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News Article | February 28, 2017

BOSTON--(BUSINESS WIRE)--Today, FDNA announces the launch of its Year of Discovery initiative. Beginning in March, the Year of Discovery initiative will unite clinicians, labs and patients worldwide to make rare disease discoveries, with a special focus on specific rare disease categories each month of 2017. Every patient and doctor who treats rare disease patients is invited to participate. The initiative is designed to create the world’s largest source of rare disease “big” data that is analyzed by artificial intelligence and made available to clinicians and researchers to more efficiently diagnose rare diseases. Currently, 1 of 10 people in the U.S. suffers from a rare disease. “We’re just at the very beginning of understanding the genetics behind rare diseases,” says FDNA CEO Dekel Glebman. “By aggregating data from clinicians and laboratories worldwide, the hope is to identify new genes and phenotypes that will lead to the diagnosis, and ultimately treatment, of new syndromes and conditions.” Doctors can make a direct impact by loading their patient phenotypes, facial photos and diagnoses to be analyzed by a HIPAA-compliant deep learning technology that can make new discoveries. Patients are invited to request that their own information be included in the analysis. The analysis will be completed using FDNA's platform, Face2Gene Suite, using facial analysis, deep learning and artificial intelligence to analyze patient facial characteristics, phenotypes and genes to discover links with syndromes and genetic variants. As a special benefit, partnering patient advocacy organizations will receive donations from partner labs in the amount of $1 for every case added to the analysis each month*. The initiative kicks off in March with Blueprint Genetics sponsoring RASopathies. “The Year of Discovery is all about gaining new insights and advancing our knowledge about how to diagnose and treat all rare diseases,” says Dekel Gelbman, CEO of FDNA. “Every patient has their own story, journey, symptoms, and genes. With the Face2Gene technology, we can learn from those stories to develop practices to efficiently recognize these syndromes and find solutions faster.” Participation in the Year of Discovery campaign will work as follows: 1. Download and fill out the patient form at 2. Submit the form to your doctor for review 3. Doctors will upload the information to FDNA’s Face2Gene platform where it will be analyzed 1. Log in or register for a free Face2Gene account at or through the app on your mobile device 2. Submit your patient photos, diagnoses and phenotypes for analysis Learn more about the Year of Discovery or get more detailed instructions at Below is the list of the ten targeted disease categories for 2017. Cases from other rare diseases can be shared as well during 2017, and they will be included in the search for discoveries as resources permit. Today, 30 million people in the United States are living with a rare disease. Each case added thanks to the Year of Discovery initiative will provide invaluable information that will improve the overall understanding of rare diseases, affecting the lives of millions every day. *All donations are provided directly by the participating sponsor in such month and at its sole responsibility. Amounts may be capped to a maximum in each month, at the participating sponsor’s sole discretion. Face2Gene is a clinical warehouse platform with a suite of phenotyping applications that facilitates comprehensive and precise genetic evaluations. FDNA uses facial analysis, deep learning and artificial intelligence to transform big data into actionable genomic insights to improve and accelerate diagnostics and therapeutics. With the world’s largest network of clinicians, labs and researchers creating one of the fastest growing and most comprehensive genomic databases, FDNA is changing the lives of rare disease patients. For more information, please visit

Hiippala A.,University of Helsinki | Tallila J.,Blueprint Genetics | Myllykangas S.,Blueprint Genetics | Myllykangas S.,University of Helsinki | And 4 more authors.
American Journal of Medical Genetics, Part A | Year: 2015

Timothy syndrome is a rare multiorgan disorder with prolonged QTc interval, congenital heart defects, syndactyly, typical facial features and neurodevelopmental problems. Ventricular tachyarrhythmia is the leading cause of death at early age. Classical Timothy syndrome type 1 (TS1) results from a recurrent de novo CACNA1C mutation, G406R in exon 8A. An atypical form of Timothy syndrome type 2 (TS2) is caused by mutations in G406R and G402S in the alternatively spliced exon 8. Only one individual for each exon 8 mutations has been described. In contrast to multiorgan disease caused by the mutation in G406R either in exon 8A or 8, the G402S carrier manifested only an isolated cardiac phenotype with LQTS and cardiac arrest. We describe a teenage patient resuscitated from ventricular fibrillation and treated with an implantable cardioverter defibrillator. She has no other organ manifestations, no syndactyly, normal neurodevelopment and her QTc has ranged between 440-480ms. There is no family history of arrhythmias or sudden death. Targeted oligonucleotide-selective sequencing (OS-Seq) of channelopathy genes revealed a de novo substitution, G402S in exon 8 of CACNA1C. Direct sequencing of blood and saliva derived DNA showed an identical mutation peak suggesting ubiquitous expression in different tissues. The phenotype of our patient and the previously described patient show an isolated arrhythmia disease with no other organ manifestations of classical Timothy syndrome. © 2015 Wiley Periodicals, Inc.

