The yield of genetic workup for middle-aged and elderly patients with neurological disorders in a real-world setting.

Genetic workup is becoming increasingly common in the clinical assessment of neurological disorders. We evaluated its yield among middle-aged and elderly neurological patients, in a real-world context. This retrospective study included 368 consecutive Israeli patients aged 50 years and older (202 [54.9%] males), who were referred to a single neurogenetics clinic between 2017 and mid-2023. All had neurological disorders, without a previous molecular diagnosis. Demographic, clinical and genetic data were collected from medical records. The mean age at first genetic counseling at the clinic was 62.3 ± 7.8 years (range 50-85 years), and the main indications for referral were neuromuscular, movement and cerebrovascular disorders, as well as cognitive impairment and dementia. Out of the 368 patients, 245 (66.6%) underwent genetic testing that included exome sequencing (ES), analysis of nucleotide repeat expansions, detection of specific mutations, targeted gene panel sequencing or chromosomal microarray analysis. Overall, 80 patients (21.7%) received a molecular diagnosis due to 36 conditions, accounting for 32.7% of the patients who performed genetic testing. The diagnostic rates were highest for neuromuscular (58/186 patients [31.2%] in this group, 39.2% of 148 tested individuals) and movement disorders (14/79 [17.7%] patients, 29.2% of 48 tested), but lower for other disorders. Testing of nucleotide repeat expansions and ES provided a diagnosis to 28/73 (38.4%) and 19/132 (14.4%) individuals, respectively. Based on our findings, genetic workup and testing are useful in the diagnostic process of neurological patients aged ≥50 years, in particular for those with neuromuscular and movement disorders.

Exploring the factors affecting classification and reporting of uncertain prenatal microarray findings, using a "virtual fetus" model-a pilot study.

OBJECTIVE: Significant discrepancy exists between laboratories in classification and reporting of copy number variants (CNVs). Studies exploring factors affecting prenatal CNV management are rare. Our "virtual fetus" pilot study examines these factors. METHOD: Ten prenatally diagnosed CNVs of uncertain significance (VUS) > 1Mb, encompassing OMIM-morbid genes, inherited from healthy parents, were classified by 15 MD geneticists from laboratory, prenatal, and preimplantation genetic testing (PGT) units. Geneticists addressed factors affecting classification, obligation to report, and recommendation for invasive testing or PGT. RESULTS: CNVs were classified likely benign (10.7%), VUS (74.7%), likely pathogenic (8.7%), or pathogenic (6.0%). Classification discrepancy was higher for losses versus gains. Classifying pathogenic/likely pathogenic was more common for losses (adjusted odds ratio [aOR] 10.9, 95% CI 1.55-76.9), and geneticists specializing in gynecology (aOR 4.9, 95% CI 1.03-23.3). 84.0% of respondents would report CNVs, depending on classification and family phenotype. Invasive testing in pregnancies was recommended for 29.3% of CNVs, depending on the classification and geneticist's specialization. PGT was recommended for 32.4%, depending on classification, experience years, and family's phenotype (38.0% for patients undergoing in vitro fertilization irrespectively, 26.7% otherwise). CONCLUSION: Factors affecting CNV classification/reporting are mainly dosage, family phenotype, geneticist specialization and experience. Understanding factors from our pilot study may facilitate developing an algorithm for clinical consensus and optimal management.

PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects.

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.

SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability.

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity.

GATA2 Deficiency in Adult Life Is Characterized by Phenotypic Diversity and Delayed Diagnosis.

