TY  - JOUR
AB  - A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity-findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.
AU  - Zanti, M.*
AU  - O'Mahony, D.G.*
AU  - Parsons, M.T.*
AU  - Li, H.*
AU  - Dennis, J.*
AU  - Aittomäkkiki, K.*
AU  - Andrulis, I.L.*
AU  - Anton-Culver, H.*
AU  - Aronson, K.J.*
AU  - Augustinsson, A.*
AU  - Becher, H.*
AU  - Bojesen, S.E.*
AU  - Bolla, M.K.*
AU  - Brenner, H.*
AU  - Brown, M.A.*
AU  - Buys, S.S.*
AU  - Canzian, F.*
AU  - Caputo, S.M.*
AU  - Castelao, J.E.*
AU  - Chang-Claude, J.*
AU  - Czene, K.*
AU  - Daly, M.B.*
AU  - De Nicolo, A.*
AU  - Devilee, P.*
AU  - Dörk, T.*
AU  - Dunning, A.M.*
AU  - Dwek, M.*
AU  - Eccles, D.M.*
AU  - Engel, C.*
AU  - Evans, D.G.*
AU  - Fasching, P.A.*
AU  - Gago-Dominguez, M.*
AU  - Garcia-Closas, M.*
AU  - García-Sáenz, J.A.*
AU  - Gentry-Maharaj, A.*
AU  - Geurts-Giele, W.R.R.*
AU  - Giles, G.G.*
AU  - Glendon, G.*
AU  - Goldberg, M.S.*
AU  - Garcia, E.B.G.*
AU  - Gündert, M.
AU  - Guénel, P.*
AU  - Hahnen, E.*
AU  - Haiman, C.A.*
AU  - Hall, P.*
AU  - Hamann, U.*
AU  - Harkness, E.F.*
AU  - Hogervorst, F.B.L.*
AU  - Hollestelle, A.*
AU  - Hoppe, R.*
AU  - Hopper, J.L.*
AU  - Houdayer, C.*
AU  - Houlston, R.S.*
AU  - Howell, A.*
AU  - Investigators, A.*
AU  - Jakimovska, M.*
AU  - Jakubowska, A.*
AU  - Jernström, H.*
AU  - John, E.M.*
AU  - Kaaks, R.*
AU  - Kitahara, C.M.*
AU  - Koutros, S.*
AU  - Kraft, P.*
AU  - Kristensen, V.N.*
AU  - Lacey, J.V.*
AU  - Lambrechts, D.*
AU  - Leone, M.*
AU  - Lindblom, A.*
AU  - Lush, M.*
AU  - Mannermaa, A.*
AU  - Manoochehri, M.*
AU  - Manoukian, S.*
AU  - Margolin, S.*
AU  - Martinez, M.E.*
AU  - Menon, U.*
AU  - Milne, R.L.*
AU  - Monteiro, A.N.*
AU  - Murphy, R.A.*
AU  - Neuhausen, S.L.*
AU  - Nevanlinna, H.*
AU  - Newman, W.G.*
AU  - Offit, K.*
AU  - Park, S.K.*
AU  - James, P.*
AU  - Peterlongo, P.*
AU  - Peto, J.*
AU  - Plaseska-Karanfilska, D.*
AU  - Punie, K.*
AU  - Radice, P.*
AU  - Rashid, M.U.*
AU  - Rennert, G.*
AU  - Romero, A.*
AU  - Rosenberg, E.H.*
AU  - Saloustros, E.*
AU  - Sandler, D.P.*
AU  - Schmidt, M.K.*
AU  - Schmutzler, R.K.*
AU  - Shu, X.*
AU  - Simard, J.*
AU  - Southey, M.C.*
AU  - Stone, J.*
AU  - Stoppa-Lyonnet, D.*
AU  - Tamimi, R.M.*
AU  - Tapper, W.J.*
AU  - Taylor, J.A.*
AU  - Teo, S.H.*
AU  - Teras, L.R.*
AU  - Terry, M.B.*
AU  - Thomassen, M.*
AU  - Troester, M.A.*
AU  - Vachon, C.M.*
AU  - Vega, A.*
AU  - Vreeswijk, M.P.G.*
AU  - Wang, Q.*
AU  - Wappenschmidt, B.*
AU  - Weinberg, C.R.*
AU  - Wolk, A.*
AU  - Zheng, W.*
AU  - Feng, B.*
AU  - Couch, F.J.*
AU  - Spurdle, A.B.*
AU  - Easton, D.F.*
AU  - Goldgar, D.E.*
AU  - Michailidou, K.*
C1  - 69795
C2  - 53868
CY  - Adam House, 3rd Fl, 1 Fitzroy Sq, London, Wit 5he, England
TI  - A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to BRCA1 and BRCA2.
JO  - Hum. Mutat.
VL  - 2023
PB  - Wiley-hindawi
PY  - 2023
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analysing possible predictors for adverse clinical outcome. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and Log-Rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and 2 deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcome. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counselling, and follow-up of affected individuals. This article is protected by copyright. All rights reserved.
AU  - Scala, M.*
AU  - Wortmann, S.B.*
AU  - Kaya, N.*
AU  - Stellingwerff, M.D.*
AU  - Pistorio, A.*
AU  - Glamuzina, E.*
AU  - van Karnebeek, C.D.M.*
AU  - Skrypnyk, C.*
AU  - Iwanicka-Pronicka, K.*
AU  - Piekutowska-Abramczuk, D.*
AU  - Ciara, E.*
AU  - Tort, F.*
AU  - Sheidley, B.R.*
AU  - Poduri, A.*
AU  - Jayakar, P.*
AU  - Jayakar, A.*
AU  - Upadia, J.*
AU  - Walano, N.*
AU  - Haack, T.B.*
AU  - Prokisch, H.
AU  - Aldhalaan, H.M.*
AU  - Karimiani, E.G.*
AU  - Yildiz, Y.*
AU  - Ceylan, A.C.*
AU  - Dameron, A.*
AU  - Yang, H.*
AU  - Toosi, M.B.*
AU  - Ashrafzadeh, F.*
AU  - Akhondian, J.*
AU  - Imannezhad, S.*
AU  - Mirzadeh, H.S.*
AU  - Maqbool, S.*
AU  - Farid, A.*
AU  - Al-Muhaizea, M.A.*
AU  - Alshwameen, M.O.*
AU  - Aldowsari, L.*
AU  - Alsagob, M.*
AU  - Alyousef, A.*
AU  - Almass, R.*
AU  - AlHargan, A.*
AU  - Alwadei, A.H.*
AU  - AlRasheed, M.M.*
AU  - Colak, D.*
AU  - Alqudairy, H.*
AU  - Khan, S.*
AU  - Lines, M.A.*
AU  - García Cazorla, M.*
AU  - Ribes, A.*
AU  - Morava, E.*
AU  - Bibi, F.*
AU  - Haider, S.*
AU  - Ferla, M.P.*
AU  - Taylor, J.C.*
AU  - Alsaif, H.S.*
AU  - Firdous, A.*
AU  - Hashem, M.*
AU  - Shashkin, C.*
AU  - Koneev, K.*
AU  - Kaiyrzhanov, R.*
AU  - Efthymiou, S.*
AU  - Genomics, Q.S.*
AU  - Schmitt-Mechelke, T.*
AU  - Ziegler, A.*
AU  - Issa, M.Y.*
AU  - Elbendary, H.M.*
AU  - Striano, P.*
AU  - Alkuraya, F.S.*
AU  - Zaki, M.S.*
AU  - Gleeson, J.G.*
AU  - Barakat, T.S.*
AU  - Bierau, J.*
AU  - van der Knaap, M.S.*
AU  - Maroofian, R.*
AU  - Houlden, H.*
C1  - 64010
C2  - 52046
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 403-419
TI  - Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency.
