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Human Genetics

Fabiola Ceroni, Domingo Aguilera-Garcia, Nicolas Chassaing, Dorine Arjanne Bax, Fiona Blanco-Kelly, Patricia Ramos, Maria Tarilonte, Cristina Villaverde, Luciana Rodrigues Jacy da Silva, Maria Juliana Ballesta-Martínez, Maria Jose Sanchez-Soler, Richard James Holt, Lisa Cooper-Charles, Jonathan Bruty, Yvonne Wallis, Dominic McMullan, Jonathan Hoffman, David Bunyan, Alison Stewart, Helen Stewart, Katherine Lachlan, Alan Fryer, Victoria McKay, Joëlle Roume, Pascal Dureau, Anand Saggar, Michael Griffiths, Patrick Calvas, Carmen Ayuso, Marta Corton, Nicola K Ragge
GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p...
February 20, 2018: Human Genetics
Xiang-He Meng, Hui Shen, Xiang-Ding Chen, Hong-Mei Xiao, Hong-Wen Deng
Genome-wide association studies (GWAS) have successfully identified numerous genetic variants associated with diverse complex phenotypes and diseases, and provided tremendous opportunities for further analyses using summary association statistics. Recently, Pickrell et al. developed a robust method for causal inference using independent putative causal SNPs. However, this method may fail to infer the causal relationship between two phenotypes when only a limited number of independent putative causal SNPs identified...
February 19, 2018: Human Genetics
Lisbeth Tranebjærg, Nicola Strenzke, Sture Lindholm, Nanna D Rendtorff, Hanne Poulsen, Himanshu Khandelia, Wojciech Kopec, Troels J Brünnich Lyngbye, Christian Hamel, Cecile Delettre, Beatrice Bocquet, Michael Bille, Hanne H Owen, Toke Bek, Hanne Jensen, Karen Østergaard, Claes Möller, Linda Luxon, Lucinda Carr, Louise Wilson, Kaukab Rajput, Tony Sirimanna, Katherine Harrop-Griffiths, Shamima Rahman, Barbara Vona, Julia Doll, Thomas Haaf, Oliver Bartsch, Hendrik Rosewich, Tobias Moser, Maria Bitner-Glindzicz
The following information was inadvertently omitted in the original publication.
February 12, 2018: Human Genetics
Leslie E W LaConte, Vrushali Chavan, Abdallah F Elias, Cynthia Hudson, Corbin Schwanke, Katie Styren, Jonathan Shoof, Fernando Kok, Sarika Srivastava, Konark Mukherjee
Deletion and truncation mutations in the X-linked gene CASK are associated with severe intellectual disability (ID), microcephaly and pontine and cerebellar hypoplasia in girls (MICPCH). The molecular origin of CASK-linked MICPCH is presumed to be due to disruption of the CASK-Tbr-1 interaction. This hypothesis, however, has not been directly tested. Missense variants in CASK are typically asymptomatic in girls. We report three severely affected girls with heterozygous CASK missense mutations (M519T (2), G659D (1)) who exhibit ID, microcephaly, and hindbrain hypoplasia...
February 9, 2018: Human Genetics
George Kanoungi, Michael Nothnagel
Complex diseases are frequently modeled as following an additive model that excludes both intra- and inter-locus interaction, while at the same time reports on non-additive biological structures are ample, prominently featuring numerous metabolic and signaling pathways. Using extensive forward population simulations, we explored the impact of three basic pathway motifs on the relationship between epidemiological parameters, including disease prevalence, relative risk, sibling recurrence risk as well as causal variant number and allele frequency...
