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  1. Article ; Online: A novel frameshift variant in

    Lähteenoja, Laura / Häkli, Sanna / Tuupanen, Sari / Kuismin, Outi / Palosaari, Tapani / Rahikkala, Elisa / Falck, Aura

    Ophthalmic genetics

    2022  Volume 43, Issue 2, Page(s) 152–158

    Abstract: Background: Pathogenic variants in the : Materials and methods: Our patients were first discovered in a registry-based study. Later, they gave their written consent for this study. In order to describe the genotype and phenotype, their historic ... ...

    Abstract Background: Pathogenic variants in the
    Materials and methods: Our patients were first discovered in a registry-based study. Later, they gave their written consent for this study. In order to describe the genotype and phenotype, their historic clinical patient data and genetic data were gathered, and a clinical ophthalmic examination and an audiogram were performed. For this review, a PubMed search using the keyword CEP78 was carried out. The first article on
    Results: A large gene panel identified a homozygous
    Conclusions: Here, we present a comprehensive review of
    MeSH term(s) Cell Cycle Proteins/genetics ; Frameshift Mutation ; Humans ; Mutation ; Pedigree ; Phenotype ; Retinitis Pigmentosa/genetics ; Retinitis Pigmentosa/pathology ; Usher Syndromes/genetics
    Chemical Substances CEP78 protein, human ; Cell Cycle Proteins
    Language English
    Publishing date 2022-03-03
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 1199279-7
    ISSN 1744-5094 ; 0167-6784 ; 1381-6810
    ISSN (online) 1744-5094
    ISSN 0167-6784 ; 1381-6810
    DOI 10.1080/13816810.2022.2045511
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  2. Article: Rare Variants in Genes Associated With Cardiomyopathy Are Not Common in Hypoplastic Left Heart Syndrome Patients With Myocardial Dysfunction.

    Helle, Emmi / Pihkala, Jaana / Turunen, Riitta / Ruotsalainen, Hanna / Tuupanen, Sari / Koskenvuo, Juha / Ojala, Tiina

    Frontiers in pediatrics

    2020  Volume 8, Page(s) 596840

    Abstract: Myocardial dysfunction is a known risk factor for morbidity and mortality in hypoplastic left heart syndrome (HLHS). Variants in some transcription factor and contractility genes, which are known to cause cardiomyopathy, have previously been associated ... ...

    Abstract Myocardial dysfunction is a known risk factor for morbidity and mortality in hypoplastic left heart syndrome (HLHS). Variants in some transcription factor and contractility genes, which are known to cause cardiomyopathy, have previously been associated with impaired right ventricular function in some HLHS patients. The care of HLHS patients is resource demanding. Identifying genetic variants associated with myocardial dysfunction would be helpful in tailoring the follow-up and therapeutic strategies. We tested whether a commercial cardiomyopathy gene panel could serve as a diagnostic tool in a Finnish cohort of HLHS patients with impaired right ventricular function to identify potentially pathogenic variants associated with poor prognosis. None of the patients had pathogenic or likely pathogenic variants in the studied cardiomyopathy-associated genes. Thus, our approach of performing a cardiomyopathy gene panel to identify pathogenic variants as directly causal or as modifiers for worse outcomes in hypoplastic left heart syndrome is not useful in clinical practice at the moment.
    Language English
    Publishing date 2020-10-30
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2711999-3
    ISSN 2296-2360
    ISSN 2296-2360
    DOI 10.3389/fped.2020.596840
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  3. Article ; Online: X-linked myotubular myopathy mimics hereditary spastic paraplegia in two female manifesting carriers of pathogenic MTM1 variant.

    Kraatari, Minna / Tuominen, Hannu / Tuupanen, Sari / Haapaniemi, Tarja / Moilanen, Jukka / Rahikkala, Elisa

    European journal of medical genetics

    2020  Volume 63, Issue 11, Page(s) 104040

    Abstract: X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy caused by pathogenic variants in the myotubularin 1 (MTM1) gene. XLMTM leads to severe weakness in male infants and majority of them die in the early postnatal period due to respiratory ... ...