JO  - Hum. Mutat.
VL  - 43
IS  - 3
PB  - Wiley
PY  - 2022
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Over the last five years, RNA sequencing (RNA-seq) has been established and is increasingly applied as an effective approach complementary to DNA sequencing in molecular diagnostics. Currently, three RNA phenotypes, aberrant expression, aberrant splicing, and allelic imbalance, are considered to provide information about pathogenic variants. By providing a high-throughput, transcriptome-wide functional readout on variants causing aberrant RNA phenotypes, RNA-seq has increased diagnostic rates by about 15% over whole-exome sequencing. This breakthrough encouraged the development of computational tools and pipelines aiming to streamline RNA-seq analysis for implementation in clinical diagnostics. Although a number of studies showed the added value of RNA-seq for the molecular diagnosis of individuals with Mendelian disorders, there is no formal consensus on assessing variant pathogenicity strength based on RNA phenotypes. Taking RNA-seq as a functional assay for genetic variants, we evaluated the value of statistical significance and effect size of RNA phenotypes as evidence for the strength of variant pathogenicity. This was determined by the analysis of 394 pathogenic variants, of which 198 were associated with aberrant RNA phenotypes and 723 benign variants. Overall, this study seeks to establish recommendations for integrating functional RNA-seq data into the ACMG/AMP guidelines classification system. This article is protected by copyright. All rights reserved.
AU  - Smirnov, D.
AU  - Schlieben, L.D.
AU  - Peymani, F.
AU  - Berutti, R.
AU  - Prokisch, H.
C1  - 65473
C2  - 52699
SP  - 1056-1070
TI  - Guidelines for clinical interpretation of variant pathogenicity using RNA phenotypes.
JO  - Hum. Mutat.
VL  - 43
IS  - 8
PY  - 2022
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals 1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual disability and autistic features. CELF2 encodes a nucleocytoplasmic shuttling RNA-binding protein that has multiple roles in RNA processing and is involved in the embryonic development of the central nervous system and heart. Whole-exome sequencing identified the following CELF2 variants: two missense variants [c.1558C>T:p.(Pro520Ser) in unrelated Individuals 1 and 2, and c.1516C>G:p.(Arg506Gly) in Individual 3], one frameshift variant in Individual 4 that removed the last amino acid of CELF2 c.1562dup:p.(Tyr521Ter), possibly resulting in escape from nonsense-mediated mRNA decay (NMD), and one canonical splice site variant, c.272-1G>C in Individual 5, also probably leading to NMD. The identified variants in Individuals 1, 2, 4, and 5 were de novo, while the variant in Individual 3 was inherited from her mosaic mother. Notably, all identified variants, except for c.272-1G>C, were clustered within 20 amino acid residues of the C-terminus, which might be a nuclear localization signal. We demonstrated the extranuclear mislocalization of mutant CELF2 protein in cells transfected with mutant CELF2 complementary DNA plasmids. Our findings indicate that CELF2 variants that disrupt its nuclear localization are associated with DEE.
AU  - Itai, T.*
AU  - Hamanaka, K.*
AU  - Sasaki, K.*
AU  - Wagner, M.
AU  - Kotzaeridou, U.*
AU  - Brosse, I.*
AU  - Ries, M.*
AU  - Kobayashi, Y.*
AU  - Tohyama, J.*
AU  - Kato, M.*
AU  - Ong, W.P.*
AU  - Chew, H.B.*
AU  - Rethanavelu, K.*
AU  - Ranza, E.*
AU  - Blanc, X.*
AU  - Uchiyama, Y.*
AU  - Tsuchida, N.*
AU  - Fujita, A.*
AU  - Azuma, Y.*
AU  - Koshimizu, E.*
AU  - Mizuguchi, T.*
AU  - Takata, A.*
AU  - Miyake, N.*
AU  - Takahashi, H.*
AU  - Miyagi, E.*
AU  - Tsurusaki, Y.*
AU  - Doi, H.*
AU  - Taguri, M.*
AU  - Antonarakis, S.E.*
AU  - Nakashima, M.*
AU  - Saitsu, H.*
AU  - Miyatake, S.*
AU  - Matsumoto, N.*
C1  - 60596
C2  - 49402
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 66-76
TI  - De novo variants in CELF2  that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy.
JO  - Hum. Mutat.
VL  - 42
IS  - 1
PB  - Wiley
PY  - 2021
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through an international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections and central/nocturnal hypopnea as core manifestations. A review of brain MRI scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing β-propeller repeats. Despite constituting nearly half of disease associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1,221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.
AU  - Neuser, S.*
AU  - Brechmann, B.*
AU  - Heimer, G.*
AU  - Brösse, I.*
AU  - Schubert, S.*
AU  - O'Grady, L.*
AU  - Zech, M.
AU  - Srivastava, S.*
AU  - Sweetser, D.A.*
AU  - Dincer, Y.*
AU  - Mall, V.*
AU  - Winkelmann, J.
AU  - Behrends, C.*
AU  - Darras, B.T.*
AU  - Graham, R.J.*
AU  - Jayakar, P.*
AU  - Byrne, B.*
AU  - El Bar-Aluma, B.*
AU  - Haberman, Y.*
AU  - Szeinberg, A.*
AU  - Aldhalaan, H.M.*
AU  - Hashem, M.*
AU  - Tenaiji, A.A.*
AU  - Ismayl, O.*
AU  - Al Nuaimi, A.E.*
AU  - Maher, K.*
AU  - Ibrahim, S.*
AU  - Khan, F.*
AU  - Houlden, H.*
AU  - Ramakumaran, V.S.*
AU  - Pagnamenta, A.T.*
AU  - Posey, J.E.*
AU  - Lupski, J.R.*
AU  - Tan, W.H.*
AU  - ElGhazali, G.*
AU  - Herman, I.*
AU  - Muñoz, T.*
AU  - Repetto, G.M.*
AU  - Seitz, A.*
AU  - Krumbiegel, M.*
AU  - Cecilia Poli, M.*
AU  - Kini, U.*
AU  - Efthymiou, S.*
AU  - Meiler, J.*
AU  - Maroofian, R.*
AU  - Alkuraya, F.S.*
AU  - Jamra, R.A.*
AU  - Popp, B.*
AU  - Ben-Zeev, B.*
AU  - Ebrahimi-Fakhari, D.*
C1  - 61776
C2  - 50471
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 762-776
TI  - Clinical, neuroimaging and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.
JO  - Hum. Mutat.
