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Human Genetics

Heather M Ochs-Balcom, Holly Shaw, Leah Preus, Julie R Palmer, Stephen A Haddad, Lynn Rosenberg, Edward A Ruiz-Narváez
Several genome-wide association studies (GWAS) have identified genetic variants associated with birth weight. To date, however, most GWAS of birth weight have focused primarily on European ancestry samples even though prevalence of low birth weight is higher among African-Americans. We conducted admixture mapping using 2918 ancestral informative markers in 2596 participants of the Black Women's Health Study, with the goal of identifying novel genomic regions where local African ancestry is associated with birth weight...
July 13, 2018: Human Genetics
Hildegard Kehrer-Sawatzki, Lan Kluwe, Reinhard E Friedrich, Anna Summerer, Eleonora Schäfer, Ute Wahlländer, Cordula Matthies, Isabel Gugel, Said Farschtschi, Christian Hagel, David N Cooper, Victor-Felix Mautner
Schwannomatosis and neurofibromatosis type 2 (NF2) are both characterized by the development of multiple schwannomas but represent different genetic entities. Whereas NF2 is caused by mutations of the NF2 gene, schwannomatosis is associated with germline mutations of SMARCB1 or LZTR1. Here, we studied 15 sporadic patients with multiple non-intradermal schwannomas, but lacking vestibular schwannomas and ophthalmological abnormalities, who fulfilled the clinical diagnostic criteria for schwannomatosis. None of them harboured germline NF2 or SMARCB1 mutations as determined by the analysis of blood samples but seven had germline LZTR1 variants predicted to be pathogenic...
July 13, 2018: Human Genetics
Yumi Yamaguchi-Kabata, Takashi Morihara, Tomoyuki Ohara, Toshiharu Ninomiya, Atsushi Takahashi, Hiroyasu Akatsu, Yoshio Hashizume, Noriyuki Hayashi, Daichi Shigemizu, Keith A Boroevich, Manabu Ikeda, Michiaki Kubo, Masatoshi Takeda, Tatsuhiko Tsunoda
Alzheimer's disease (AD) is a common neurological disease that causes dementia in humans. Although the reports of associated pathological genes have been increasing, the molecular mechanism leading to the accumulation of amyloid-β (Aβ) in human brain is still not well understood. To identify novel genes that cause accumulation of Aβ in AD patients, we conducted an integrative analysis by combining a human genetic association study and transcriptome analysis in mouse brain. First, we examined genome-wide gene expression levels in the hippocampus, comparing them to amyloid Aβ level in mice with mixed genetic backgrounds...
July 13, 2018: Human Genetics
Anna Summerer, Victor-Felix Mautner, Meena Upadhyaya, Kathleen B M Claes, Josef Högel, David N Cooper, Ludwine Messiaen, Hildegard Kehrer-Sawatzki
The breakpoints of type-1 NF1 deletions encompassing 1.4-Mb are located within NF1-REPa and NF1-REPc, which exhibit a complex structure comprising different segmental duplications in direct and inverted orientation. Here, we systematically assessed the proportion of type-1 NF1 deletions caused by nonallelic homologous recombination (NAHR) and those mediated by other mutational mechanisms. To this end, we analyzed 236 unselected type-1 deletions and observed that 179 of them (75.8%) had breakpoints located within the NAHR hotspot PRS2, whereas 39 deletions (16...
July 10, 2018: Human Genetics
Guney Bademci, Clemer Abad, Armagan Incesulu, Abolfazl Rad, Ozgul Alper, Susanne M Kolb, Filiz B Cengiz, Oscar Diaz-Horta, Fatma Silan, Ercan Mihci, Emre Ocak, Maryam Najafi, Reza Maroofian, Elanur Yilmaz, Banu G Nur, Duygu Duman, Shengru Guo, David W Sant, Gaofeng Wang, Paula V Monje, Thomas Haaf, Susan H Blanton, Barbara Vona, Katherina Walz, Mustafa Tekin
While recent studies have revealed a substantial portion of the genes underlying human hearing loss, the extensive genetic landscape has not been completely explored. Here, we report a loss-of-function variant (c.72delA) in MPZL2 in three unrelated multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss. The variant co-segregates with moderate sensorineural hearing loss in all three families. We show a shared haplotype flanking the variant in our families implicating a single founder...
July 7, 2018: Human Genetics
Paola Bovolenta, Juan-Ramón Martinez-Morales
Embryological manipulations in chick embryos have been pivotal in our understanding of many aspects of vertebrate eye formation. This research was particularly important in uncovering the role of tissue interactions as drivers of eye morphogenesis and to dissect the function of critical genes. Here, we have highlighted a few of these past experiments to endorse their value in searching for hitherto unknown causes of rare congenital eye anomalies, such as microphthalmia, anophthalmia and coloboma. We have also highlighted a number of similarities between the chicken and human eye, which might be exploited to address other eye pathologies, including degenerative ocular diseases...