    Abstract X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy caused by pathogenic variants in the myotubularin 1 (MTM1) gene. XLMTM leads to severe weakness in male infants and majority of them die in the early postnatal period due to respiratory failure. Disease manifestations in female carriers vary from asymptomatic to severe, generalized congenital weakness. The symptomatic female carriers typically have limb-girdle weakness, asymmetric muscle weakness and skeletal size, urinary incontinence, facial weakness, ptosis and ophthalmoplegia. Here we describe a Finnish family with two females with lower limb spasticity and hyperreflexia resembling spastic paraplegia, gait difficulties and asymmetric muscle weakness in the limbs. A whole exome sequencing identified a heterozygous pathogenic missense variant MTM1 c.1262G > A, p.(Arg421Gln) segregating in the family. The variant has previously been detected in male and female patients with XLMTM. Muscle biopsy of one of the females showed variation in the myofiber diameter, atrophic myofibers, central nuclei and necklace fibers consistent with a diagnosis of XLMTM. This report suggests association between spastic paraplegia and pathogenic MTM1 variants expanding the phenotypic spectrum potentially associated with XLMTM, but the possible association needs to be confirmed by additional cases.
    MeSH term(s) Adult ; Aged ; Diagnosis, Differential ; Female ; Genetic Testing ; Heterozygote ; Humans ; Mutation, Missense ; Myopathies, Structural, Congenital/diagnosis ; Myopathies, Structural, Congenital/genetics ; Pedigree ; Phenotype ; Protein Tyrosine Phosphatases, Non-Receptor/genetics ; Spastic Paraplegia, Hereditary/diagnosis ; Spastic Paraplegia, Hereditary/genetics
    Chemical Substances Protein Tyrosine Phosphatases, Non-Receptor (EC 3.1.3.48) ; myotubularin (EC 3.1.3.48)
    Language English
    Publishing date 2020-08-14
    Publishing country Netherlands
    Document type Case Reports ; Journal Article
    ZDB-ID 2184135-4
    ISSN 1878-0849 ; 1769-7212
    ISSN (online) 1878-0849
    ISSN 1769-7212
    DOI 10.1016/j.ejmg.2020.104040
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  4. Article ; Online: Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy.

    Hawer, Harmen / Mendelsohn, Bryce A / Mayer, Klaus / Kung, Ann / Malhotra, Amit / Tuupanen, Sari / Schleit, Jennifer / Brinkmann, Ulrich / Schaffrath, Raffael

    European journal of human genetics : EJHG

    2020  Volume 28, Issue 11, Page(s) 1497–1508

    Abstract: We describe a novel type of ribosomopathy that is defined by deficiency in diphthamidylation of translation elongation factor 2. The ribosomopathy was identified by correlating phenotypes and biochemical properties of previously described patients with ... ...

    Abstract We describe a novel type of ribosomopathy that is defined by deficiency in diphthamidylation of translation elongation factor 2. The ribosomopathy was identified by correlating phenotypes and biochemical properties of previously described patients with diphthamide biosynthesis gene 1 (DPH1) deficiencies with a new patient that carried inactivating mutations in both alleles of the human diphthamide biosynthesis gene 2 (DPH2). The human DPH1 syndrome is an autosomal recessive disorder associated with developmental delay, abnormal head circumference (microcephaly or macrocephaly), short stature, and congenital heart disease. It is defined by variants with reduced functionality of the DPH1 gene observed so far predominantly in consanguineous homozygous patients carrying identical mutant alleles of DPH1. Here we report a child with a very similar phenotype carrying biallelic variants of the human DPH2. The gene products DPH1 and DPH2 are components of a heterodimeric enzyme complex that mediates the first step of the posttranslational diphthamide modification on the nonredundant eukaryotic translation elongation factor 2 (eEF2). Diphthamide deficiency was shown to reduce the accuracy of ribosomal protein biosynthesis. Both DPH2 variants described here severely impair diphthamide biosynthesis as demonstrated in human and yeast cells. This is the first report of a patient carrying compound heterozygous DPH2 loss-of-function variants with a DPH1 syndrome-like phenotype and implicates diphthamide deficiency as the root cause of this patient's clinical phenotype as well as of DPH1-syndrome. These findings define "diphthamide-deficiency syndrome" as a special ribosomopathy due to reduced functionality of components of the cellular machinery for eEF2-diphthamide synthesis.
    MeSH term(s) Cell Line ; Developmental Disabilities/genetics ; Developmental Disabilities/metabolism ; Developmental Disabilities/pathology ; Heart Defects, Congenital/genetics ; Heart Defects, Congenital/metabolism ; Heart Defects, Congenital/pathology ; Histidine/analogs & derivatives ; Histidine/deficiency ; Histidine/metabolism ; Humans ; Infant ; Loss of Function Mutation ; Male ; Megalencephaly/genetics ; Megalencephaly/metabolism ; Megalencephaly/pathology ; Proteins/genetics ; Proteins/metabolism ; Ribosomes/metabolism ; Saccharomyces cerevisiae ; Syndrome
    Chemical Substances DPH2 protein, human ; Proteins ; Histidine (4QD397987E) ; diphthamide (75645-22-6)
    Language English
    Publishing date 2020-06-23
    Publishing country England
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1141470-4
    ISSN 1476-5438 ; 1018-4813
    ISSN (online) 1476-5438
    ISSN 1018-4813
    DOI 10.1038/s41431-020-0668-y
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    Zs.A 3589: Show issues Location:
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  5. Article ; Online: Prevalence of RPGR-Mediated Retinal Dystrophy in an Unselected Cohort of Over 5000 Patients.

