@article {523, title = {Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {689-703}, abstract = {

Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in TSPEAR, associated with syndromic and isolated TA in one family each; a variant in LAMB3 associated with syndromic TA in one family; and a variant in BCOR plus a disease-associated WNT10A variant in one family with syndromic TA. With the notable exception of WNT10A (Tooth agenesis, selective, 4, MIM $\#$150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes: TSPEAR (Deafness, autosomal recessive 98, MIM $\#$614861), LAMB3 (Amelogenesis imperfecta, type IA, MIM $\#$104530; Epidermolysis bullosa, junctional, MIMs $\#$226700 and $\#$226650), and BCOR (Microphthalmia, syndromic 2, MIM $\#$300166). We provide evidence supporting the candidacy of these genes with TA, and propose TSPEAR as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the BCOR and WNT10A loci, underscoring the complexity of the genotype-phenotype relationship in the common complex trait of TA.

}, keywords = {Anodontia, Cell Adhesion Molecules, Child, Child, Preschool, Female, Genetic Markers, Humans, Male, Mutation, Pedigree, Phenotype, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Turkey, Wnt Proteins}, issn = {1432-1203}, doi = {10.1007/s00439-018-1907-y}, author = {Du, Renqian and Dinckan, Nuriye and Song, Xiaofei and Coban-Akdemir, Zeynep and Jhangiani, Shalini N and Guven, Yeliz and Aktoren, Oya and Kayserili, H{\"u}lya and Petty, Lauren E and Muzny, Donna M and Below, Jennifer E and Boerwinkle, Eric and Wu, Nan and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R and Letra, Ariadne and Uyguner, Z Oya} } @article {49, title = {Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Jun 02}, pages = {1146-1158}, abstract = {

Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia, sometimes associated with monosomy 7. Here, in the four-generation family UW-AP, linkage analysis revealed four regions that provided the maximal LOD scores possible, one of which was in a commonly microdeleted chromosome 7q region. Exome sequencing identified a missense mutation (c.2640C>A, p.His880Gln) in the sterile alpha motif domain containing 9-like gene (SAMD9L) that completely cosegregated with disease. By targeted sequencing of SAMD9L, we subsequently identified a different missense mutation (c.3587G>C, p.Cys1196Ser) in affected members of the first described family with AP syndrome, Li-AP. Neither variant is reported in the public databases, both affect highly conserved amino acid residues, and both are predicted to be damaging. With time in culture, lymphoblastic cell lines (LCLs) from two affected individuals in family UW-AP exhibited copy-neutral loss of heterozygosity for large portions of the long arm of chromosome 7, resulting in retention of only the wild-type SAMD9L allele. Newly established LCLs from both individuals demonstrated the same phenomenon. In addition, targeted capture and sequencing of SAMD9L in uncultured blood DNA from both individuals showed bias toward the wild-type allele. These observations indicate in~vivo hematopoietic mosaicism. The hematopoietic cytopenias that characterize AP syndrome and the selective advantage for clones that have lost the mutant allele support the postulated role of SAMD9L in the regulation of cell proliferation. Furthermore, we show that AP syndrome is distinct from the dyskeratoses congenita telomeropathies, with which it shares some clinical characteristics.

}, keywords = {Adolescent, Adult, Cerebellar Ataxia, Child, Chromosome Aberrations, Chromosomes, Human, Pair 7, Exome, Female, Genetic Linkage, Genotype, High-Throughput Nucleotide Sequencing, Humans, Intracellular Signaling Peptides and Proteins, Loss of Heterozygosity, Male, Middle Aged, Mutation, Missense, Pancytopenia, Pedigree, Proteins, Tumor Suppressor Proteins, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.04.009}, author = {Chen, Dong-Hui and Below, Jennifer E and Shimamura, Akiko and Keel, Sioban B and Matsushita, Mark and Wolff, John and Sul, Youngmee and Bonkowski, Emily and Castella, Maria and Taniguchi, Toshiyasu and Nickerson, Deborah and Papayannopoulou, Thalia and Bird, Thomas D and Raskind, Wendy H} } @article {43, title = {PADRE: Pedigree-Aware Distant-Relationship Estimation.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Jul 07}, pages = {154-62}, abstract = {

Accurate estimation of shared ancestry is an important component of many genetic studies; current prediction tools accurately estimate pairwise genetic relationships up to the ninth degree. Pedigree-aware distant-relationship estimation (PADRE) combines relationship likelihoods generated by estimation of recent shared ancestry (ERSA) with likelihoods from family networks reconstructed by pedigree reconstruction and identification of a maximum unrelated set (PRIMUS), improving the power to detect distant relationships between pedigrees. Using PADRE, we estimated relationships from simulated pedigrees and three extended pedigrees, correctly predicting 20\% more fourth- through ninth-degree simulated relationships than when using ERSA alone. By leveraging pedigree information, PADRE can even identify genealogical relationships between individuals who are genetically unrelated. For example, although 95\% of 13(th)-degree relatives are genetically unrelated, in simulations, PADRE correctly predicted 50\% of 13(th)-degree relationships to within one degree of relatedness. The improvement in prediction accuracy was consistent between simulated and actual pedigrees. We also applied PADRE to the HapMap3 CEU samples and report new cryptic relationships and validation of previously described relationships between families. PADRE greatly expands the range of relationships that can be estimated by using genetic data in pedigrees.