July 6, 2018: Human Genetics
Anil Chekuri, Aditya A Guru, Pooja Biswas, Kari Branham, Shyamanga Borooah, Angel Soto-Hermida, Michael Hicks, Naheed W Khan, Hiroko Matsui, Akhila Alapati, Pongali B Raghavendra, Susanne Roosing, Sripriya Sarangapani, Sinnakaruppan Mathavan, Amalio Telenti, John R Heckenlively, S Amer Riazuddin, Kelly A Frazer, Paul A Sieving, Radha Ayyagari
Whole genome sequencing (WGS) was performed to identify the variants responsible for inherited retinal degeneration (IRD) in a Caucasian family. Segregation analysis of selected rare variants with pathogenic potential identified a set of compound heterozygous changes p.Arg266*:c.796C>T and p.Ala568Thr:c.1702G>A in the intraflagellar transport protein-88 (IFT88) gene segregating with IRD. Expression of IFT88 with the p.Arg266* and p.Ala568Thr mutations in mIMDC3 cells by transient transfection and in HeLa cells by introducing the mutations using CRISPR-cas9 system suggested that both mutations result in the formation of abnormal ciliary structures...
July 5, 2018: Human Genetics
Nicola Ragge, Bertrand Isidor, Pierre Bitoun, Sylvie Odent, Irina Giurgea, Benjamin Cogné, Wallid Deb, Marie Vincent, Jessica Le Gall, Jenny Morton, Derek Lim, Guylène Le Meur, Celia Zazo Seco, Dimitra Zafeiropoulou, Dorine Bax, Petra Zwijnenburg, Anara Arteche, Saoud Tahsin Swafiri, Ruth Cleaver, Meriel McEntagart, Usha Kini, William Newman, Carmen Ayuso, Marta Corton, Yvan Herenger, Médéric Jeanne, Patrick Calvas, Nicolas Chassaing
Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ('Lenz'-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome ('Lenz') usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c...
July 4, 2018: Human Genetics
Isabelle Schrauwen, Imen Chakchouk, Khurram Liaqat, Abid Jan, Abdul Nasir, Shabir Hussain, Deborah A Nickerson, Michael J Bamshad, Asmat Ullah, Wasim Ahmad, Suzanne M Leal
Hereditary hearing impairment is a common sensory disorder that is genetically and phenotypically heterogeneous. In this study, we used a homozygosity mapping and exome sequencing strategy to study a consanguineous Pakistani family with autosomal recessive severe-to-profound hearing impairment. This led to the identification of a missense variant (p.Ile369Thr) in the LMX1A gene affecting a conserved residue in the C-terminus of the protein, which was predicted damaging by an in silico bioinformatics analysis...
July 3, 2018: Human Genetics
Isabelle Schrauwen, Elina Kari, Jacob Mattox, Lorida Llaci, Joanna Smeeton, Marcus Naymik, David W Raible, James A Knowles, J Gage Crump, Matthew J Huentelman, Rick A Friedman
Congenital inner ear malformations affecting both the osseous and membranous labyrinth can have a devastating impact on hearing and language development. With the exception of an enlarged vestibular aqueduct, non-syndromic inner ear malformations are rare, and their underlying molecular biology has thus far remained understudied. To identify molecular factors that might be important in the developing inner ear, we adopted a family-based trio exome sequencing approach in young unrelated subjects with severe inner ear malformations...
June 28, 2018: Human Genetics
Li Wang, Yong Feng, Denise Yan, Litao Qin, M'hamed Grati, Rahul Mittal, Tao Li, Abhiraami Kannan Sundhari, Yalan Liu, Prem Chapagain, Susan H Blanton, Shixiu Liao, Xuezhong Liu
Identification of genes with variants causing non-syndromic hearing loss (NSHL) is challenging due to genetic heterogeneity. The difficulty is compounded by technical limitations that in the past prevented comprehensive gene identification. Recent advances in technology, using targeted capture and next-generation sequencing (NGS), is changing the face of gene identification and making it possible to rapidly and cost-effectively sequence the whole human exome. Here, we characterize a five-generation Chinese family with progressive, postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL)...
June 2, 2018: Human Genetics
Yuan Lin, Lu Liu, Sen Yang, Yun Li, Dongxin Lin, Xuejun Zhang, Xianyong Yin
Genotype imputation is now routinely performed in genomic analysis. Reference panel size, that is, the number of haplotypes in the reference panel, has been well established to be one major driving factor of imputation accuracy. For that reason, huge efforts have been made worldwide to provide large reference panels, with the Haplotype Reference Consortium (HRC) being currently the largest available in the public domain. The imputation performance of HRC, whose major samples are Europeans, has been mainly evaluated in Europeans...
May 31, 2018: Human Genetics
Mieke Wesdorp, Pia A M de Koning Gans, Margit Schraders, Jaap Oostrik, Martijn A Huynen, Hanka Venselaar, Andy J Beynon, Judith van Gaalen, Vitória Piai, Nicol Voermans, Michelle M van Rossum, Bas P Hartel, Stefan H Lelieveld, Laurens Wiel, Berit Verbist, Liselotte J Rotteveel, Marieke F van Dooren, Peter Lichtner, Henricus P M Kunst, Ilse Feenstra, Ronald J C Admiraal, Helger G Yntema, Lies H Hoefsloot, Ronald J E Pennings, Hannie Kremer
Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein-protein interactions...