The transcription factor GATA2 plays a key role in the survival and self-renewal of hematopoietic stem and progenitor cells. Autosomal dominant variants in GATA2 cause a broad spectrum of heterogeneous phenotypes. Here, we present our experience with GATA2 deficiency in a retrospective multicenter analysis of computerized medical records of adult patients (age ≥18 years) treated between 2018 and 2022 at Shaare Zedek Medical Center in Jerusalem and Sheba Tel-Hashomer Medical Center in Ramat Gan, Israel. Two male and two female patients with GATA2 deficiency were identified. Three of the patients presented with symptoms in adult life and all patients were diagnosed as adults. Age at presentation was 10.5-36 years and age at diagnosis 24-47 years. Diagnosis was delayed in all patients by 1-24.5 years. The phenotypic diversity was notable. Patients presented with myelodysplastic syndrome (n=2), pulmonary alveolar proteinosis (n=1), and recurrent viral (n=1), bacterial (n=3), and mycobacterial (n=1) infections. Bone marrow biopsy revealed cytogenetic abnormalities in one patient (monosomy 7). Patients were diagnosed by exome sequencing (n=3) and Sanger sequencing of the coding exons in GATA2 (n=1). Novel heterozygous GATA2 variants (c.177C>A, p.Y59* and c.610dup, p.R204Pfs*78) were identified in two patients. Immune workup revealed B cell lymphopenia and monocytopenia in all tested patients. One patient died from overwhelming sepsis despite all patients being treated with antibiotics and anti-mycobacterials. Our cohort highlights the phenotypic diversity, late presentation, and delayed diagnosis of GATA2 deficiency. Increased awareness of this primary immune deficiency presenting in adult life is needed and should involve a high index of suspicion.

Mutations in RPS19 may affect ribosome function and biogenesis in Diamond Blackfan anemia.

Ribosomes, the cellular organelles translating the genetic code to proteins, are assemblies of RNA chains and many proteins (RPs) arranged in precise fine-tuned interwoven structures. Mutated ribosomal genes cause ribosomopathies, including Diamond Blackfan anemia (DBA, a rare heterogeneous red-cell aplasia connected to ribosome malfunction) or failed biogenesis. Combined bioinformatical, structural, and predictive analyses of potential consequences of possibly expressed mutations in eS19, the protein product of the highly mutated RPS19, suggest that mutations in its exposed surface could alter its positioning during assembly and consequently prevent biogenesis, implying a natural selective strategy to avoid malfunctions in ribosome assembly. A search for RPS19 pseudogenes indicated > 90% sequence identity with the wild-type, hinting at its expression in cases of absent or truncated gene products.

A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies.

Exome sequencing (ES) is an important diagnostic tool for individuals with neurodevelopmental disorders (NDD) and/or multiple congenital anomalies (MCA). However, the cost of ES limits the test's accessibility for many patients. We evaluated the yield of publicly funded clinical ES, performed at a tertiary center in Israel, over a 3-year period (2018-2020). Probands presented with (1) moderate-to-profound global developmental delay (GDD)/intellectual disability (ID); or (2) mild GDD/ID with epilepsy or congenital anomaly; and/or (3) MCA. Subjects with normal chromosomal microarray analysis who met inclusion criteria were included, totaling 280 consecutive cases. Trio ES (proband and parents) was the default option. In 252 cases (90.0%), indication of NDD was noted. Most probands were males (62.9%), and their mean age at ES submission was 9.3 years (range 1 month to 51 years). Molecular diagnosis was reached in 109 probands (38.9%), mainly due to de novo variants (91/109, 83.5%). Disease-causing variants were identified in 92 genes, 15 of which were implicated in more than a single case. Male sex, families with multiple-affected members and premature birth were significantly associated with lower ES yield (p < 0.05). Other factors, including MCA and coexistence of epilepsy, autism spectrum disorder, microcephaly or abnormal brain magnetic resonance imaging findings, were not associated with the yield. To conclude, our findings support the utility of clinical ES in a real-world setting, as part of a publicly funded genetic workup for individuals with GDD/ID and/or MCA.

Chromosomal Microarray Analysis in Pregnancies With Corpus Callosum or Posterior Fossa Anomalies.