    Tuupanen, Sari / Gall, Kimberly / Sistonen, Johanna / Saarinen, Inka / Kämpjärvi, Kati / Wells, Kirsty / Merkkiniemi, Katja / von Nandelstadh, Pernilla / Sarantaus, Laura / Känsäkoski, Johanna / Mårtenson, Emma / Västinsalo, Hanna / Schleit, Jennifer / Sankila, Eeva-Marja / Kere, Annakarin / Junnila, Heidi / Siivonen, Pauli / Andreevskaya, Margarita / Kytölä, Ville /
    Muona, Mikko / Salmenperä, Pertteli / Myllykangas, Samuel / Koskenvuo, Juha / Alastalo, Tero-Pekka

    Translational vision science & technology

    2022  Volume 11, Issue 1, Page(s) 6

    Abstract: Purpose: Comprehensive genetic testing for inherited retinal dystrophy (IRD) is challenged by difficult-to-sequence genomic regions, which are often mutational hotspots, such as RPGR ORF15. The purpose of this study was to evaluate the diagnostic ... ...

    Abstract Purpose: Comprehensive genetic testing for inherited retinal dystrophy (IRD) is challenged by difficult-to-sequence genomic regions, which are often mutational hotspots, such as RPGR ORF15. The purpose of this study was to evaluate the diagnostic contribution of RPGR variants in an unselected IRD patient cohort referred for testing in a clinical diagnostic laboratory.
    Methods: A total of 5201 consecutive patients were analyzed with a clinically validated next-generation sequencing (NGS)-based assay, including the difficult-to-sequence RPGR ORF15 region. Copy number variant (CNV) detection from NGS data was included. Variant interpretation was performed per the American College of Medical Genetics and Genomics guidelines.
    Results: A confirmed molecular diagnosis in RPGR was found in 4.5% of patients, 24.0% of whom were females. Variants in ORF15 accounted for 74% of the diagnoses; 29% of the diagnostic variants were in the most difficult-to-sequence central region of ORF15 (c.2470-3230). Truncating variants made up the majority (91%) of the diagnostic variants. CNVs explained 2% of the diagnostic cases, of which 80% were one- or two-exon deletions outside of ORF15.
    Conclusions: Our findings indicate that high-throughput, clinically validated NGS-based testing covering the difficult-to-sequence region of ORF15, in combination with high-resolution CNV detection, can help to maximize the diagnostic yield for patients with IRD.
    Translational relevance: These results demonstrate an accurate and scalable method for the detection of RPGR-related variants, including the difficult-to-sequence ORF15 hotspot, which is relevant given current and emerging therapeutic opportunities.
    MeSH term(s) Exons ; Eye Proteins/genetics ; Female ; Humans ; Pedigree ; Prevalence ; Retinal Dystrophies/diagnosis ; Retinal Dystrophies/epidemiology ; Retinal Dystrophies/genetics
    Chemical Substances Eye Proteins ; RPGR protein, human
    Language English
    Publishing date 2022-01-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2674602-5
    ISSN 2164-2591 ; 2164-2591
    ISSN (online) 2164-2591
    ISSN 2164-2591
    DOI 10.1167/tvst.11.1.6
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  6. Article: delGA (rs67491583) variant and colorectal cancer risk in an indigenous African population.

    Ogundiran, T / Tuupanen, S / Aaltonen, L A / Akarolo-Anthony, S / Adebamowo, C

    African journal of medicine and medical sciences

    2013  Volume 41, Issue 3, Page(s) 271–275

    Abstract: Background: A recent study showed a higher frequency of GA deletion at rs67491583 in African American colorectal cancer (CRC) patients compared to controls, suggesting a likely contribution of this allele to racial disparity in CRC risk predisposition. ... ...

