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Shearer A.E.,University of Iowa | Eppsteiner R.W.,University of Iowa | Booth K.T.,University of Iowa | Ephraim S.S.,University of Iowa | And 28 more authors.
American Journal of Human Genetics | Year: 2014

Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) >0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness. © 2014 by The American Society of Human Genetics. All rights reserved. Source


Anderson S.L.,Fordham University | Jalas C.,Center for Rare Jewish Genetic Disorders | Fedick A.,Rutgers Robert Wood Johnson Medical School | Reid K.F.,Fordham University | And 5 more authors.
Clinical Genetics | Year: 2015

Osteopetrosis is a rare and heterogeneous genetic disorder characterized by dense bone mass that is a consequence of defective osteoclast function and/or development. Autosomal recessive osteopetrosis (ARO) is the most severe form and is often fatal within the first years of life; early hematopoietic stem cell transplant (HSCT) remains the only curative treatment for ARO. The majority of the ARO-causing mutations are located in the TCIRG1 gene. We report here the identification and characterization of an A to T transversion in the fourth base of the intron 2 donor splice site (c.117+4A→T) in TCIRG1, a mutation not previously seen in the Ashkenazi Jewish (AJ) population. Analysis of a random sample of individuals of AJ descent revealed a carrier frequency of approximately 1 in 350. Genotyping of five loci adjacent to the c.117+4A→T-containing TCIRG1 allele revealed that the presence of this mutation in the AJ population is due to a single founder. The identification of this mutation will enable population carrier testing and will facilitate the identification and treatment of individuals homozygous for this mutation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Source


Edvardson S.,Hebrew University of Jerusalem | Shaag A.,Hebrew University of Jerusalem | Zenvirt S.,Hebrew University of Jerusalem | Erlich Y.,Cold Spring Harbor Laboratory | And 7 more authors.
American Journal of Human Genetics | Year: 2010

Patients with Joubert syndrome 2 (JBTS2) suffer from a neurological disease manifested by psychomotor retardation, hypotonia, ataxia, nystagmus, and oculomotor apraxia and variably associated with dysmorphism, as well as retinal and renal involvement. Brain MRI results show cerebellar vermis hypoplasia and additional anomalies of the fourth ventricle, corpus callosum, and occipital cortex. The disease has previously been mapped to the centromeric region of chromosome 11. Using homozygosity mapping in 13 patients from eight Ashkenazi Jewish families, we identified a homozygous mutation, R12L, in the TMEM216 gene, in all affected individuals. Thirty individuals heterozygous for the mutation were detected among 2766 anonymous Ashkenazi Jews, indicating a carrier rate of 1:92. Given the small size of the TMEM216 gene relative to other JBTS genes, its sequence analysis is warranted in all JBTS patients, especially those who suffer from associated anomalies. © 2010 The American Society of Human Genetics. Source


Jalas C.,Center for Rare Jewish Genetic Disorders | Anderson S.L.,Fordham University | Laufer T.,Fordham University | Martimucci K.,Fordham University | And 4 more authors.
Blood Cells, Molecules, and Diseases | Year: 2011

Congenital amegakaryocytic thrombocytopenia (MIM #. 604498) (CAMT) is a rare inherited disease presenting as severe thrombocytopenia in infancy. Untreated, many CAMT patients develop aplastic anemia within the first decade of life; the only effective treatment of CAMT is bone marrow transplantation. CAMT is the result of the presence of homozygous or compound heterozygous mutations in the thrombopoietin receptor-encoding gene, MPL. We report here the identification and characterization of a founder mutation in MPL in the Ashkenazi Jewish (AJ) population. This mutation, termed c.79. +. 2T > A, is a T to A transversion in the invariant second base of the intron 1 donor splice site. Analysis of a random sample of 2018 individuals of AJ descent revealed a carrier frequency of approximately 1 in 75. Genotyping of six loci adjacent to the MPL gene in the proband and in the 27 individuals identified as carriers of the c.79. +. 2T > A mutation revealed that the presence of this mutation in the AJ population is due to a single founder. The observed carrier frequency predicts an incidence of CAMT in the AJ population of approximately 1 in 22,500 pregnancies. The identification of this mutation will enable population carrier testing and will facilitate the identification and treatment of individuals homozygous for this mutation. © 2011 Elsevier Inc. Source


Flint D.,University of Alabama at Birmingham | Li R.,University of Alabama at Birmingham | Webster L.S.,University of Alabama at Birmingham | Naidu S.,Kennedy Krieger Institute | And 10 more authors.
Human Mutation | Year: 2012

Alexander disease (AxD) is a usually fatal astrogliopathy primarily caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament protein expressed in astrocytes. We describe three patients with unique characteristics, and whose mutations have implications for AxD diagnosis and studies of intermediate filaments. Patient 1 is the first reported case with a noncoding mutation. The patient has a splice site change producing an in-frame deletion of exon 4 in about 10% of the transcripts. Patient 2 has an insertion and deletion at the extreme end of the coding region, resulting in a short frameshift. In addition, the mutation was found in buccal DNA but not in blood DNA, making this patient the first reported chimera. Patient 3 has a single-base deletion near the C-terminal end of the protein, producing a short frameshift. These findings recommend inclusion of intronic splice site regions in genetic testing for AxD, indicate that alteration of only a small fraction of GFAP can produce disease, and provide caution against tagging intermediate filaments at their C-terminal end for cell biological investigations. © 2012 Wiley Periodicals, Inc. Source

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