February 8, 2018: Human Genetics
Chunyu Liu, Jessica L Fetterman, Poching Liu, Yan Luo, Martin G Larson, Ramachandran S Vasan, Jun Zhu, Daniel Levy
Increasing evidence implicates mitochondrial dysfunction in aging and age-related conditions. But little is known about the molecular basis for this connection. A possible cause may be mutations in the mitochondrial DNA (mtDNA), which are often heteroplasmic-the joint presence of different alleles at a single locus in the same individual. However, the involvement of mtDNA heteroplasmy in aging and age-related conditions has not been investigated thoroughly. We deep-sequenced the complete mtDNA genomes of 356 Framingham Heart Study participants (52% women, mean age 43, mean coverage 4570-fold), identified 2880 unique mutations and comprehensively annotated them by MITOMAP and PolyPhen-2...
February 8, 2018: Human Genetics
Zhongzhong Chen, Lele Kuang, Richard H Finnell, Hongyan Wang
Neural tube defects (NTDs), which include spina bifida and anencephaly, are the second most common form of human structural congenital malformations. While it is well established that SHROOM3 plays a pivotal role in the complex morphogenetic processes involved in neural tube closure (NTC), the underlying genetic contributions of SHROOM gene family members in the etiology of human NTDs remain poorly understood. Herein, we systematically investigated the mutation patterns of SHROOM1-4 in a Chinese population composed of 343 NTD cases and 206 controls, using targeted next-generation sequencing...
February 8, 2018: Human Genetics
Kathryn B Manheimer, Felix Richter, Lisa J Edelmann, Sunita L D'Souza, Lisong Shi, Yufeng Shen, Jason Homsy, Marko T Boskovski, Angela C Tai, Joshua Gorham, Christopher Yasso, Elizabeth Goldmuntz, Martina Brueckner, Richard P Lifton, Wendy K Chung, Christine E Seidman, J G Seidman, Bruce D Gelb
Mosaicism due to somatic mutations can cause multiple diseases including cancer, developmental and overgrowth syndromes, neurodevelopmental disorders, autoinflammatory diseases, and atrial fibrillation. With the increased use of next generation sequencing technology, multiple tools have been developed to identify low-frequency variants, specifically from matched tumor-normal tissues in cancer studies. To investigate whether mosaic variants are implicated in congenital heart disease (CHD), we developed a pipeline using the cancer somatic variant caller MuTect to identify mosaic variants in whole-exome sequencing (WES) data from a cohort of parent/affected child trios (n = 715) and a cohort of healthy individuals (n = 416)...
February 7, 2018: Human Genetics
Mahmoud Aarabi, Olivia Sniezek, Huaiyang Jiang, Devereux N Saller, Daniel Bellissimo, Svetlana A Yatsenko, Aleksandar Rajkovic
Whole exome sequencing (WES) is an emerging technique in prenatal diagnosis. In this retrospective study, we examined diagnostic utility and limitations of WES in prenatal cases with structural birth defects. DNA from 20 trios (fetal and parental), with normal karyotype and microarray findings, underwent WES and variant interpretation at a reference laboratory. The WES results were later re-evaluated in our academic center utilizing prenatal and postnatal phenotyping. Initial analysis using only prenatal ultrasound findings revealed no pathogenic or likely pathogenic variants in 20 pregnancies with structural birth defects...
February 1, 2018: Human Genetics
Chee-Wei Yew, Dongsheng Lu, Lian Deng, Lai-Ping Wong, Rick Twee-Hee Ong, Yan Lu, Xiaoji Wang, Yushimah Yunus, Farhang Aghakhanian, Siti Shuhada Mokhtar, Mohammad Zahirul Hoque, Christopher Lok-Yung Voo, Thuhairah Abdul Rahman, Jong Bhak, Maude E Phipps, Shuhua Xu, Yik-Ying Teo, Subbiah Vijay Kumar, Boon-Peng Hoh
Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28-37×. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays...
January 30, 2018: Human Genetics
Abigail W Bigham, Kevin Magnaye, Diane M Dunn, Robert B Weiss, Michael Bamshad
The human MN blood group antigens are isoforms of glycophorin A (GPA) encoded by the gene, GYPA, and are the most abundant erythrocyte sialoglycoproteins. The distribution of MN antigens has been widely studied in human populations yet the evolutionary and/or demographic factors affecting population variation remain elusive. While the primary function of GPA is yet to be discovered, it serves as the major binding site for the 175-kD erythrocyte-binding antigen (EB-175) of the malarial parasite, Plasmodium falciparum, a major selective pressure in recent human history...