Akinrinade O.,University of Helsinki | Alastalo T.-P.,University of Helsinki | Alastalo T.-P.,Blueprint Genetics | Koskenvuo J.W.,Blueprint Genetics | Koskenvuo J.W.,University of Helsinki
Clinical Genetics | Year: 2016

Dilated cardiomyopathy (DCM), a genetically heterogeneous cardiac disease characterized by left ventricular dilatation and systolic dysfunction, is caused majorly by truncations of titin (TTN), especially in A-band region. Clinical interpretation of TTN-truncating variants (TTNtv) has been challenged by the existing inaccurate variant assessment strategies and uncertainty in the true frequency of TTNtv across the general population. We aggregated TTNtv identified in 1788 DCM patients and compared the variants with those reported in over 60,000 Exome Aggregation Consortium reference population. We implemented our current variant assessment strategy that prioritizes TTNtv affecting all transcripts of the gene, and observed a decline in the prevalence of TTNtv in DCM. Despite this decline, TTNtv are more prevalent in DCM patients compared with reference population (p = 4.1 × 10−295). Moreover, our extended analyses confirmed the enrichment of TTNtv not only in the A-band but also in the I/A-band junction of TTN. We estimated the probability of pathogenicity of TTNtv affecting all transcripts of TTN, identified in unselected DCM patients to be 97.8% (likelihood ratio (LR) = 42.2). We emphasize that identifying a TTNtv, especially in the A-band region, has a higher risk of being disease-causing than previously anticipated, and recommend prioritizing TTNtv affecting at least five transcripts of the gene. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

PubMed | Blueprint Genetics and University of Helsinki
Type: Journal Article | Journal: American journal of medical genetics. Part A | Year: 2016

We report a 10-year-old girl presenting with severe neonatal hypertrophic cardiomyopathy (HCM), feeding difficulties, mildly abnormal facial features, and progressive skeletal muscle symptoms but with normal cognitive development. Targeted oligonucleotide-selective sequencing of 101 cardiomyopathy genes revealed the genetic diagnosis, and the mutation was verified by Sanger sequencing in the patient and her parents. To offer insights into the potential mechanism of patient mutation, protein structural analysis was performed using the resolved structure of human activated HRAS protein with bound GTP analogue (PDB id 5P21) in Discovery Studio 4.5 (Dassault Systmes Biovia, San Diego, CA). The patient with hypertrophic cardiomyopathy and normal cognitive development was diagnosed with an HRAS mutation c.173C>T (p.T58I), a milder variant of Costello syndrome affecting a highly conserved amino acid, threonine 58. Our analysis suggests that the p.G12 mutations slow GTP hydrolysis rendering HRAS unresponsive to GTPase activating proteins, and resulting in permanently active state. The p.T58I mutation likely affects binding of guanidine-nucleotide-exchange factors, thereby promoting the active state but also allowing for slow inactivation. Patients with the HRAS mutation c.173C>T (p.T58I) might go undiagnosed because of the milder phenotype compared with other mutations causing Costello syndrome. We expand the clinical and molecular picture of the rare HRAS mutation by reporting the first case in Europe and the fourth case in the literature. Our protein structure analysis offers insights into the mechanism of the mildly activating p.T58I mutation. 2016 Wiley Periodicals, Inc.