OBJECTIVE: We investigated the detection rate of clinically significant chromosomal microarray analysis (CMA) results in pregnancies with sonographic diagnosis of fetal corpus callosum anomalies (CCA) or posterior fossa anomalies (PFA). METHODS: All CMA tests in pregnancies with CCA or PFA performed between January 2015 and June 2020 were retrospectively evaluated from the Israeli Ministry of Health database. The rate of CMA with clinically significant (pathogenic or likely pathogenic) findings was calculated and compared to a local Israeli cohort of 5,541 pregnancies with normal ultrasound. RESULTS: One hundred eighty-two pregnancies were enrolled: 102 cases with CCA and 89 with PFA (9 cases had both). Clinically significant CMA results were found in 7/102 of CCA (6.9%) and in 7/89 of PFA (7.9%) cases. The CMA detection rate in pregnancies with isolated CCA (2/57, 3.5%) or PFA (2/50, 4.0%) was lower than in nonisolated cases, including additional CNS and/or extra-CNS sonographic anomalies (CCA-5/45, 11.1%; PFA-5/39, 12.8%), but this was not statistically significant. However, the rate among pregnancies that had extra-CNS anomalies, with or without additional CNS involvement (CCA-5/24, 20.8%; PFA-5/29, 17.2%), was significantly higher compared to all other cases (p = 0.0075 for CCA; p = 0.035 for PFA). Risk of CMA with clinically significant results for all and nonisolated CCA or PFA pregnancies was higher compared to the background risk reported in the control cohort (p < 0.001), but was not significant for isolated cases. CONCLUSIONS: Our findings suggest that CMA testing is beneficial for the genetic workup of pregnancies with CCA or PFA, and is probably most informative when additional extra-CNS anomalies are observed.

Reduction in Filamin C transcript is associated with arrhythmogenic cardiomyopathy in Ashkenazi Jews.

BACKGROUND: Filamin C is a cytoskeletal protein expressed in cardiac cells. Nonsense variations in the filamin C gene (FLNC) were associated with dilated and arrhythmogenic cardiomyopathies. METHODS AND RESULTS: We identified an intronic variation in FLNC gene (c.3791-1G > C) in three unrelated Ashkenazi Jewish families with variable expression of arrhythmia and cardiomyopathy. cDNA was prepared from a mutation carrier's cultured skin fibroblasts. Quantitative PCR demonstrated a reduction in total FLNC transcript, and no other FLNC splice variants were found. Single-nucleotide polymorphism (SNP) analysis revealed heterozygous variations in the genomic DNA that were not expressed in the messenger RNA. Immunohistochemical analysis of cardiac sections detected a normal distribution of filamin C protein in the heart ventricles. CONCLUSION: The transcript that included the FLNC variant was degraded. Haploinsufficiency in filamin C underlies arrhythmogenic cardiomyopathy with variable symptoms.

Anti-MDA5 Positive Dermatomyositis Associated with Rapidly Progressive Interstitial Lung Disease and Correlation between Serum Ferritin Level and Treatment Response.

Clinically amyopathic dermatomyositis is an uncommon autoimmune disorder in the Middle East. The clinical picture of clinically amyopathic dermatomyositis is characterized mainly by pulmonary and dermatological manifestations. Occasionally muscle symptoms are observed as well. Serum anti-MDA5 autoantibody positivity is associated with rapidly progressive interstitial lung disease among clinically amyopathic dermatomyositis patients. Moreover, high serum ferritin level is correlated with poor prognosis and high mortality. Herein we describe the case of an Israeli patient with rapidly progressive interstitial lung disease and without pathognomonic dermatological features who was diagnosed with anti-MDA5 positive clinically amyopathic dermatomyositis and did not survive despite immunomodulatory therapy followed by reduction in serum ferritin levels.

What have we learned from 691 prenatal chromosomal microarrays for ventricular septal defects?

INTRODUCTION: Ventricular septal defect (VSD) represents the most common type of congenital cardiac anomaly, affecting more than 1 in 300 live births. The objective of this study was to examine the incidence and nature of abnormal chromosomal microarray analysis (CMA) results in a large cohort of pregnancies with VSD. MATERIAL AND METHODS: Data acquisition was performed through the Ministry of Health computerized database. All CMA results performed due to VSD during 2013-2017 were included. The rates of clinically significant CMA results of cases with isolated and non-isolated VSD were compared with two control populations-a systematic review of 9272 pregnancies and a local cohort of 5541 fetuses with normal ultrasound. RESULTS: Overall, 691 CMA analyses performed due to a sonographic indication of VSD were detected. Of 568 pregnancies with isolated VSD, eight (1.4%) clinically significant copy number variants were detected, a nonsignificant difference compared with low risk pregnancies. Of the 123 pregnancies with non-isolated VSDs, 18 (14.6%) clinically significant CMA results were detected, a considerably increased risk compared with control pregnancies. Karyotype-detectable anomalies constituted 12 of the 18 abnormal CMA results in non-isolated VSD group (66.7%), a significantly higher proportion compared with 2 of 8 (25%) in isolated VSD cohort. CONCLUSIONS: The outcomes of our study, representing the largest number of CMA results in pregnancies with VSD, suggest that the rate of abnormal CMA findings in isolated VSD does not differ from pregnancies with normal ultrasound. This observation is true for populations undergoing routine common trisomy screening tests and early sonographic evaluation, as well as widely available non-invasive prenatal screening. Conversely, CMA analysis yields a high detection rate in pregnancies with non-isolated VSD. Our results question the recommendation to perform invasive prenatal testing for CMA in pregnancies with isolated VSD.