January 23, 2018: Human Genetics
Yongyi Zou, Wanxia He, Kangli Wang, Hailong Han, Tingting Xiao, Xumeng Chen, Bin Zhou, Jieqiong Tan, Kun Xia, Beisha Tang, Chao Chen, Lu Shen, Riqiang Yan, Zhuohua Zhang
Reticulon 3 (RTN3) is a neuronally-expressed reticulon family protein that was previously shown to negatively regulate BACE1, a protease that is required for the generation of β-amyloid peptides (Aβ) from amyloid precursor protein. Despite biochemical and morphological evidence that supports a role of RTN3 in the formation of neuritic amyloid plaques, no systematic analyses of RTN3 mutations in patients with Alzheimer's disease (AD) have yet been reported. RTN3 were targeted sequenced in 154 sporadic early-onset and 285 late-onset AD patients...
January 22, 2018: Human Genetics
Rakesh Tamang, Gyaneshwer Chaubey, Amrita Nandan, Periyasamy Govindaraj, Vipin Kumar Singh, Niraj Rai, Chandana Basu Mallick, Vishwas Sharma, Varun Kumar Sharma, Anish M Shah, Albert Lalremruata, Alla G Reddy, Deepa Selvi Rani, Pilot Doviah, Neetu Negi, Yarin Hadid, Veena Pande, Satti Vishnupriya, George van Driem, Doron M Behar, Tikaram Sharma, Lalji Singh, Richard Villems, Kumarasamy Thangaraj
The rugged topography of the Himalayan region has hindered large-scale human migrations, population admixture and assimilation. Such complexity in geographical structure might have facilitated the existence of several small isolated communities in this region. We have genotyped about 850,000 autosomal markers among 35 individuals belonging to the four major populations inhabiting the Himalaya and adjoining regions. In addition, we have genotyped 794 individuals belonging to 16 ethnic groups from the same region, for uniparental (mitochondrial and Y chromosomal DNA) markers...
January 22, 2018: Human Genetics
J M Sikela, V B Searles Quick
Evolution often deals in genomic trade-offs: changes in the genome that are beneficial overall persist even though they also produce disease in a subset of individuals. Here, we explore the possibility that such trade-offs have occurred as part of the evolution of the human brain. Specifically, we provide support for the possibility that the same key genes that have been major contributors to the rapid evolutionary expansion of the human brain and its exceptional cognitive capacity also, in different combinations, are significant contributors to autism and schizophrenia...
January 15, 2018: Human Genetics
Takuya Hiraide, Mitsuko Nakashima, Kaori Yamoto, Tokiko Fukuda, Mitsuhiro Kato, Hiroko Ikeda, Yoko Sugie, Kazushi Aoto, Tadashi Kaname, Kazuhiko Nakabayashi, Tsutomu Ogata, Naomichi Matsumoto, Hirotomo Saitsu
SETD1B (SET domain containing 1B) is a component of SET1 histone methyltransferase complex, which mediates the methylation of histone H3 on lysine 4 (H3K4). Here, we describe two unrelated individuals with de novo variants in SETD1B identified by trio-based whole exome sequencing: c.5524C>T, p.(Arg1842Trp) and c.5575C>T, p.(Arg1859Cy). The two missense variants occurred at evolutionarily conserved amino acids and are located within the SET domain, which plays a pivotal role in catalyzing histone methylation...