VL  - 42
IS  - 6
PB  - Wiley
PY  - 2021
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Ferrodoxin reductase (FDXR) deficiency is a mitochondrial disease described in recent years primarily in association with optic atrophy, acoustic neuropathy, and developmental delays. Here, we identified seven unpublished patients with FDXR deficiency belonging to six independent families. These patients show a broad clinical spectrum ranging from Leigh syndrome with early demise and severe infantile-onset encephalopathy, to milder movement disorders. In total nine individual pathogenic variants, of which seven were novel, were identified in FDXR using whole exome sequencing in suspected mitochondrial disease patients. Over 80% of these variants are missense, a challenging variant class in which to determine pathogenic consequence, especially in the setting of nonspecific phenotypes and in the absence of a reliable biomarker, necessitating functional validation. Here we implement an Arh1-null yeast model to confirm the pathogenicity of variants of uncertain significance in FDXR, bypassing the requirement for patient-derived material.
AU  - Stenton, S.
AU  - Piekutowska-Abramczuk, D.*
AU  - Kulterer, L.
AU  - Kopajtich, R.
AU  - Claeys, K.G.*
AU  - Ciara, E.*
AU  - Eisen, J.*
AU  - Płoski, R.*
AU  - Pronicka, E.*
AU  - Malczyk, K.*
AU  - Wagner, M.
AU  - Wortmann, S.B.
AU  - Prokisch, H.
C1  - 60970
C2  - 49616
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 310-319
TI  - Expanding the clinical and genetic spectrum of FDXR deficiency by functional validation of variants of uncertain significance.
JO  - Hum. Mutat.
VL  - 42
IS  - 3
PB  - Wiley
PY  - 2021
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Isolated biochemical deficiency of mitochondrial complex I is the most frequent signature amongst mitochondrial diseases and is associated with a wide variety of clinical symptoms. Leigh syndrome represents the most frequent neuroradiological finding in patients with complex I defect and >80 monogenic causes have been involved in the disease. In this report, we describe 7 patients from four unrelated families harbouring novel NDUFA12 variants, 6 of them presenting with Leigh syndrome. Molecular genetic characterization was performed using next generation sequencing combined with the Sanger method. Biochemical and protein studies were achieved by enzymatic activities, blue native gel electrophoresis and Western blotting. All patients displayed novel homozygous mutations in the NDUFA12 gene leading to the virtual absence of the corresponding protein. Surprisingly, despite in none of the analyzed patients NDUFA12 protein was detected, they present a different onset and clinical course of the disease. Our report expands the array of genetic alterations in NDUFA12 and underlines phenotype variability associated with NDUFA12 defect.
AU  - Torraco, A.*
AU  - Nasca, A.*
AU  - Verrigni, D.*
AU  - Pennisi, A.*
AU  - Zaki, M.S.*
AU  - Olivieri, G.*
AU  - Assouline, Z.*
AU  - Martinelli, D.*
AU  - Maroofian, R.*
AU  - Rizza, T.*
AU  - Di Nottia, M.*
AU  - Invernizzi, F.*
AU  - Lamantea, E.*
AU  - Longo, D.*
AU  - Houlden, H.*
AU  - Prokisch, H.
AU  - Rötig, A.*
AU  - Dionisi-Vici, C.*
AU  - Bertini, E.*
AU  - Ghezzi, D.*
AU  - Carrozzo, R.*
AU  - Diodato, D.*
C1  - 61540
C2  - 50331
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 699-710
TI  - Novel NDUFA12 variants are associated with isolated complex I defect and variable clinical manifestation.
JO  - Hum. Mutat.
VL  - 42
IS  - 6
PB  - Wiley
PY  - 2021
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state-in trans with c.1462-1G>T-in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities.
AU  - Ascari, G.*
AU  - Peelman, F.*
AU  - Farinelli, P.*
AU  - Rosseel, T.*
AU  - Lambrechts, N.*
AU  - Wunderlich, K.A.*
AU  - Wagner, M.
AU  - Nikopoulos, K.*
AU  - Martens, P.*
AU  - Balikova, I.*
AU  - Derycke, L.*
AU  - Holtappels, G.*
AU  - Krysko, O.*
AU  - Van Laethem, T.*
AU  - De Jaegere, S.*
AU  - Guillemyn, B.*
AU  - De Rycke, R.*
AU  - de Bleecker, J.*
AU  - Creytens, D.*
AU  - Van Dorpe, J.*
AU  - Gerris, J.*
AU  - Bachert, C.*
AU  - Neuhofer, C.*
AU  - Walraedt, S.*
AU  - Bischoff, A.*
AU  - Pedersen, L.B.*
AU  - Klopstock, T.*
AU  - Rivolta, C.*
AU  - Leroy, B.P.*
AU  - de Baere, E.*
AU  - Coppieters, F.*
C1  - 58688
C2  - 48241
SP  - 998-1011
TI  - Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility.
JO  - Hum. Mutat.
VL  - 41
IS  - 5
PY  - 2020
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Mutations in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, responsible for endonucleolytic cleavage of the 3 ' ends of mitochondrial pre-tRNAs. Here, we report the identification of 16 novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy (HCM), and lactic acidosis. We provide evidence for the pathogenicity of the novel missense variants by studying the RNase Z activity in an in vitro system. We also modeled the residues affected by a missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the affected individuals have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile-onset forms of HCM and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism
AU  - Saoura, M.*
AU  - Powell, C.A.*
AU  - Kopajtich, R.
AU  - Alahmad, A.*
AU  - Al-Balool, H.H.*
AU  - Albash, B.*
AU  - Alfadhel, M.*
AU  - Alston, C.L.*
AU  - Bertini, E.*
AU  - Bonnen, P.*
AU  - Bratkovic, D.*
AU  - Carrozzo, R.*
AU  - Donati, M.A.*
AU  - Nottia, M.D.*
AU  - Ghezzi, D.*
AU  - Goldstein, A.*
AU  - Haan, E.*
AU  - Horvath, R.*
AU  - Hughes, J.*
AU  - Invernizzi, F.*
AU  - Lamantea, E.*
AU  - Lucas, B.*
AU  - Pinnock, K.G.*
AU  - Pujantell, M.*
AU  - Rahman, S.*
AU  - Rebelo-Guiomar, P.*
AU  - Santra, S.*
AU  - Verrigni, D.*
AU  - McFarland, R.
AU  - Prokisch, H.
AU  - Taylor, R.W.*
AU  - Levinger, L.*
AU  - Minczuk, M.*
C1  - 55976
C2  - 46730
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1731-1748
TI  - Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3 '-end processing.
JO  - Hum. Mutat.
VL  - 40
IS  - 10
PB  - Wiley
PY  - 2019
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - We report four unrelated children with homozygous loss-of-function variants in TASP1 and an overlapping phenotype comprising developmental delay with hypotonia and microcephaly, feeding difficulties with failure-to-thrive, recurrent respiratory infections, cardiovascular malformations, cryptorchidism, happy demeanor, and distinctive facial features. Two children had a homozygous founder deletion encompassing exons 5–11 of TASP1, the third had a homozygous missense variant, c.701 C>T (p.Thr234Met), affecting the active site of the encoded enzyme, and the fourth had a homozygous nonsense variant, c.199 C>T (p.Arg67*). TASP1 encodes taspase 1 (TASP1), which is responsible for cleaving, thus activating, the lysine methyltransferases KMT2A and KMT2D, which are essential for histone methylation and transcription regulation. The consistency of the phenotype, the critical biological function of TASP1, the deleterious nature of the TASP1 variants, and the overlapping features with Wiedemann–Steiner and Kabuki syndromes respectively caused by pathogenic variants in KMT2A and KMT2D all support that TASP1 is a disease-related gene.