[HANTAVIRUS PULMONARY SYNDROME DIAGNOSED IN A RETURNED TRAVELER FROM THE USA].

INTRODUCTION: Hantavirus pulmonary syndrome (HPS) is a rare and sometimes fatal respiratory disease in humans. The infection is acquired mainly through inhalation of aerosolized rodent secretions which serves as the reservoir for the virus. HPS cases are mostly reported from the American continent. In this article we describe a case of fulminant HPS in a 47 years old man who had traveled with his family on vacation to the southwestern region of the United States. The patient was hospitalized one month after his return to Israel and the diagnosis of hantavirus infection (species Sin Nombre Virus), was performed on samples sent to the CDC's Viral Special Pathogens Branch. Clinicians should be aware of this special entity and consider HPS in the differential diagnosis of patients with respiratory failure and fever, when there is a history of travel to the endemic area.

A large screen for paraneoplastic neurological autoantibodies; diagnosis and predictive values.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are a group of syndromes that affect the central and peripheral neuromuscular system in association with cancer. Specific antibodies may assist in the diagnosis of PNS. The antibodies tested can be classified into those directed against intracellular neuronal proteins ("well characterized" PNS: Hu, Yo, RI, CV2, amphiphysin, Ma1, Ma2) and those directed against neural surface antigens (autoimmune encephalitis syndromes: NMDA, AMPA, LGI1, CASPR2, GABAR). We aimed to characterize patients with unexplained neuropsychiatric symptoms, in whom positive PNS antibodies were detected in the Sheba medical center, a large referral hospital. METHODS: Clinical and demographic data of patients with positive PNS antibodies were collected during the years 2002-2016. Antibodies were tested by either Line immunoassay or by cell-based indirect immunofluorscent assay. RESULTS: During the follow up of 14 years, 4010 PNS tests were performed in patients with unexplained neuropsychiatric symptoms. Seventy-two were found to be positive; among them we had full clinical data access to 44. The most frequent antibodies were anti-Hu (31.8%), anti-Yo (18.2%), anti-CV2 (13.6%), and anti-NMDA (9.1%), and the most common cancers were small-cell lung (SCLC) and ovarian cancers. In the well characterized paraneoplastic group, cancer was diagnosed in 55.9% of the patients, and in the autoimmune encephalitis group, 40.0% were diagnosed with cancer. A positive correlation between antibody titer and the presence of cancer was found. Ninety percent of the tests in patients who were found positive were ordered by a neurologist or neuro-oncologist. CONCLUSIONS: The titers of PNS auto-antibodies can predict cancer in patients whom anti-PNS antibodies are tested. In addition, consultation with a specialist should be considered before this test is ordered.

Chromosomal Microarray Analysis Results From Pregnancies With Various Ultrasonographic Anomalies.

OBJECTIVE: To examine chromosomal microarray analysis results in pregnancies with various ultrasonographic anomalies and to characterize the copy number variants in diverse fetal phenotypes. METHODS: We retrospectively examined chromosomal microarray analyses of amniocenteses performed nationwide as a result of fetal ultrasonographic anomalies (structural defects, fetal growth restriction, and polyhydramnios) between January 2013 and September 2017. The rate of abnormal chromosomal microarray findings was compared between the different phenotypes and with a previously described control population of 15,225 pregnancies with normal ultrasonographic findings. RESULTS: Clinically significant chromosomal microarray aberrations were detected in 272 of 5,750 pregnancies (4.7%): 115 (2%) karyotype-detectable and 157 (2.7%) submicroscopic. Most commonly detected copy number variants were 22q11.21 deletions (0.4%) followed by 22q11.21 gain of copy number (0.2%). Specific copy number variants detected among pregnancies with abnormal ultrasonographic findings were up to 20-fold more prevalent compared with low-risk pregnancies. Some variants were associated with specific phenotypes (eg, 22q11.21 microdeletions with cardiovascular and 17q12 microdeletions with genitourinary defects). CONCLUSION: The rate of abnormal amniotic chromosomal microarray analysis results is twice that of karyotypic abnormalities in pregnancies with various abnormal ultrasonographic findings.