    Abstract Background: A recent study showed a higher frequency of GA deletion at rs67491583 in African American colorectal cancer (CRC) patients compared to controls, suggesting a likely contribution of this allele to racial disparity in CRC risk predisposition. We conducted a pilot study in an indigenous African population to evaluate this potential CRC risk variant.
    Methods: We collected epidemiological data and biological specimen from consenting consecutive CRC cases and controls presenting at the Oncology Clinic of University College Hospital, Ibadan from 2001 to 2007. We examined germline DNA for delGA by PCR-amplification of two overlapping fragments using standard primers. The products were directly sequenced using Applied Biosystems BigDye v3.1 sequencing chemistry and AB 13730 automatic DNA sequencer.
    Results: There were 45 cases and 45 controls of which genotyping was successful in 39 cases and 38 controls. There were 5 heterozygous and 2 homozygous GA deletions with frequency of 11.54% (9/78) among cases whereas there were 8 heterozygous and 1 homozygous GA deletions among controls with frequency of 13.15% (10/76). (p= 0.79, OR 0.88, 95% CI 0.34-2.28).
    Conclusion: This study suggests that there is no association between the delGA (rs67491583) variant and CRC risk in this indigenous African population. However our sample size was small and the participants were not ethnically homogenous. Further studies are required to evaluate this marker in African CRC.
    MeSH term(s) Adult ; Chromosome Deletion ; Colorectal Neoplasms/ethnology ; Colorectal Neoplasms/genetics ; DNA, Neoplasm ; Female ; Genetic Variation ; Humans ; Male ; Middle Aged ; Nigeria ; Pilot Projects ; Seroepidemiologic Studies
    Chemical Substances DNA, Neoplasm
    Language English
    Publishing date 2013-02-14
    Publishing country Nigeria
    Document type Journal Article
    ZDB-ID 429127-x
    ISSN 0309-3913 ; 1116-4077
    ISSN 0309-3913 ; 1116-4077
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  7. Article ; Online: A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis.

    Schiff, Elena R / Daich Varela, Malena / Robson, Anthony G / Pierpoint, Karen / Ba-Abbad, Rola / Nutan, Savita / Zein, Wadih M / Ullah, Ehsan / Huryn, Laryssa A / Tuupanen, Sari / Mahroo, Omar A / Michaelides, Michel / Burke, Derek / Harvey, Katie / Arno, Gavin / Hufnagel, Robert B / Webster, Andrew R

    American journal of medical genetics. Part C, Seminars in medical genetics

    2020  Volume 184, Issue 3, Page(s) 631–643

    Abstract: Pathogenic variants in the gene HGSNAT (heparan-α-glucosaminide N-acetyltransferase) have been reported to underlie two distinct recessive conditions, depending on the specific genotype, mucopolysaccharidosis type IIIC (MPSIIIC)-a severe childhood-onset ... ...

    Abstract Pathogenic variants in the gene HGSNAT (heparan-α-glucosaminide N-acetyltransferase) have been reported to underlie two distinct recessive conditions, depending on the specific genotype, mucopolysaccharidosis type IIIC (MPSIIIC)-a severe childhood-onset lysosomal storage disorder, and adult-onset nonsyndromic retinitis pigmentosa (RP). Here we describe the largest cohort to-date of HGSNAT-associated nonsyndromic RP patients, and describe their retinal phenotype, leukocyte enzymatic activity, and likely pathogenic genotypes. We identified biallelic HGSNAT variants in 17 individuals (15 families) as the likely cause of their RP. None showed any other symptoms of MPSIIIC. All had a mild but significant reduction of HGSNAT enzyme activity in leukocytes. The retinal condition was generally of late-onset, showing progressive degeneration of a concentric area of paramacular retina, with preservation but reduced electroretinogram responses. Symptoms, electrophysiology, and imaging suggest the rod photoreceptor to be the cell initially compromised. HGSNAT enzymatic testing was useful in resolving diagnostic dilemmas in compatible patients. We identified seven novel sequence variants [p.(Arg239Cys); p.(Ser296Leu); p.(Phe428Cys); p.(Gly248Ala); p.(Gly418Arg), c.1543-2A>C; c.1708delA], three of which were considered to be retina-disease-specific alleles. The most prevalent retina-disease-specific allele p.(Ala615Thr) was observed heterozygously or homozygously in 8 and 5 individuals respectively (7 and 4 families). Two siblings in one family, while identical for the HGSNAT locus, but discordant for retinal disease, suggest the influence of trans-acting genetic or environmental modifying factors.
    MeSH term(s) Acetyltransferases/genetics ; Adolescent ; Adult ; Child ; Female ; Genotype ; Humans ; Leukocytes/metabolism ; Male ; Middle Aged ; Mucopolysaccharidosis III/complications ; Mucopolysaccharidosis III/genetics ; Mucopolysaccharidosis III/pathology ; Pedigree ; Retina/pathology ; Retinal Diseases/complications ; Retinal Diseases/genetics ; Retinal Diseases/pathology ; Retinitis Pigmentosa/complications ; Retinitis Pigmentosa/genetics ; Retinitis Pigmentosa/pathology ; Young Adult
    Chemical Substances Acetyltransferases (EC 2.3.1.-) ; HGSNAT protein, human (EC 2.3.1.78)
    Language English
    Publishing date 2020-08-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2108622-9
    ISSN 1552-4876 ; 0148-7299 ; 1552-4868
    ISSN (online) 1552-4876
    ISSN 0148-7299 ; 1552-4868
    DOI 10.1002/ajmg.c.31822
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  8. Article ; Online: Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy.