AU  - Suleiman, J.*
AU  - Riedhammer, K.M.
AU  - Jicinsky, T.*
AU  - Mundt, M.*
AU  - Werner, L.*
AU  - Gusic, M.
AU  - Burgemeister, A.L.*
AU  - Alsaif, H.S.*
AU  - Abdulrahim, M.*
AU  - Moghrabi, N.N.*
AU  - Nicolas-Jilwan, M.*
AU  - AlSayed, M.*
AU  - Bi, W.*
AU  - Sampath, S.*
AU  - Alkuraya, F.S.*
AU  - El-Hattab, A.W.*
C1  - 56343
C2  - 47014
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
SP  - 1985-1992
TI  - Homozygous loss-of-function variants of TASP1, a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies.
JO  - Hum. Mutat.
VL  - 40
IS  - 11
PB  - Wiley
PY  - 2019
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi-allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA-synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring VARS2 mutations. All patients except one, who manifested with a less severe disease course, presented at birth exhibiting severe encephalomyopathy and cardiomyopathy. Features included hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal cranial MRI, and elevated lactate. The biochemical phenotype comprised a combined Complex I and Complex IV OXPHOS defect in muscle, with patient fibroblasts displaying normal OXPHOS activity. Homology modeling supported the pathogenicity of VARS2 missense variants. The detailed description of this cohort further delineates our understanding of the clinical presentation associated with pathogenic VARS2 variants and we recommend that this gene should be considered in early-onset mitochondrial encephalomyopathies or encephalocardiomyopathies.
AU  - Bruni, F.*
AU  - Meo, I.D.*
AU  - Bellacchio, E.*
AU  - Webb, B.D.*
AU  - McFarland, R.*
AU  - Chrzanowska-Lightowlers, Z.M.A.*
AU  - He, L.*
AU  - Skorupa, E.*
AU  - Moroni, I.*
AU  - Ardissone, A.*
AU  - Walczak, A.*
AU  - Tyynismaa, H.*
AU  - Isohanni, P.*
AU  - Mandel, H.*
AU  - Prokisch, H.*
AU  - Haack, T.B.
AU  - Bonnen, P.E.*
AU  - Enrico, B.*
AU  - Pronicka, E.*
AU  - Ghezzi, D.*
AU  - Taylor, R.W.*
AU  - Diodato, D.*
C1  - 52701
C2  - 44234
CY  - Hoboken
SP  - 563-578
TI  - Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease.
JO  - Hum. Mutat.
VL  - 39
IS  - 4
PB  - Wiley
PY  - 2018
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype–phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies.
AU  - El-Hattab, A.W.*
AU  - Dai, H.*
AU  - Almannai, M.*
AU  - Wang, J.*
AU  - Faqeih, E.A.*
AU  - Al Asmari, A.*
AU  - Saleh, M.A.M.*
AU  - Elamin, M.A.O.*
AU  - Alfadhel, M.*
AU  - Alkuraya, F.S.*
AU  - Hashem, M.*
AU  - Aldosary, M.S.*
AU  - Almass, R.*
AU  - Almutairi, F.B.*
AU  - Alsagob, M.*
AU  - Al-Owain, M.*
AU  - Al-Sharfa, S.*
AU  - Al-Hassnan, Z.N.*
AU  - Rahbeeni, Z.*
AU  - Al-Muhaizea, M.A.*
AU  - Makhseed, N.*
AU  - Foskett, G.K.*
AU  - Stevenson, D.A.*
AU  - Gomez-Ospina, N.*
AU  - Lee, C.*
AU  - Boles, R.G.*
AU  - Schrier Vergano, S.A.*
AU  - Wortmann, S.B.
AU  - Sperl, W.*
AU  - Opladen, T.*
AU  - Hoffmann, G.F.*
AU  - Hempel, M.*
AU  - Prokisch, H.
AU  - Alhaddad, B.
AU  - Mayr, J.A.*
AU  - Chan, W.*
AU  - Kaya, N.*
AU  - Wong, L.J.C.*
C1  - 52274
C2  - 43868
SP  - 1649-1659
TI  - Molecular and clinical spectra of FBXL4 deficiency.
JO  - Hum. Mutat.
VL  - 38
IS  - 12
PY  - 2017
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - In many human diseases, associated genetic changes tend to occur within non-coding regions, whose effect might be related to transcriptional control. A central goal in human genetics is to understand the function of such non-coding regions: Given a region that is statistically associated with changes in gene expression (expression Quantitative Trait Locus; eQTL), does it in fact play a regulatory role? And if so, how is this role "coded" in its sequence? These questions were the subject of the Critical Assessment of Genome Interpretation eQTL challenge. Participants were given a set of sequences that flank eQTLs in humans and were asked to predict whether these are capable of regulating transcription (as evaluated by massively parallel reporter assays), and whether this capability changes between alternative alleles. Here, we report lessons learned from this community effort. By inspecting predictive properties in isolation, and conducting meta-analysis over the competing methods, we find that using chromatin accessibility and transcription factor binding as features in an ensemble of classifiers or regression models leads to the most accurate results. We then characterize the loci that are harder to predict, putting the spotlight on areas of weakness, which we expect to be the subject of future studies.
AU  - Kreimer, A.*
AU  - Zeng, H.*
AU  - Edwards, M.D.*
AU  - Guo, Y.*
AU  - Tian, K.*
AU  - Shin, S.*
AU  - Welch, R.*
AU  - Wainberg, M.*
AU  - Mohan, R.*
AU  - Sinnott-Armstrong, N.A.*
AU  - Li, Y.*
AU  - Eraslan, G.
AU  - Amin, T.B.*
AU  - Goke, J.*
AU  - Müller, N.S.
AU  - Kellis, M.*
AU  - Kundaje, A.*
AU  - Beer, M.A.*
AU  - Keles, S.*
AU  - Gifford, D.K.*
AU  - Yosef, N.*
C1  - 50642
C2  - 42673
CY  - Hoboken
SP  - 1240-1250
TI  - Predicting gene expression in massively parallel reporter assays: A comparative study.
JO  - Hum. Mutat.
VL  - 38
IS  - 9
PB  - Wiley
PY  - 2017
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Wiley Periodicals, Inc. Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support. Our findings expand the genotypic and phenotypic spectrum of LCCS11 and demonstrate that the condition may not necessarily be lethal in the neonatal period.
AU  - Wambach, J.A.*
AU  - Stettner, G.M.*
AU  - Haack, T.B.
AU  - Writzl, K.*
AU  - Škofljanec, A.*
AU  - Maver, A.*
AU  - Munell, F.*
AU  - Ossowski, S.*
AU  - Bosio, M.*
AU  - Wegner, D.J.*
AU  - Shinawi, M.*
AU  - Baldridge, D.*
AU  - Alhaddad, B.*
AU  - Strom, T.M.
