining the phenotype of our patient in order to investigate the possibility of a genotype-phenotype correlation.

Congenital aural atresia associated with agenesis of internal carotid artery in a girl with a FOXI3 deletion.

We report on the molecular characterization of a microdeletion of approximately 2.5 Mb at 2p11.2 in a female baby with left congenital aural atresia, microtia, and ipsilateral internal carotid artery agenesis. The deletion was characterized by fluorescence in situ hybridization, array comparative genomic hybridization, and whole genome re-sequencing. Among the genes present in the deleted region, we focused our attention on the FOXI3 gene. Foxi3 is a member of the Foxi class of Forkhead transcription factors. In mouse, chicken and zebrafish Foxi3 homologues are expressed in the ectoderm and endoderm giving rise to elements of the jaw as well as external, middle and inner ear. Homozygous Foxi3-/- mice have recently been generated and show a complete absence of the inner, middle, and external ears as well as severe defects in the jaw and palate. Recently, a 7-bp duplication within exon 1 of FOXI3 that produces a frameshift and a premature stop codon was found in hairless dogs. Mild malformations of the outer auditory canal (closed ear canal) and ear lobe have also been noted in a fraction of FOXI3 heterozygote Peruvian hairless dogs. Based on the phenotypes of Foxi3 mutant animals, we propose that FOXI3 may be responsible for the phenotypic features of our patient. Further characterization of the genomic region and the analysis of similar patients may help to demonstrate this point.

Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2.

Autosomal-recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is mainly characterized by recurrent, often fatal, respiratory and gastrointestinal infections. About 50% of patients carry mutations in the DNA methyltransferase 3B gene (DNMT3B) (ICF1). The remaining patients carry unknown genetic defects (ICF2) but share with ICF1 patients the same immunological and epigenetic features, including hypomethylation of juxtacentromeric repeat sequences. We performed homozygosity mapping in five unrelated ICF2 patients with consanguineous parents and then performed whole-exome sequencing in one of these patients and Sanger sequencing in all to identify mutations in the zinc-finger- and BTB (bric-a-bric, tramtrack, broad complex)-domain-containing 24 (ZBTB24) gene in four consanguineously descended ICF2 patients. Additionally, we found ZBTB24 mutations in an affected sibling pair and in one patient for whom it was not known whether his parents were consanguineous. ZBTB24 belongs to a large family of transcriptional repressors that include members, such as BCL6 and PATZ1, with prominent regulatory roles in hematopoietic development and malignancy. These data thus indicate that ZBTB24 is involved in DNA methylation of juxtacentromeric DNA and in B cell development and/or B and T cell interactions. Because ZBTB24 is a putative DNA-binding protein highly expressed in the lymphoid lineage, we predict that by studying the molecular function of ZBTB24, we will improve our understanding of the molecular pathophysiology of ICF syndrome and of lymphocyte biology in general.

Paradoxical worsening of seizure activity with pregabalin in an adult with isodicentric 15 (IDIC-15) syndrome involving duplications of the GABRB3, GABRA5 and GABRG3 genes.

BACKGROUND: Isodicentric 15 syndrome (IDIC-15) is due to partial duplications of chromosome 15 that may includes the q11-13 region that includes genes encoding the α5 (GABRA5) and ß3 - γ3 (GABRB3) receptor subunits. The disease causes intellectual and physical developmental delay, seizures, intellectual disability and behavioral disorders that may be related to abnormal GABA receptor function and morphology. Seizures are often severe and may be refractory to treatment. There are however no specific guidelines for the treatment of the seizures and it is unknown whether drugs that affect the GABAergic system have a different effect in IDIC-15 seizures. CASE PRESENTATION: We report the case of an adult individual with IDIC-15 whose complex-partial seizures worsened dramatically after the introduction of pregabalin, with increased seizure frequency, frequent generalization, and appearance of new seizure pattern. Her cognitive function and verbal skills also worsened during treatment with pregabalin. Her seizures and cognitive skills quickly improved after pregabalin was discontinued and treatment with lacosamide started. DISCUSSION: As her genetic testing confirmed that her region of duplication included GABA receptor encoding genes, it is plausible that the worsening of seizures were due to induction of an abnormal GABAergic response to pregabalin. CONCLUSION: As her genetic testing confirmed that her region of duplication included GABA receptor encoding genes, it is plausible that the worsening of seizures were due to induction of an abnormal GABAergic response to pregabalin.This case may help define proper therapeutic strategies for the treatment of IDIC-15 associated seizures.

Diagnosis and treatment of peripheral arterial disease in CKD patients.