    Koskenvuo, Juha W / Saarinen, Inka / Ahonen, Saija / Tommiska, Johanna / Weckström, Sini / Seppälä, Eija H / Tuupanen, Sari / Kangas-Kontio, Tiia / Schleit, Jennifer / Heliö, Krista / Hathaway, Julie / Gummesson, Anders / Dahlberg, Pia / Ojala, Tiina H / Vepsäläinen, Ville / Kytölä, Ville / Muona, Mikko / Sistonen, Johanna / Salmenperä, Pertteli /
    Gentile, Massimiliano / Paananen, Jussi / Myllykangas, Samuel / Alastalo, Tero-Pekka / Heliö, Tiina

    PloS one

    2021  Volume 16, Issue 2, Page(s) e0245681

    Abstract: Background: Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without ... ...

    Abstract Background: Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis. Recently, biallelic protein-truncating variants (PTVs) in the nebulin-related anchoring protein gene (NRAP) were identified in a few patients with sporadic DCM.
    Methods and results: We determined the frequency of rare NRAP variants in a cohort of DCM patients and control patients to further evaluate role of this gene in cardiomyopathies. A retrospective analysis of our internal variant database consisting of 31,639 individuals who underwent genetic testing (either panel or direct exome sequencing) was performed. The DCM group included 577 patients with either a confirmed or suspected DCM diagnosis. A control cohort of 31,062 individuals, including 25,912 individuals with non-cardiac (control group) and 5,150 with non-DCM cardiac indications (Non-DCM cardiac group). Biallelic (n = 6) or two (n = 5) NRAP variants (two PTVs or PTV+missense) were identified in 11 unrelated probands with DCM (1.9%) but none of the controls. None of the 11 probands had an alternative molecular diagnosis. Family member testing supports co-segregation. Biallelic or potentially biallelic NRAP variants were enriched in DCM vs. controls (OR 1052, p<0.0001). Based on the frequency of NRAP PTVs in the gnomAD reference population, and predicting full penetrance, biallelic NRAP variants could explain 0.25%-2.46% of all DCM cases.
    Conclusion: Loss-of-function in NRAP is a cause for autosomal recessive dilated cardiomyopathy, supporting its inclusion in comprehensive genetic testing.
    MeSH term(s) Adult ; Cardiomyopathy, Dilated/diagnosis ; Cardiomyopathy, Dilated/genetics ; Child, Preschool ; Female ; Genetic Testing ; Humans ; Loss of Function Mutation ; Male ; Middle Aged ; Muscle Proteins/genetics ; Retrospective Studies ; Young Adult
    Chemical Substances Muscle Proteins ; NRAP protein, human
    Language English
    Publishing date 2021-02-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0245681
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  9. Article ; Online: Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients.

    Hathaway, Julie / Heliö, Krista / Saarinen, Inka / Tallila, Jonna / Seppälä, Eija H / Tuupanen, Sari / Turpeinen, Hannu / Kangas-Kontio, Tiia / Schleit, Jennifer / Tommiska, Johanna / Kytölä, Ville / Valori, Miko / Muona, Mikko / Sistonen, Johanna / Gentile, Massimiliano / Salmenperä, Pertteli / Myllykangas, Samuel / Paananen, Jussi / Alastalo, Tero-Pekka /
    Heliö, Tiina / Koskenvuo, Juha

    BMC cardiovascular disorders

    2021  Volume 21, Issue 1, Page(s) 126

    Abstract: Background: Genetic testing in hypertrophic cardiomyopathy (HCM) is a published guideline-based recommendation. The diagnostic yield of genetic testing and corresponding HCM-associated genes have been largely documented by single center studies and ... ...