AU  - Grange, D.K.*
AU  - Wilichowski, E.*
AU  - Troxell, R.*
AU  - Collins, J.E.*
AU  - Warner, B.B.*
AU  - Schmidt, R.E.*
AU  - Pestronk, A.*
AU  - Cole, F.S.*
AU  - Steinfeld, R.*
C1  - 52128
C2  - 43739
CY  - Hoboken
SP  - 1477-1484
TI  - Survival among children with “Lethal” congenital contracture syndrome 11 caused by novel mutations in the gliomedin gene (GLDN).
JO  - Hum. Mutat.
VL  - 38
IS  - 11
PB  - Wiley
PY  - 2017
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Mitochondrial protein synthesis involves an intricate interplay between mitochondrial DNA encoded RNAs and nuclear DNA encoded proteins, such as ribosomal proteins and aminoacyl-tRNA synthases. Eukaryotic cells contain 17 mitochondria-specific aminoacyl-tRNA synthases. WARS2 encodes mitochondrial tryptophanyl-tRNA synthase (mtTrpRS), a homodimeric class Ic enzyme (mitochondrial tryptophan-tRNA ligase; EC 6.1.1.2). Here, we report six individuals from five families presenting with either severe neonatal onset lactic acidosis, encephalomyopathy and early death or a later onset, more attenuated course of disease with predominating intellectual disability. Respiratory chain enzymes were usually normal in muscle and fibroblasts, while a severe combined respiratory chain deficiency was found in the liver of a severely affected individual. Exome sequencing revealed rare biallelic variants in WARS2 in all affected individuals. An increase of uncharged mitochondrial tRNA(Trp) and a decrease of mtTrpRS protein content were found in fibroblasts of affected individuals. We hereby define the clinical, neuroradiological and metabolic phenotype of WARS2 defects. This confidently implicates that mutations in WARS2 cause mitochondrial disease with a broad spectrum of clinical presentation.
AU  - Wortmann, S.B.
AU  - Timal, S.*
AU  - Venselaar, H.*
AU  - Wintjes, L.T.*
AU  - Kopajtich, R.
AU  - Feichtinger, R.G.*
AU  - Onnekink, C.*
AU  - Mühlmeister, M.*
AU  - Brandt, U.*
AU  - Smeitink, J.A.M.*
AU  - Veltman, J.A.*
AU  - Sperl, W.*
AU  - Lefeber, D.J.*
AU  - Pruijn, G.J.M.*
AU  - Stojanovic, V.*
AU  - Freisinger, P.*
AU  - V Spronsen, F.*
AU  - Derks, T.G.*
AU  - Veenstra-Knol, H.E.*
AU  - Mayr, J.A.*
AU  - Rötig, A.*
AU  - Tarnopolsky, M.*
AU  - Prokisch, H.
AU  - Rodenburg, R.J.*
C1  - 51893
C2  - 43554
CY  - Hoboken
SP  - 1786-1795
TI  - Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy.
JO  - Hum. Mutat.
VL  - 38
IS  - 12
PB  - Wiley
PY  - 2017
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, while mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and 9 were shown to be de novo. We give an up-to-date overview of all published mutations for the two Kabuki syndrome genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well defined X-linked KS type 2, and comment on phenotype-genotype correlations as well as sex-specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki-like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients. This article is protected by copyright. All rights reserved.
AU  - Bögershausen, N.*
AU  - Gatinois, V.*
AU  - Riehmer, V.*
AU  - Kayserili, H.*
AU  - Becker, J.*
AU  - Thoenes, M.*
AU  - Simsek-Kiper, P.*
AU  - Barat-Houari, M.*
AU  - Elcioğlu, N.H.*
AU  - Wieczorek, D.*
AU  - Tinschert, S.*
AU  - Sarrabay, G.*
AU  - Strom, T.M.
AU  - Fabre, A.*
AU  - Baynam, G.*
AU  - Sanchez, E.*
AU  - Nurnberg, G.*
AU  - Altunoglu, U.*
AU  - Capri, Y.*
AU  - Isidor, B.*
AU  - Lacombe, D.*
AU  - Corsini, C.*
AU  - Cormier-Daire, V.*
AU  - Sanlaville, D.*
AU  - Giuliano, F.*
AU  - Sang, K.L.*
AU  - Kayirangwa, H.*
AU  - Nürnberg, P.*
AU  - Meitinger, T.
AU  - Boduroglu, K.*
AU  - Zoll, B.*
AU  - Lyonnet, S.*
AU  - Tzschach, A.*
AU  - Verloes, A.*
AU  - Donato, N.D.*
AU  - Touitou, I.*
AU  - Netzer, C.*
AU  - Li, Y.*
AU  - Geneviève, D.*
AU  - Yigit, G.*
AU  - Wollnik, B.*
C1  - 48929
C2  - 41513
CY  - Hoboken
SP  - 847-864
TI  - Mutation update for Kabuki syndrome genes KMT2D and KDM6A and further delineation of X-linked Kabuki syndrome subtype 2.
JO  - Hum. Mutat.
VL  - 37
IS  - 9
PB  - Wiley-blackwell
PY  - 2016
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - By way of whole-exome sequencing we identified: a homozygous missense mutation in VARS2, in one subject with microcephaly and epilepsy associated with isolated deficiency of the mitochondrial respiratory chain (MRC) complex I; and compound heterozygous mutations in TARS2, in two siblings presenting with axial hypotonia and severe psychomotor delay associated with multiple MRC defects. The nucleotide variants segregated within the families, were absent in SNP databases, and are predicted to be deleterious. The amount of VARS2 and TARS2 proteins and valyl-tRNA and threonyl-tRNA levels were decreased in samples of afflicted patients according to the genetic defect. Expression of the corresponding wild-type transcripts in immortalized mutant fibroblasts rescued the biochemical impairment of mitochondrial respiration and yeast modeling of the VARS2 mutation confirmed its pathogenic role. Taken together, these data demonstrate the role of the identified mutations for these mitochondriopathies. Our study reports the first mutations in the VARS2 and TARS2 genes, which encode two mitochondrial aminoacyl-tRNA synthetases, as causes of clinically distinct, early-onset mitochondrial encephalopathies.
AU  - Diodato, D.*
AU  - Melchionda, L.*
AU  - Haack, T.B.
AU  - Dallabona, C.*
AU  - Baruffini, E.*
AU  - Donnini, C.*
AU  - Granata, T.*
AU  - Ragona, F.*
AU  - Balestri, P.*
AU  - Margollicci, M.*
AU  - Lamantea, E.*
AU  - Nasca, A.*
AU  - Powell, C.A.*
AU  - Minczuk, M.*
AU  - Strom, T.M.
AU  - Meitinger, T.
AU  - Prokisch, H.
AU  - Lamperti, C.*
AU  - Zeviani, M.*
AU  - Ghezzi, D.*
C1  - 31535
C2  - 34533
CY  - Hoboken
SP  - 983-989
TI  - VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies.
JO  - Hum. Mutat.