Peripheral arterial disease (PAD) is a cardiovascular disease risk equivalent and is a common problem in chronic kidney disease patients. Unlike in the general population, PAD in CKD occurs due to medial calcification as opposed to intimal atherosclerotic process. PAD intervention should be performed in select symptomatic patients, as described by the guidelines, and CVD risk factor modification should occur in all CKD patient, regardless of the presence of PAD. As a discipline, Interventional Nephrology has emerged out of a desire to create better outcomes for our patients and to "fix a problem." The core values of our discipline have evolved out of this fundamental desire to meet an unmet clinical need, to provide insight into a disease state specific to our patients, and to offer clinical/academic excellence in doing so. We must endeavor to follow a similar path in our approach to PAD. The purpose of this review is to educate interventional nephrologists in the diagnosis and treatment of PAD in their CKD patients.

Chronic total occlusion and successful drug-eluting stent placement in Takayasu arteritis-induced renal artery stenosis.

Takayasu arteritis-induced renal artery stenosis (TARAS) is a condition rarely described in the literature. Although percutaneous transluminal angioplasty and stenting has been well-described in the treatment of atherosclerotic renal artery stenosis, its role has not been established in non-atherosclerotic TARAS. We report a case of a female, age 17 years, with Takayasu arteritis who presented to the hospital with seizures and hypertensive crisis. A renal angiogram showed chronic total occlusion (CTO) of the left renal artery. Renal angioplasty and stenting was successfully performed after multiple attempts to deliver a wire distal to the CTO. After sequential balloon predilation, a drug-eluting stent was deployed, resulting in full reperfusion of the kidney. The patient's blood pressure improved dramatically, and patency of the stent was demonstrated with magnetic resonance angiography over 9 months after the procedure.

Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAE genes in a family with developmental delay and behavioural problems.

BACKGROUND: Deletions and duplications of the PAFAH1B1 and YWHAE genes in 17p13.3 are associated with different clinical phenotypes. In particular, deletion of PAFAH1B1 causes isolated lissencephaly while deletions involving both PAFAH1B1 and YWHAE cause Miller-Dieker syndrome. Isolated duplications of PAFAH1B1 have been associated with mild developmental delay and hypotonia, while isolated duplications of YWHAE have been associated with autism. In particular, different dysmorphic features associated with PAFAH1B1 or YWHAE duplication have suggested the need to classify the patient clinical features in two groups according to which gene is involved in the chromosomal duplication. METHODS: We analyze the proband and his family by classical cytogenetic and array-CGH analyses. The putative rearrangement was confirmed by fluorescence in situ hybridization. RESULTS: We have identified a family segregating a 17p13.3 duplication extending 329.5 kilobases by FISH and array-CGH involving the YWHAE gene, but not PAFAH1B1, affected by a mild dysmorphic phenotype with associated autism and mental retardation. We propose that BHLHA9, YWHAE, and CRK genes contribute to the phenotype of our patient. The small chromosomal duplication was inherited from his mother who was affected by a bipolar and borderline disorder and was alcohol addicted. CONCLUSIONS: We report an additional familial case of small 17p13.3 chromosomal duplication including only BHLHA9, YWHAE, and CRK genes. Our observation and further cases with similar microduplications are expected to be diagnosed, and will help better characterise the clinical spectrum of phenotypes associated with 17p13.3 microduplications.

Pre PCI hospital antithrombotic therapy for ST elevation myocardial infarction: striving for consensus.

Strong evidence exists in favor of rapid transfer of a patient suffering an ST-elevation myocardial infarction (STEMI) to the nearest hospital with primary percutaneous coronary intervention (PCI) capability, assuming the time from first medical contact to balloon inflation can be achieved in less than 90 min. In many areas, PCI hospitals have successfully collaborated with regional non-PCI hospitals to provide primary PCI for STEMI; however, significant variations exist in how these programs are executed. For example, the pre PCI hospital administration of antithrombotic agents by emergency medical personnel can include aspirin, clopidogrel, unfractionated heparin, low molecular weight heparin, partial or full dose fibrinolytics or combinations thereof. There is little consensus on the optimal cocktail, dose and route of administration. Standardizing the pre PCI antithrombotic regimen across hospital systems may be one approach to improve timely administration of these therapies, and potentially improve STEMI outcomes.

LUCAS compression device-related severe injuries in a series of patients presenting with outside hospital cardiac arrest.

This case series presents patients who presented to the hospital with an outside hospital cardiac arrest and were initially resuscitated successfully. All patients suffered fatal traumatic injuries during the resuscitation process with the common variable being the use of mechanical cardiopulmonary resuscitation (CPR) device. The goal of this case series is to describe the limitations and potential fatal side effects of CPR. We also present a review of literature with our impressions of the appropriate indications for the use of mechanical CPR. Learning objectives: 1) Recognize appropriate indications for the use of mechanical vs manual cardiopulmonary resuscitation (CPR). 2) Identify signs and symptoms of mechanical CPR-related complications.