PubMed | Blueprint Genetics and University of Helsinki
Type: Journal Article | Journal: European heart journal | Year: 2015

Despite our increased understanding of the genetic basis of dilated cardiomyopathy (DCM), the clinical utility and yield of clinically meaningful findings of comprehensive next-generation sequencing (NGS)-based genetic diagnostics in DCM has been poorly described. We utilized a high-quality oligonucleotide-selective sequencing (OS-Seq)-based targeted sequencing panel to investigate the genetic landscape of DCM in Finnish population and to evaluate the utility of OS-Seq technology as a novel comprehensive diagnostic tool.Using OS-Seq, we targeted and sequenced the coding regions and splice junctions of 101 genes associated with cardiomyopathies in 145 unrelated Finnish patients with DCM. We developed effective bioinformatic variant filtering strategy and implemented strict variant classification scheme to reveal diagnostic yield and genotype-phenotype correlations. Implemented OS-Seq technology provided high coverage of the target region (median coverage 410 and 99.42% of the nucleotides were sequenced at least 15 read depth). Diagnostic yield was 35.2% (familial 47.6% and sporadic 25.6%, P = 0.004) when both pathogenic and likely pathogenic variants are considered as disease causing. Of these, 20 (53%) were titin (TTN) truncations (non-sense and frameshift) affecting all TTN transcripts. TTN truncations accounted for 20.6% and 14.6% of the familial and sporadic DCM cases, respectively.Panel-based, high-quality NGS enables high diagnostic yield especially in the familial form of DCM, and bioinformatic variant filtering is a reliable step in the process of interpretation of genomic data in a clinical setting.

PubMed | Blueprint Genetics and University of Helsinki
Type: | Journal: Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance | Year: 2015

Autosomal dominantly inherited PRKAG2 cardiac syndrome is due to a unique defect of the cardiac cell metabolism and has a distinctive histopathology with excess intracellular glycogen, and prognosis different from sarcomeric hypertrophic cardiomyopathy. We aimed to define the distinct characteristics of PRKAG2 using cardiovascular magnetic resonance (CMR).CMR (1.5T) and genetic testing were performed in two families harboring PRKAG2 mutations. On CMR, segmental analysis of left ventricular (LV) hypertrophy (LVH), function, native T1 mapping, and late gadolinium enhancement (LGE) were performed.Six individuals (median age 23years, range 16-48; two females) had a PRKAG2 mutation: five with an R302Q mutation (family 1), and one with a novel H344P mutation (family 2). Three of six mutation carriers had LV mass above age and gender limits (203g/m2, 157g/m2 and 68g/m2) and others (with R302Q mutation) normal LV masses. All mutation carriers had LVH in at least one segment, with the median maximal wall thickness of 13mm (range 11-37mm). Two R302Q mutation carriers with markedly increased LV mass (203g/m2 and 157g/m2) showed a diffuse pattern of hypertrophy but predominantly in the interventricular septum, while other mutation carriers exhibited a non-symmetric mid-infero-lateral pattern of hypertrophy. In family 1, the mutation negative male had a mean T1 value of 963ms, three males with the R302Q mutation, LVH and no LGE a mean value of 91811ms, and the oldest male with the R302Q mutation, extensive hypertrophy and LGE a mean value of 973ms. Of six mutations carriers, two with advanced disease had LGE with 11 and 22% enhancement of total LV volume.PRKAG2 cardiac syndrome may present with eccentric distribution of LVH, involving focal mid-infero-lateral pattern in the early disease stage, and more diffuse pattern but focusing on interventricular septum in advanced cases. In patients at earlier stages of disease, without LGE, T1 values may be reduced, while in the advanced disease stage T1 mapping may result in higher values caused by fibrosis. CMR is a valuable tool in detecting diffuse and focal myocardial abnormalities in PRKAG2 cardiomyopathy.

PubMed | Blueprint Genetics and University of Helsinki
Type: Journal Article | Journal: SpringerPlus | Year: 2016

Using small RNA sequencing of libraries established from cervical samples and cervical cancer cell lines, we have previously reported identification of nine and validation of five putative microRNA species encoded by human papillomaviruses (HPV) including five microRNAs encoded by HPV 16. Here we have studied the expression of HPV 16 encoded microRNAs in cervical samples and in HPV 16 containing cell lines. Different sample matrices were collected for the study: 20 paraffin embedded cervical tissue samples, 16 liquid cytology samples, and 16 cervical cell samples from women attending colposcopy due to cervical abnormalities, as well as four HPV 16 containing cell lines. Total RNA was extracted, the samples were spiked with small synthetic control RNAs, and the expression of five HPV 16 encoded microRNAs was assessed by real-time PCR amplification. HPV encoded microRNAs could be frequently detected, albeit at high cycle counts. HPV16-miR-H1 was detected in 3.6%, HPV16-miR-H3 in 23.6%, HPV16-miR-H5 in 7.3%, and HPV16-miR-H6 in 18.2% of all valid samples. True positive signals for HPV16-miR-H2 could not be detected in any of the samples. Viral microRNAs were detected most frequently in paraffin-embedded samples: in one sample representing normal squamous epithelium, in one cervical intraepithelial neoplasia (CIN) grade 1, one CIN2, three CIN3, two squamous cell carcinoma, three adenocarcinoma in situ, and two adenocarcinoma samples. One liquid cytology sample from a patient with CIN3 as well as all four cell lines were positive for HPV16-miR-H3. In all cases HPV encoded microRNAs were expressed at low levels.