VL  - 35
IS  - 8
PB  - Wiley-Blackwell
PY  - 2014
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - We report three families presenting with hypertrophic cardiomyopathy, lactic acidosis, and multiple defects of mitochondrial respiratory chain activities. By direct sequencing of the candidate gene MTO1, encoding the mitochondrial-tRNA modifier 1, or whole exome sequencing analysis, we identified novel missense mutations. All MTO1 mutations were predicted to be deleterious on MTO1 function. Their pathogenic role was experimentally validated in a recombinant yeast model, by assessing oxidative growth, respiratory activity, mitochondrial protein synthesis and complex IV activity. In one case, we also demonstrated that expression of wt MTO1 could rescue the respiratory defect in mutant fibroblasts. The severity of the yeast respiratory phenotypes partly correlated with the different clinical presentations observed in MTO1 mutant patients, although the clinical outcome was highly variable in patients with the same mutation and seemed also to depend on timely start of pharmacological treatment, centered on the control of lactic acidosis by dichloroacetate. Our results indicate that MTO1 mutations are commonly associated with a presentation of hypertrophic cardiomyopathy, lactic acidosis and mitochondrial respiratory chain deficiency, and that ad hoc recombinant yeast models represent a useful system to test the pathogenic potential of uncommon variants, and provide insight into their effects on the expression of a biochemical phenotype.
AU  - Baruffini, E.*
AU  - Dallabona, C.*
AU  - Invernizzi, F.*
AU  - Yarham, J.W.*
AU  - Melchionda, L.*
AU  - Blakely, E.L.*
AU  - Lamantea, E.*
AU  - Donnini, C.*
AU  - Santra, S.*
AU  - Vijayaraghavan, S.*
AU  - Roper, H.P.*
AU  - Burlina, A.*
AU  - Kopajtich, R.
AU  - Walther, A.
AU  - Strom, T.M.
AU  - Haack, T.B.
AU  - Prokisch, H.
AU  - Taylor, R.W.*
AU  - Ferrero, I.*
AU  - Zeviani, M.*
AU  - Ghezzi, D.*
C1  - 27564
C2  - 32723
SP  - 1501-1509
TI  - MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast.
JO  - Hum. Mutat.
VL  - 34
IS  - 11
PB  - Wiley-Blackwell
PY  - 2013
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - POU3F4 is a POU domain transcription factor that is required for hearing. In the ear, POU3F4 is essential for mesenchymal remodeling of the bony labyrinth and is the causative gene for DFNX2 human nonsyndromic deafness. Ear abnormalities underlie this form of deafness, characterized previously in multiple spontaneous, radiation-induced and transgenic mouse mutants. Here, we report three novel mutations in the POU3F4 gene that result in profound hearing loss in both humans and mice. A p.Gln79* mutation was identified in a child from an Israeli family, revealed by massively parallel sequencing (MPS). This strategy demonstrates the strength of MPS for diagnosis with only one affected individual. A second mutation, p.Ile285Argfs*43, was identified by Sanger sequencing. A p.Cys300* mutation was found in an ENU-induced mutant mouse, schwindel (sdl), by positional cloning. The mutation leads to a predicted truncated protein, similar to the human mutations, providing a relevant mouse model. The p.Ile285Argfs*43 and p.Cys300* mutations lead to a shift of Pou3f4 nuclear localization to the cytoplasm, demonstrated in cellular localization studies and in the inner ears of the mutant mice. The discovery of these mutations facilitates a deeper comprehension of the molecular basis of inner ear defects due to mutations in the POU3F4 transcription factor.
AU  - Parzefall, T.*
AU  - Shivatzki, S.*
AU  - Lenz, D.R.*
AU  - Rathkolb, B.
AU  - Ushakov, K.*
AU  - Karfunkel, D.*
AU  - Shapira, Y.*
AU  - Wolf, M.*
AU  - Mohr, M.*
AU  - Wolf, E.*
AU  - Sabrautzki, S.
AU  - Hrabě de Angelis, M.
AU  - Frydman, M.*
AU  - Brownstein, Z.*
AU  - Avraham, K.B.*
C1  - 25697
C2  - 31890
SP  - 1102-1110
TI  - Cytoplasmic mislocalization of POU3F4 due to novel mutations leads to deafness in humans and mice.
JO  - Hum. Mutat.
VL  - 34
IS  - 8
PB  - Wiley-Blackwell
PY  - 2013
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Mental retardation affects 2-3% of the population and shows a high heritability.Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors.We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language.
AU  - Horn, D.*
AU  - Kapeller, J.*
AU  - Rivera-Brugues, N.
AU  - Moog, U.*
AU  - Lorenz-Depiereux, B.
AU  - Eck, S.H.
AU  - Hempel, M.*
AU  - Wagenstaller, J.
AU  - Gawthrope, A.*
AU  - Monaco, A.P.*
AU  - Bonin, M.*
AU  - Riess, O.*
AU  - Wohlleber, E.*
AU  - Illig, T.
AU  - Bezzina, C.R.*
AU  - Franke, A.*
AU  - Spranger, S.*
AU  - Villavicencio-Lorini, P.*
AU  - Seifert, W.*
AU  - Rosenfeld, J.*
AU  - Klopocki, E.*
AU  - Rappold, G.A.*
AU  - Strom, T.M.
C1  - 618
C2  - 28015
SP  - E1851-E1860
TI  - Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits.
JO  - Hum. Mutat.
VL  - 31
IS  - 11
PB  - Wiley-Blackwell
PY  - 2010
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Multiple endocrine neoplasia (MEN) syndromes are characterized by tumors involving two or more endocrine glands. Two MEN syndromes have long been known: MEN1 and MEN2,caused by germline mutations in MEN1 or RET, respectively. Recently, mutations in CDKN1B,encoding the cyclin-dependent kinase (Cdk) inhibitor p27, were identified in patients having a MEN1-like phenotype but no MEN1 gene mutations. Currently, the molecular mechanisms mediating the role of p27 in tumor predisposition are ill defined. We here report a novel germline missense variant in CDKN1B (c.678C>T, p.P69L) found in a patient with multiple endocrine tumors. We previously reported a nonsense p27 mutation (c.692G>A, p.W76X) in two patients with MEN1-like phenotype. Functional assays were used to characterize p27P69L and p27W76X in vitro. We show that p27P69L is expressed at reduced level and is impaired in both binding toCdk2 and inhibiting cell growth. p27W76X, which is mislocalized to the cytoplasm, can no longer efficiently bind Cyclins-Cdks, nor inhibit cell growth or induce apoptosis. In the patient’s tumor tissues, p27P69L associates with reduced/absent p27 expression and in one tumor with loss-of heterozygosity.Our results extend previous findings of CDKN1B mutations in patients with MEN1-related states and support the hypothesis of a tumor suppressor role for p27 in neuroendocrine cells.
AU  - Molatore, S.
AU  - Marinoni, I.
AU  - Lee, M.S.
AU  - Pulz, E.
AU  - Ambrosio, M.R.*
AU  - degli Uberti, E.C.*
AU  - Zatelli, M.C.*
AU  - Pellegata, N.S.
C1  - 2160
C2  - 27710
SP  - E1825-E1835
TI  - A novel germline CDKN1B mutation causing multiple endocrine tumors: Clinical, genetic and functional characterization.
JO  - Hum. Mutat.