    Abstract Background: Genetic testing in hypertrophic cardiomyopathy (HCM) is a published guideline-based recommendation. The diagnostic yield of genetic testing and corresponding HCM-associated genes have been largely documented by single center studies and carefully selected patient cohorts. Our goal was to evaluate the diagnostic yield of genetic testing in a heterogeneous cohort of patients with a clinical suspicion of HCM, referred for genetic testing from multiple centers around the world.
    Methods: A retrospective review of patients with a suspected clinical diagnosis of HCM referred for genetic testing at Blueprint Genetics was undertaken. The analysis included syndromic, myopathic and metabolic etiologies. Genetic test results and variant classifications were extracted from the database. Variants classified as pathogenic (P) or likely pathogenic (LP) were considered diagnostic.
    Results: A total of 1376 samples were analyzed. Three hundred and sixty-nine tests were diagnostic (26.8%); 373 P or LP variants were identified. Only one copy number variant was identified. The majority of diagnostic variants involved genes encoding the sarcomere (85.0%) followed by 4.3% of diagnostic variants identified in the RASopathy genes. Two percent of diagnostic variants were in genes associated with a cardiomyopathy other than HCM or an inherited arrhythmia. Clinical variables that increased the likelihood of identifying a diagnostic variant included: an earlier age at diagnosis (p < 0.0001), a higher maximum wall thickness (MWT) (p < 0.0001), a positive family history (p < 0.0001), the absence of hypertension (p = 0.0002), and the presence of an implantable cardioverter-defibrillator (ICD) (p = 0.0004).
    Conclusion: The diagnostic yield of genetic testing in this heterogeneous cohort of patients with a clinical suspicion of HCM is lower than what has been reported in well-characterized patient cohorts. We report the highest yield of diagnostic variants in the RASopathy genes identified in a laboratory cohort of HCM patients to date. The spectrum of genes implicated in this unselected cohort highlights the importance of pre-and post-test counseling when offering genetic testing to the broad HCM population.
    MeSH term(s) Adolescent ; Adult ; Cardiomyopathy, Hypertrophic/diagnosis ; Cardiomyopathy, Hypertrophic/genetics ; Cardiomyopathy, Hypertrophic/physiopathology ; Child ; Child, Preschool ; Female ; Genetic Markers ; Genetic Predisposition to Disease ; Genetic Testing ; Genetic Variation ; Humans ; Infant ; Male ; Phenotype ; Predictive Value of Tests ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Young Adult
    Chemical Substances Genetic Markers
    Language English
    Publishing date 2021-03-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 2059859-2
    ISSN 1471-2261 ; 1471-2261
    ISSN (online) 1471-2261
    ISSN 1471-2261
    DOI 10.1186/s12872-021-01927-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Lessons from functional analysis of genome-wide association studies.

    Sur, Inderpreet / Tuupanen, Sari / Whitington, Thomas / Aaltonen, Lauri A / Taipale, Jussi

    Cancer research

    2013  Volume 73, Issue 14, Page(s) 4180–4184

    Abstract: Most cancer-associated single-nucleotide polymorphisms (SNP) identified using genome-wide association studies are located outside of protein-coding regions, and their significance and mode of action have been a source of continuing debate. One proposed ... ...

    Abstract Most cancer-associated single-nucleotide polymorphisms (SNP) identified using genome-wide association studies are located outside of protein-coding regions, and their significance and mode of action have been a source of continuing debate. One proposed mechanism of action of the SNPs is that they would affect the activity of enhancer elements regulating critical target genes. In this review, we summarize recent results that substantiate this model. These studies have identified a cancer-specific enhancer element at the 8q24 gene desert that controls the expression of the MYC oncogene. We further discuss implications of the observed difference between normal growth control and cancer for drug development, and the inherent features of genome-wide association studies that may specifically lead to identification of disease-specific regulatory elements.
    MeSH term(s) Animals ; Enhancer Elements, Genetic ; Genes, myc ; Genome-Wide Association Study/methods ; Humans ; Polymorphism, Single Nucleotide
    Language English
    Publishing date 2013-07-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-13-0789
    Database MEDical Literature Analysis and Retrieval System OnLINE

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