PubMed | Blueprint Genetics and University of Helsinki
Type: Journal Article | Journal: PloS one | Year: 2015

Truncating titin (TTN) mutations, especially in A-band region, represent the most common cause of dilated cardiomyopathy (DCM). Clinical interpretation of these variants can be challenging, as these variants are also present in reference populations. We carried out systematic analyses of TTN truncating variants (TTNtv) in publicly available reference populations, including, for the first time, data from Exome Aggregation Consortium (ExAC). The goal was to establish more accurate estimate of prevalence of different TTNtv to allow better clinical interpretation of these findings.Using data from 1000 Genomes Project, Exome Sequencing Project (ESP) and ExAC, we estimated the prevalence of TTNtv in the population. In the three population datasets, 52-54% of TTNtv were not affecting all TTN transcripts. The frequency of truncations affecting all transcripts in ExAC was 0.36% (0.32% - 0.41%, 95% CI) and 0.19% (0.16% - 0.23%, 95% CI) for those affecting the A-band. In the A-band region, the prevalences of frameshift, nonsense and essential splice site variants were 0.057%, 0.090%, and 0.047% respectively. Cga/Tga (arginine/nonsense-R/*) transitional change at CpG mutation hotspots was the most frequent type of TTN nonsense mutation accounting for 91.3% (21/23) of arginine residue nonsense mutation (R/*) at TTN A-band region. Non-essential splice-site variants had significantly lower proportion of private variants and higher proportion of low-frequency variants compared to essential splice-site variants (P = 0.01; P = 5.1 X 10-4, respectively).A-band TTNtv are more rare in the general population than previously reported. Based on this analysis, one in 500 carries a truncation in TTN A-band suggesting the penetrance of these potentially harmful variants is still poorly understood, and some of these variants do not manifest as autosomal dominant DCM. This calls for caution when interpreting TTNtv in individuals and families with no history of DCM. Considering the size of TTN, expertise in DNA library preparation, high coverage NGS strategies, validated bioinformatics approach, accurate variant assessment strategy, and confirmatory sequencing are prerequisites for reliable evaluation of TTN in clinical settings, and ideally with the inclusion of mRNA and/or protein level assessment for a definite diagnosis.

Genomic research has come a long way in recent years. Once the legal and regulatory issues are figured out, the research may provide the basis for a new data-driven care delivery model that could revolutionize health care. One company that’s pushing the puck forward is genetics startup Blueprint Genetics, which has developed a new way of sequencing the genome based on Stanford research, and a proprietary software for gleaning diagnostic information from it. Blueprint says its method is faster and more cost-efficient than other methods. And today, the company announced a new $3.9 million funding round raised from unnamed investors. Academic research has identified the molecular genetic backgrounds of more than 3,500 inherited diseases. But health organizations have lacked software systems sophisticated enough to quickly and accurately diagnose disease using that data. And that’s where Blueprint is finding its niche. This is how it works: The care provider sends some of a patient’s genetic material to Blueprint. The company then sequences the genome and returns its diagnostic results via a website. All reports include a geneticist statement evaluating the patient history and describing the pathological mutation findings. “All of our diagnostic panels represent the latest research on the field and analyses and clinical interpretations are made by our clinicians and geneticists,” Blueprint says at its website. The service differs from that of 23andMe in that it is available only to health care professionals, not consumers. In 2013, the company entered the market with its first product category, providing diagnostics for inherited cardiovascular disorders. Blueprint already has more than 60 hospital customers in 10 countries. It’ll use its new funding money to bring its technology to hospitals in the U.S.

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