VL  - 31
IS  - 11
PB  - Wiley-Blackwell
PY  - 2010
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Age-related macular degeneration (AMD) is a frequent, multifactorial disease of the central retina and a major cause of irreversible vision loss in industrialized countries. Apolipoprotein E (APOE) has been consistently associated with AMD, particularly ist two functional isoforms E2 (predisposing) and E4 (protective). The biological correlate of this association, however, is still unclear. In this study, we have defined an extended haplotype block encompassing the entire APOE gene locus, including known coding as well as cis-regulatory promoter variants. Of the five extended APOE haplotypes common in the general population, two were found to be significantly associated with AMD, namely G-G-G-G-epsilon 2 (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.19-2.12) and T-G-A-G-epsilon 4 (OR, 0.76; 95% CI, 0.58-0.99). When analyzing common extended haplotype combinations, T-C-G-G-epsilon 3/T-G-A-G-epsilon 4 exhibited the most prominent effect (OR, 0.32; 95% CI, 0.20-0.51). Intriguingly, we also found one extended epsilon 3-haplotype, G-G-G-A-epsilon 3 to be protective in the homozygous state (OR, 0.65; 95% CI, 0.49-0.87). Since single nucleotide polymorphism (SNT) rs405509:G > T is a constituent of the extended epsilon-haplotype block and is known to significantly influence APOE promoter activity, we hypothesize that both the relative rate of APOE isoform. Expression in conjunction with established functional differences of the respective isoforms may be crucial in mediating AMD pathology. This would also imply that genotyping of the core epsilon-haplotypes alone is not sufficient to estimate AMD risk, but that determination of extended haplotype combinations, including the functional promoter SNP rs405509, is required instead.
AU  - Fritsche, L.G.*
AU  - Freitag-Wolf, S.*
AU  - Bettecken, T.*
AU  - Meitinger, T.
AU  - Keilhauer, C.N.*
AU  - Krawczak, M.*
AU  - Weber, B.H.F.*
C1  - 2466
C2  - 26446
SP  - 1048-1053
TI  - Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene.
JO  - Hum. Mutat.
VL  - 30
IS  - 7
PB  - Wiley-Blackwell
PY  - 2009
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - In a consanguineous Turkish family, a locus for autosomal recessive nonsyndromic hearing impairment (ARNSHI) was mapped to chromosome 2q31.1-2q33.1. Microsatellite marker analysis in the complete family determined the critical linkage interval that overlapped with DFNB27, for which the causative gene has not yet been identified, and DFNB59, a recently described auditory neuropathy caused by missense mutations in the DFNB59 gene. The 352-amino acid (aa) DFNB59 gene product pejvakin is present in hair cells, supporting cells, spiral ganglion cells, and the first three relays of the afferent auditory pathway. A novel homozygous nonsense mutation (c.499C>T; p.R167X) was detected in the DFNB59 gene, segregating with the deafness in the family. The mRNA derived from the mutant allele was found not to be degraded in lymphocytes, indicating that a truncated pejvakin protein of 166 aa may be present in the affected individuals. Screening of 67 index patients from additional consanguineous Turkish families with autosomal recessive hearing impairment revealed a homozygous missense mutation (c.547C>T; p.R183W) that segregates with the hearing impairment in one family. Furthermore, in a panel of 83 Dutch patients, two additional novel mutations (c.509_512delCACT; p.S170CfsX35 and c.731T>G; p.L244R), which were not present in ethnically matched controls, were found heterozygously. Together, our data indicate that also nonsense mutations in DFNB59 cause nonsyndromic hearing loss, but that mutations in DFNB59 are not a major cause of nonsyndromic hearing impairment in the Turkish and Dutch population.
AU  - Collin, R.W.*
AU  - Kalay, E.*
AU  - Oostrik, J.*
AU  - Caylan, R.*
AU  - Wollnik, B.*
AU  - Arslan, S.*
AU  - den Hollander, A.I.*
AU  - Birinci, Y.*
AU  - Lichtner, P.
AU  - Strom, T.M.
AU  - Toraman, B.*
AU  - Hoefsloot, L.H.*
AU  - Cremers, C.W.*
AU  - Brunner, H.G.*
AU  - Cremers, F.P.*
AU  - Karaguzel, A.*
AU  - Kremer, H.*
C1  - 2727
C2  - 24775
SP  - 718-723
TI  - Involvement of DFNB59 mutations in autosomal recessive nonsyndromic hearing impairment.
JO  - Hum. Mutat.
VL  - 28
IS  - 7
PB  - Wiley-Blackwell
PY  - 2007
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - This article reports a well-powered age-related macular degeneration (AMD) case-control association study in the HMCN1 gene, showing that common variants do not account for a substantial proportion of AMD cases. Thus, the consistent linkage peak observed by several genome-wide linkage scans within the 1q32 region is unlikely to be attributed to polymorphisms at the HMCN1 locus. In addition, the analysis provides comprehensive data suggesting that low-frequency variants encoding possible functional amino acid polymorphisms in the HMCN1 gene may not contribute substantially to disease, although HMCN1 mutations may still confer disease susceptibility in a small subset of patients. Interestingly, the HMCN1 p.Gln5346Arg mutation, which is thought to be a causal mutation in a large AMD pedigree segregating the disease as a single-gene trait, appears to occur in our control cohort as a low-frequency polymorphism with an allele frequency of approximately 0.0026.
AU  - Fisher, S.A.*
AU  - Rivera, A.*
AU  - Fritsche, L.G.*
AU  - Keilhauer, C.N.*
AU  - Lichtner, P.
AU  - Meitinger, T.
AU  - Rudolph, G.*
AU  - Weber, B.H.F.*
C1  - 4167
C2  - 24792
SP  - 406-413
TI  - Case-control genetic association study of fibulin-6 (FBLN6 or HMCN1) variants in age-related macular degeneration (AMD).
JO  - Hum. Mutat.
VL  - 28
IS  - 4
PB  - Wiley-Blackwell
PY  - 2007
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - Plasma and serum samples were often the only biological material collected for earlier epidemiological studies. These studies have a huge informative content, especially due to their long follow-up and would be an invaluable treasure for genetic investigations. However, often no banked DNA is available. To use the small amounts of DNA present in plasma, in a first step, we applied magnetic bead technology to extract this DNA, followed by a whole-genome amplification (WGA) using phi29-polymerase. We assembled 88 sample pairs, each consisting of WGA plasma DNA and the corresponding whole-blood DNA. We genotyped nine highly polymorphic short tandem repeats (STRs) and 23 SNPs in both DNA sources. The average within-pair discordance was 3.8% for SNPs and 15.9% for STR genotypes, respectively. We developed an algorithm based on one-half of the sample pairs and validated on the other one-half to identify the samples with high WGA plasma DNA quality to assure low genotyping error and to exclude plasma DNA samples with insufficient quality: excluding samples showing homozygosity at five or more of the nine STR loci yielded exclusion of 22.7% of all samples and decreased average discordance for STR and SNP markers to 3.92% and 0.63%, respectively. For SNPs, this is very close to the error observed for genomic DNA in many laboratories. Our workflow and sample selection algorithm offers new opportunities to recover reliable DNA from stored plasma material. This algorithm is superior to testing the amount of input DNA.
AU  - Schoenborn, V.*
AU  - Gohlke, H.
AU  - Heid, I.M.
AU  - Illig, T.