Prognosis of paradoxical low-flow low-gradient aortic stenosis after transcatheter aortic valve replacement.

AIMS: In paradoxical low-flow low-gradient severe aortic stenosis (PLFLG AS) patients, stroke volume index (SVI) is reduced despite preserved left ventricular ejection fraction (LVEF). Although reduced SVI is already known as a poor prognostic predictor, the outcomes of PLFLG AS patients after transcatheter aortic valve replacement (TAVR) have not been clearly defined. We retrospectively investigated the post-TAVR outcomes of PLFLG AS patients in comparison with normal-flow high-gradient aortic stenosis (NFHG AS) patients. METHODS: The current observational study included 245 patients with NFHG AS (mean transaortic pressure gradient ≥40 mmHg and LVEF ≥ 50%) and 48 patients with PLFLG AS (mean transaortic pressure gradient <40 mmHg, LVEF ≥ 50% and SVI < 35 ml/m2). The endpoints were all-cause mortality, hospitalization for valve-related symptoms or worsening congestive heart failure and New York Heart Association functional class III or IV. RESULTS: PLFLG AS patients had a significantly higher proportion with a history of atrial fibrillation/flutter as compared with NFHG AS patients. All-cause mortality of PLFLG AS patients was worse than that of NFHG AS patients (P = 0.047). Hospitalization for valve-related symptoms or worsening congestive heart failure was more frequent in PLFLG AS patients than in NFHG AS patients (P = 0.041). New York Heart Association functional class III-IV after TAVR was more frequently observed in PLFLG AS patients (P = 0.019). CONCLUSION: The outcomes of PLFLG AS patients were worse than those of NFHG AS patients in this study. Preexisting atrial fibrillation/flutter was frequent in PLFLG AS patients, and may affect their post-TAVR outcomes. Therefore, closer post-TAVR follow-up should be considered for these patients.

The Prognosis of Elderly Patients with Aortic Stenosis after Transcatheter Aortic Valve Replacement.

Objective Aortic stenosis (AS) is common among elderly patients. Since transcatheter aortic valve replacement (TAVR) is a less invasive procedure than surgical aortic valve replacement for symptomatic severe AS, super-elderly patients have tended to undergo TAVR. We retrospectively investigated the post-TAVR outcome in super-elderly patients with severe AS. Methods This analysis included 433 patients who underwent TAVR in the University of Wisconsin Hospital and Clinics from 2012 to 2017. Post-TAVR mortality, complications in-hospital, rehospitalization, the New York Heart Association (NYHA) functional class and echocardiographic parameters were compared between patients <85 years old (n = 290) and ≥85 years old (n = 143). Results The patients ≥85 years old less frequently had a history of coronary artery disease (73.1% vs. 62.2%, p=0.026) and hypertension (87.2% vs. 77.6%, p=0.012) than younger patients. Furthermore, the patients ≥85 years old had moderate-severe mitral regurgitation more frequently (19.3% vs. 28.7%, p=0.037) at baseline than younger patients. There was no significant difference in in-hospital outcomes between the age groups. The 30-day mortality was worse in patients ≥85 years old than in younger ones (0.7% vs. 3.5%, p=0.042). While there was no significant difference in the long-term mortality between the 2 groups, the estimated 1-year mortality from Kaplan-Meier curves were 9.6% in patients <85 years old and 14.9% in patients ≥85 years old. The rate of in-hospital complications, rehospitalization rate, improvement in the NYHA functional class and echocardiographic parameters were comparable between the two groups. Conclusion The outcomes of super-elderly patients after TAVR were acceptable, suggesting that these patients could benefit from TAVR.

Expanding the phenotype associated with interstitial 6p25.1p24.3 microdeletion: a new case and review of the literature.

Interstitial 6p25.1p24.3 microdeletions are rare events and a clear karyotype/phenotype correlation has not yet been determined. In this study, we present the clinical and molecular description of a child with a de novo 6p25.1p24.3 microdeletion, characterized by array-CGH, associated with mild intellectual disability, facial dysmorphisms, hypopigmentation of the skin of the abdomen, heart defects, mild pontine hypoplasia and hypotonia. This deleted region contains 14 OMIM genes (NRN1, F13A1, RREB1, SSR1, RIOK1, DSP, BMP6, TXNDC5, BLOC1S5, EEF1E1, SLC35B3 and HULC). To the best of our knowledge until now only six cases have been reported presenting an interstitial microdeletion, but a unique case carries a deleted region containing the same genes of our patient. We compared clinical features and genetic data with that of the previously reported patient. We also analysed the gene content of the deleted region to investigate the possible role of specific genes in the clinical phenotype of our patient.