Smoking and the intestinal microbiome.

Studies are emerging alluding to the role of intestinal microbiome in the pathogenesis of diseases. Intestinal microbiome is susceptible to the influence of environmental factors such as smoking, and recent studies have indicated microbiome alterations in smokers. The aim of the study was to review the literature regarding the impact of smoking on the intestinal microbiome. A literature review of publications in PUBMED was performed using combinations of the terms "Intestinal/Gut/Gastrointestinal/Colonic" with "Microbiome/Microbiota/Microbial/Flora" and "Smoking/Smoker/Tobacco". We selected studies that were published between the years 2000 and 2016 as our inclusion criteria. Observational and interventional studies suggest that the composition of intestinal microbiome is altered due to smoking. In these studies, Proteobacteria and Bacteroidetes phyla were increased, as well as the genera of Clostridium, Bacteroides and Prevotella. On the other hand, Actinobacteria and Firmicutes phyla as well as the genera Bifidobacteria and Lactococcus were decreased. Smoking also decreased the diversity of the intestinal microbiome. Mechanisms that have been suggested to explain the effect of smoking on intestinal microbiome include: oxidative stress enhancement, alterations of intestinal tight junctions and intestinal mucin composition, and changes in acid-base balance. Interestingly, some smoking-induced alterations of intestinal microbiome resemble those demonstrated in conditions such as inflammatory bowel disease and obesity. Further studies should be performed to investigate this connection. Smoking has an effect on intestinal microbiome and is suggested to alter its composition. This interaction may contribute to the development of intestinal and systemic diseases, particularly inflammatory bowel diseases.

Leadless Pacemaker Implantation in a Pediatric Patient with Prolonged Sinus Pauses.

Permanent cardiac pacing is the only effective solution for patients with symptomatic bradycardia and heart block. About 10% of patients undergoing implantation of the conventional pacing system develop complications related to the subcutaneous pocket or the leads and in pediatric patients lead problems may rise in up to 30% of the patients. The leadless pacemaker devices were developed in order to minimize some of those complications. We present a case of an 11-year-old patient who presented after the sudden death of his older brother, with recurrent episodes of syncope and documented prolonged sinus pauses. The patient underwent percutaneous implantation of a leadless Micra™ pacemaker device with optimal results.

A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations via Dysregulation of Retinoic Acid Signaling.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of CKD in the first three decades of life. However, for most patients with CAKUT, the causative mutation remains unknown. We identified a kindred with an autosomal dominant form of CAKUT. By whole-exome sequencing, we identified a heterozygous truncating mutation (c.279delG, p.Trp93fs*) of the nuclear receptor interacting protein 1 gene (NRIP1) in all seven affected members. NRIP1 encodes a nuclear receptor transcriptional cofactor that directly interacts with the retinoic acid receptors (RARs) to modulate retinoic acid transcriptional activity. Unlike wild-type NRIP1, the altered NRIP1 protein did not translocate to the nucleus, did not interact with RARα, and failed to inhibit retinoic acid-dependent transcriptional activity upon expression in HEK293 cells. Notably, we also showed that treatment with retinoic acid enhanced NRIP1 binding to RARα RNA in situ hybridization confirmed Nrip1 expression in the developing urogenital system of the mouse. In explant cultures of embryonic kidney rudiments, retinoic acid stimulated Nrip1 expression, whereas a pan-RAR antagonist strongly reduced it. Furthermore, mice heterozygous for a null allele of Nrip1 showed a CAKUT-spectrum phenotype. Finally, expression and knockdown experiments in Xenopus laevis confirmed an evolutionarily conserved role for NRIP1 in renal development. These data indicate that dominant NRIP1 mutations can cause CAKUT by interference with retinoic acid transcriptional signaling, shedding light on the well documented association between abnormal vitamin A levels and renal malformations in humans, and suggest a possible gene-environment pathomechanism in this disease.

Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies.