May 12, 2018: Human Genetics
M Krall, S Htun, D Anand, D Hart, S A Lachke, A M Slavotinek
The authors noticed that Fig. 5A and B aspect ratios appeared sub-optimal in the online published version. This has now been changed.
May 11, 2018: Human Genetics
Lot Snijders Blok, Susan M Hiatt, Kevin M Bowling, Jeremy W Prokop, Krysta L Engel, J Nicholas Cochran, E Martina Bebin, Emilia K Bijlsma, Claudia A L Ruivenkamp, Paulien Terhal, Marleen E H Simon, Rosemarie Smith, Jane A Hurst, Heather McLaughlin, Richard Person, Amy Crunk, Michael F Wangler, Haley Streff, Joseph D Symonds, Sameer M Zuberi, Katherine S Elliott, Victoria R Sanders, Abigail Masunga, Robert J Hopkin, Holly A Dubbs, Xilma R Ortiz-Gonzalez, Rolph Pfundt, Han G Brunner, Simon E Fisher, Tjitske Kleefstra, Gregory M Cooper
Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders...
May 8, 2018: Human Genetics
Elisabetta Manduchi, Scott M Williams, Alessandra Chesi, Matthew E Johnson, Andrew D Wells, Struan F A Grant, Jason H Moore
Although Genome Wide Association Studies (GWAS) have led to many valuable insights into the genetic bases of common diseases over the past decade, the issue of missing heritability has surfaced, as the discovered main effect genetic variants found to date do not account for much of a trait's predicted genetic component. We present a workflow, integrating epigenomics and topologically associating domain data, aimed at discovering trait-associated SNP pairs from GWAS where neither SNP achieved independent genome-wide significance...
May 2018: Human Genetics
Daniel Fritzen, Alma Kuechler, Mona Grimmel, Jessica Becker, Sophia Peters, Marc Sturm, Hela Hundertmark, Axel Schmidt, Martina Kreiß, Tim M Strom, Dagmar Wieczorek, Tobias B Haack, Stefanie Beck-Wödl, Kirsten Cremer, Hartmut Engels
Intellectual disability (ID) has an estimated prevalence of 1.5-2%. In most affected individuals, its genetic basis remains unclear. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that a large proportion of sporadic ID cases results from de novo mutations. Here, we present two unrelated individuals with similar clinical features and deleterious de novo variants in FBXO11 detected by WES. Individual 1, a 14-year-old boy, has mild ID as well as mild microcephaly, corrected cleft lip and alveolus, hyperkinetic disorder, mild brain atrophy and minor facial dysmorphism...
May 2018: Human Genetics
Sara Lindström, Marine Germain, Marta Crous-Bou, Erin N Smith, Pierre-Emmanuel Morange, Astrid van Hylckama Vlieg, Hugoline G de Haan, Daniel Chasman, Paul Ridker, Jennifer Brody, Mariza de Andrade, John A Heit, Weihong Tang, Immaculata De Vivo, Francine Grodstein, Nicholas L Smith, David Tregouet, Christopher Kabrhel
The co-author name Immaculata DeVivo was incorrectly published. The correct name is given below.
May 2018: Human Genetics
Lisa Neuhäusler, Anna Summerer, David N Cooper, Victor-F Mautner, Hildegard Kehrer-Sawatzki
Neurofibromatosis type 1 (NF1) is caused, in 4.7-11% of cases, by large deletions encompassing the NF1 gene and its flanking regions within 17q11.2. Different types of large NF1 deletion occur which are distinguishable by their breakpoint location and underlying mutational mechanism. Most common are the type-1 NF1 deletions of 1.4 Mb which exhibit recurrent breakpoints caused by nonallelic homologous recombination (NAHR), also termed unequal crossover. Here, we analyzed 37 unrelated families of patients with de novo type-1 NF1 deletions by means of short tandem repeat (STR) profiling to determine the parental origin of the deletions...
May 2018: Human Genetics
Andrew J Mowat, Michael Crompton, Joanna L Ziff, Christopher P Aldren, Jeremy A Lavy, Shakeel R Saeed, Sally J Dawson
Otosclerosis is a common form of hearing loss which typically presents in young adults. The disease has a familial, monogenic form and a non-familial form with a more complex aetiology. A previous genome wide association study identified evidence that variants within RELN are associated with the condition. Other genes in which an association has been reported include BMP2, COL1A1, FGF2, PPP2R5B and TGFB1. However, follow up studies have often failed to replicate initial positive results. The aim of this study was to establish if an association exists between eight single nucleotide polymorphisms (SNPs) in these six previously implicated genes and otosclerosis in a British case-control cohort (n = 748)...
May 2018: Human Genetics
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