January 10, 2018: Human Genetics
Lisbeth Tranebjærg, Nicola Strenzke, Sture Lindholm, Nanna D Rendtorff, Hanne Poulsen, Himanshu Khandelia, Wojciech Kopec, Troels J Brünnich Lyngbye, Christian Hamel, Cecile Delettre, Beatrice Bocquet, Michael Bille, Hanne H Owen, Toke Bek, Hanne Jensen, Karen Østergaard, Claes Möller, Linda Luxon, Lucinda Carr, Louise Wilson, Kaukab Rajput, Tony Sirimanna, Katherine Harrop-Griffiths, Shamima Rahman, Barbara Vona, Julia Doll, Thomas Haaf, Oliver Bartsch, Hendrik Rosewich, Tobias Moser, Maria Bitner-Glindzicz
Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN)...
January 5, 2018: Human Genetics
Phil H Lee, Christian Lee, Xihao Li, Brian Wee, Tushar Dwivedi, Mark Daly
Over a decade of genome-wide association, studies have made great strides toward the detection of genes and genetic mechanisms underlying complex traits. However, the majority of associated loci reside in non-coding regions that are functionally uncharacterized in general. Now, the availability of large-scale tissue and cell type-specific transcriptome and epigenome data enables us to elucidate how non-coding genetic variants can affect gene expressions and are associated with phenotypic changes. Here, we provide an overview of this emerging field in human genomics, summarizing available data resources and state-of-the-art analytic methods to facilitate in-silico prioritization of non-coding regulatory mutations...
December 29, 2017: Human Genetics
Shams Anazi, Sateesh Maddirevula, Vincenzo Salpietro, Yasmine T Asi, Saud Alsahli, Amal Alhashem, Hanan E Shamseldin, Fatema AlZahrani, Nisha Patel, Niema Ibrahim, Firdous M Abdulwahab, Mais Hashem, Nadia Alhashmi, Fathiya Al Murshedi, Adila Al Kindy, Ahmad Alshaer, Ahmed Rumayyan, Saeed Al Tala, Wesam Kurdi, Abdulaziz Alsaman, Ali Alasmari, Selina Banu, Tipu Sultan, Mohammed M Saleh, Hisham Alkuraya, Mustafa A Salih, Hesham Aldhalaan, Tawfeg Ben-Omran, Fatima Al Musafri, Rehab Ali, Jehan Suleiman, Brahim Tabarki, Ayman W El-Hattab, Caleb Bupp, Majid Alfadhel, Nada Al Tassan, Dorota Monies, Stefan T Arold, Mohamed Abouelhoda, Tammaryn Lashley, Henry Houlden, Eissa Faqeih, Fowzan S Alkuraya
Variant nomenclature discrepancy was identified in the article.
December 29, 2017: Human Genetics
Wentao Shi, Andrea Massaia, Sandra Louzada, Ruby Banerjee, Pille Hallast, Yuan Chen, Anders Bergström, Yong Gu, Steven Leonard, Michael A Quail, Qasim Ayub, Fengtang Yang, Chris Tyler-Smith, Yali Xue
We describe the variation in copy number of a ~ 10 kb region overlapping the long intergenic noncoding RNA (lincRNA) gene, TTTY22, within the IR3 inverted repeat on the short arm of the human Y chromosome, leading to individuals with 0-3 copies of this region in the general population. Variation of this CNV is common, with 266 individuals having 0 copies, 943 (including the reference sequence) having 1, 23 having 2 copies, and two having 3 copies, and was validated by breakpoint PCR, fibre-FISH, and 10× Genomics Chromium linked-read sequencing in subsets of 1234 individuals from the 1000 Genomes Project...
January 2018: Human Genetics
Maureen Wilson-Genderson, K Laura Barker, Heather M Gardiner, Maghboeba Mosavel, Jeffrey Thomas, Laura A Siminoff
Tissues from deceased donors provide important data for genomic research and Organ Procurement Organizations (OPOs) play a significant role. To understand the decisions of families who donated for transplantation and made decisions about donation to the Genotype-Tissue Expression Project (GTEx), we examined donation decisions of family decision makers (FDMs). 413 families were interviewed by telephone. The OPO staff who made the transplant and research requests completed self-administered surveys; a total of 309 matching surveys from 99 OPO staff were obtained...
January 2018: Human Genetics
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