BACKGROUND: Filamin C (encoded by the FLNC gene) is essential for sarcomere attachment to the plasmatic membrane. FLNC mutations have been associated with myofibrillar myopathies, and cardiac involvement has been reported in some carriers. Accordingly, since 2012, the authors have included FLNC in the genetic screening of patients with inherited cardiomyopathies and sudden death. OBJECTIVES: The aim of this study was to demonstrate the association between truncating mutations in FLNC and the development of high-risk dilated and arrhythmogenic cardiomyopathies. METHODS: FLNC was studied using next-generation sequencing in 2,877 patients with inherited cardiovascular diseases. A characteristic phenotype was identified in probands with truncating mutations in FLNC. Clinical and genetic evaluation of 28 affected families was performed. Localization of filamin C in cardiac tissue was analyzed in patients with truncating FLNC mutations using immunohistochemistry. RESULTS: Twenty-three truncating mutations were identified in 28 probands previously diagnosed with dilated, arrhythmogenic, or restrictive cardiomyopathies. Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 patients with hypertrophic cardiomyopathy. Fifty-four mutation carriers were identified among 121 screened relatives. The phenotype consisted of left ventricular dilation (68%), systolic dysfunction (46%), and myocardial fibrosis (67%); inferolateral negative T waves and low QRS voltages on electrocardiography (33%); ventricular arrhythmias (82%); and frequent sudden cardiac death (40 cases in 21 of 28 families). Clinical skeletal myopathy was not observed. Penetrance was >97% in carriers older than 40 years. Truncating mutations in FLNC cosegregated with this phenotype with a dominant inheritance pattern (combined logarithm of the odds score: 9.5). Immunohistochemical staining of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations. CONCLUSIONS: Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death. Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC.

Prenatal diagnosis of 17q12 deletion syndrome: from fetal hyperechogenic kidneys to high risk for autism.

OBJECTIVE: The linkage between 17q12 microdeletions, renal anomalies, and higher risk for neurodevelopmental disorders is well described in the literature. The current study presents prenatal diagnosis of normal-sized fetal hyperechogenic kidneys leading to the diagnosis of 17q12 deletion syndrome and autism spectrum disorder. METHODS: Over a period of 9 years in a single referral center, seven fetuses were diagnosed with hyperechogenic renal parenchyma and were followed up prospectively. Amniocentesis for molecular diagnosis was performed in all cases, and subsequently, five fetuses were found to harbor a 17q12 deletion by chromosomal microarray analysis. Postnatal evaluation was carried out by a developmental neurologist. RESULTS: Five of the seven fetuses had molecular diagnosis of 17q12 deletion. One patient elected termination of pregnancy. On long-term follow-up, all of the four children showed symptoms consistent with neurodevelopmental disorders. The two fetuses with no deletion have a normal follow-up with regression of the renal hyperechogenicity. CONCLUSIONS: We report a strikingly high correlation between prenatal hyperechogenic kidneys, 17q12 microdeletion, and autism spectrum disorder with the advantage of optimal prenatal counseling as well as early diagnosis and intervention. © 2016 John Wiley & Sons, Ltd.

[RARE DISEASES DTC: DIAGNOSIS, TREATMENT AND CARE].

Rare diseases are chronic, progressive genetic disorders, which affect around 6-8% of the general population, mainly children. Therefore, in Israel approximately 500,000 people are probably affected by a rare disease. In this article, we review some of the issues pertaining to rare diseases, such as the need for accurate diagnosis which is necessary not only for specific care and treatment but also for informed family planning. In addition, we review the impact of the activities of patients' organizations on the awareness of rare diseases and their involvement in the creation of the Orphan Drug Act, which was the leading point on the way to drug development worldwide. During the last few years networks for reaching leading specialists' opinions on the way to proper diagnosis were created. Thereafter, the next generation genetic technologies, such as exome sequencing, have been a revolution in terms of options and hope for patients with rare undiagnosed diseases. Patients with rare diseases and their families are a challenge to the health care system, not only in terms of diagnosis and therapy, but also in terms of special needs. In addition, deciphering molecular pathways of rare diseases might be the key for understanding molecular events involved in common disorders. We emphasize the duty to ensure appropriate capacity and equal access to follow-up and clinical management of patients with rare diseases in Israel.