AU  - Utermann, G.*
AU  - Kronenberg, F.*
C1  - 4769
C2  - 24941
SP  - 1141-1149
TI  - Sample selection algorithm to improve quality of genotyping from plasma-derived DNA: To separate the wheat from the chaff.
JO  - Hum. Mutat.
VL  - 28
IS  - 11
PB  - Wiley-Blackwell
PY  - 2007
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - In two large Turkish consanguineous families, a locus for autosomal recessive nonsyndromic hearing loss (ARNSHL) was mapped to chromosome 6p21.3 by genome-wide linkage analysis in an interval overlapping with the loci DFNB53 (COL11A2), DFNB66, and DFNB67. Fine mapping excluded DFNB53 and subsequently homozygous mutations were identified in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene, also named tetraspan membrane protein of hair cell stereocilia (TMHS) gene, which was recently shown to be mutated in the "hurry scurry" mouse and in two DFNB67-linked families from Pakistan. In one family, we found a homozygous one-base pair deletion, c.649delG (p.Glu216ArgfsX26) and in the other family we identified a homozygous transition c.494C>T (p.Thr165Met). Further screening of index patients from 96 Turkish ARNSHL families and 90 Dutch ARNSHL patients identified one additional Turkish family carrying the c.649delG mutation. Haplotype analysis revealed that the c.649delG mutation was located on a common haplotype in both families. Mutation screening of the LHFPL5 homologs LHFPL3 and LHFPL4 did not reveal any disease causing mutation. Our findings indicate that LHFPL5 is essential for normal function of the human cochlea. © 2006 Wiley-Liss, Inc.
AU  - Kalay, E.*
AU  - Li, Y.*
AU  - Uzumcu, A.*
AU  - Uyguner, O.*
AU  - Collin, R.W.*
AU  - Caylan, R.*
AU  - Ulubil-Emiroglu, M.*
AU  - Kersten, F.F.*
AU  - Hafiz, G.*
AU  - van Wijk, E.*
AU  - Kayserili, H.*
AU  - Rohmann, E.*
AU  - Wagenstaller, J.*
AU  - Hoefsloot, L.H.*
AU  - Strom, T.M.*
AU  - Nurnberg, G.*
AU  - Baserer, N.*
AU  - den Hollander, A.I.*
AU  - Cremers, F.P.*
AU  - Cremers, C.W.*
AU  - Becker, C.*
AU  - Brunner, H.G.*
AU  - Nürnberg, P.*
AU  - Karaguzel, A.*
AU  - Basaran, S.*
AU  - Kubisch, C.*
AU  - Kremer, H.*
AU  - Wollnik, B.*
C1  - 4533
C2  - 23671
SP  - 633-639
TI  - Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss.
JO  - Hum. Mutat.
VL  - 27
IS  - 7
PB  - Wiley
PY  - 2006
SN  - 1059-7794
ER  - 

TY  - JOUR
AU  - Jaremko, M.*
AU  - Justenhoven, C.*
AU  - Abraham, B.K.*
AU  - Schroth, W.*
AU  - Fritz, P.*
AU  - Brod, S.*
AU  - Vollmert, C.
AU  - Illig, T.
AU  - Brauch, H.*
C1  - 4547
C2  - 22619
SP  - 232-238
TI  - MALDI-TOF MS and TaqMan® assisted SNP genotyping of DNA isolated from formalin-fixed and paraffin-embedded tissues (FFPET).
JO  - Hum. Mutat.
VL  - 25
PB  - Wiley
PY  - 2005
SN  - 1059-7794
ER  - 

TY  - JOUR
AB  - The aim of the study is to validate the etiological role of KIAA0027/MLC1 in childhood-onset megalencephalic leukoencephalopathy with subcortical cysts (MLC) and in schizophrenia, particularly the catatonic subtype, which were reported to be allelic diseases. Among a series of five patients with MLC, four mutant alleles were detected: one case of compound heterozygosity for a splice site mutation and a six-base-pair in-frame deletion, one patient with a homozygous frameshifting insertion-deletion, and a further case heterozygous for a A157E substitution. A systematic mutation screening in 140 index cases with schizophrenia revealed 13 different single nucleotide polymorphisms (SNPs): one SNP in the 5'-UTR, seven SNPs in intronic regions, two synonymous codon variants (T52, Y199), and three coding variants. Two of them, C171F and N218K, were observed in controls at a significant frequency. The L309M variant that was previously supposed to be the causative factor for chromosome 22q(tel) linked-periodic catatonia was found nonsegregating in a further multiplex pedigree. Furthermore, a complicated 33-bp insertion/deletion polymorphism at the 5'-end of exon 11 of MLC1 was found at equal frequency among schizophrenic patients and controls. In summary, our study provides further evidence for allelic heterogeneity in megalencephalic leukoencephalopathy, excludes MLC1 as a susceptibility locus for schizophrenia, and thereby rules out that MLC and schizophrenia are allelic disorders.
AU  - Rubie, C.*
AU  - Lichtner, P.
AU  - Gärtner, J.*
AU  - Siekiera, M.*
AU  - Uziel, G.*
AU  - Kohlmann, B.*
AU  - Kohlschütter, A.*
AU  - Meitinger, T.
AU  - Stöber, G.*
AU  - Bettecken, T.
C1  - 22431
C2  - 31085
SP  - 45-52
TI  - Sequence diversity of KIAA0027/MLC1: Are megalencephalic leukoencephalopathy and schizophrenia allelic disorders?
JO  - Hum. Mutat.
VL  - 21
IS  - 1
PB  - Wiley
PY  - 2003
SN  - 1059-7794
ER  - 

TY  - JOUR
AU  - Calzada-Wack, J.
AU  - Schnitzbauer, U.
AU  - Walch, A.K.*
AU  - Wurster, K.-H.*
AU  - Kappler, R.
AU  - Nathrath, M.
AU  - Hahn, H.
C1  - 9529
C2  - 21284
SP  - 233-234
TI  - Analysis of the PTCH Coding Region in Human Rhabdomyosarcoma.
JO  - Hum. Mutat.
VL  - 20
PB  - Wiley
PY  - 2002
SN  - 1059-7794
ER  - 

TY  - JOUR
AU  - von Brederlow, B.*
AU  - Bolz, H.*
AU  - Janecke, A.*
AU  - La O Cabrera, A.*
AU  - Rudolph, G.
AU  - Lorenz, B.*
AU  - Schwinger, E.*
AU  - Gal, A.*
C1  - 9528
C2  - 20554
SP  - 268-273
TI  - Identification and In Vitro Expression of Novel CDH23 Mutations of Patients with Usher Syndrome Type 1D.
JO  - Hum. Mutat.
VL  - 19
PB  - Wiley
PY  - 2002
SN  - 1059-7794
ER  - 

TY  - JOUR
AU  - Werner, M.
AU  - Sych, M.*
AU  - Herbon, N.
AU  - Illig, T.
AU  - König, I.R.*
AU  - Wjst, M.
C1  - 22066
C2  - 20704
SP  - 57-64
TI  - Large-Scale Determination of SNP Allele Frequencies in DNA Pools Using MALDI-TOF Mass Spectrometry.
JO  - Hum. Mutat.
VL  - 20
PB  - Wiley
PY  - 2002
SN  - 1059-7794
ER  -