}, keywords = {Algorithms, Female, Haplotypes, Humans, Male, Models, Genetic, Pedigree, Reproducibility of Results}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.05.020}, author = {Staples, Jeffrey and Witherspoon, David J and Jorde, Lynn B and Nickerson, Deborah A and Below, Jennifer E and Huff, Chad D} } @article {123, title = {PRIMUS: improving pedigree reconstruction using mitochondrial and Y haplotypes.}, journal = {Bioinformatics}, volume = {32}, year = {2016}, month = {2016 Feb 15}, pages = {596-8}, abstract = {

UNLABELLED: PRIMUS is a pedigree reconstruction algorithm that uses estimates of genome-wide identity by descent to reconstruct pedigrees consistent with observed genetic data. However, when genetic data for individuals within a pedigree are missing, often multiple pedigrees can be reconstructed that fit the data. We report a major expansion of PRIMUS that uses mitochondrial (mtDNA) and non-recombining Y chromosome (NRY) haplotypes to eliminate many pedigree structures that are inconsistent with the genetic data. We demonstrate that discordances in mtDNA and NRY haplotypes substantially reduce the number of potential pedigrees, and often lead to the identification of the correct pedigree.

AVAILABILITY AND IMPLEMENTATION: We have implemented PRIMUS updates in PERL and it is available at primus.gs.washington.edu.

}, keywords = {Algorithms, Chromosomes, Human, Y, Computer Simulation, DNA, Mitochondrial, Genetics, Population, Haplotypes, Humans, Linkage Disequilibrium, Pedigree, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btv618}, author = {Staples, Jeffrey and Ekunwe, Lynette and Lange, Ethan and Wilson, James G and Nickerson, Deborah A and Below, Jennifer E} } @article {210, title = {PRIMUS: rapid reconstruction of pedigrees from genome-wide estimates of identity by descent.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Nov 06}, pages = {553-64}, abstract = {

Understanding and correctly utilizing relatedness among samples is essential for genetic analysis; however, managing sample records and pedigrees can often be error prone and incomplete. Data sets ascertained by random sampling often harbor cryptic relatedness that can be leveraged in genetic analyses for maximizing power. We have developed a method that uses genome-wide estimates of~pairwise identity by descent to identify families and quickly reconstruct and score all possible pedigrees that fit the genetic data by using up to third-degree relatives, and we have included it in the software package PRIMUS (Pedigree Reconstruction and Identification of the~Maximally Unrelated Set). Here, we validate its performance on simulated, clinical, and HapMap pedigrees. Among these samples, we demonstrate that PRIMUS can verify reported pedigree structures and identify cryptic relationships. Finally, we show that PRIMUS reconstructed pedigrees, all of which were previously unknown, for 203 families from a cohort collected in Starr County, TX (1,890 samples).

}, keywords = {Base Sequence, Computer Simulation, Exome, Gene Frequency, Genetics, Population, Humans, Molecular Sequence Data, Pedigree, Pulmonary Disease, Chronic Obstructive, Sequence Analysis, DNA, Software, Texas}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.10.005}, author = {Staples, Jeffrey and Qiao, Dandi and Cho, Michael H and Silverman, Edwin K and Nickerson, Deborah A and Below, Jennifer E} } @article {254, title = {TCIRG1-associated congenital neutropenia.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Jul}, pages = {824-7}, abstract = {

Severe congenital neutropenia (SCN) is a rare hematopoietic disorder, with estimated incidence of 1 in 200,000 individuals of European descent, many cases of which are inherited in an autosomal dominant pattern. Despite the fact that several causal genes have been identified, the genetic basis for >30\% of cases remains unknown. We report a five-generation family segregating a novel single nucleotide variant (SNV) in TCIRG1. There is perfect cosegregation of the SNV with congenital neutropenia in this family; all 11 affected, but none of the unaffected, individuals carry this novel SNV. Western blot analysis show reduced levels of TCIRG1 protein in affected individuals, compared to healthy controls. Two unrelated patients with SCN, identified by independent investigators, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1.

}, keywords = {DNA Mutational Analysis, Heterozygote, Humans, Mutation, Neutropenia, Pedigree, Vacuolar Proton-Translocating ATPases}, issn = {1098-1004}, doi = {10.1002/humu.22563}, author = {Makaryan, Vahagn and Rosenthal, Elisabeth A and Bolyard, Audrey Anna and Kelley, Merideth L and Below, Jennifer E and Bamshad, Michael J and Bofferding, Kathryn M and Smith, Joshua D and Buckingham, Kati and Boxer, Laurence A and Skokowa, Julia and Welte, Karl and Nickerson, Deborah A and Jarvik, Gail P and Dale, David C} } @article {314, title = {Mutations in ECEL1 cause distal arthrogryposis type 5D.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Jan 10}, pages = {150-6}, abstract = {

Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and ~50\% of cases are caused by mutations in genes that encode contractile proteins of skeletal myofibers. DA type 5D (DA5D) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain ~70\% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes.

}, keywords = {Arthrogryposis, Consanguinity, Female, Genetic Linkage, Humans, Male, Metalloendopeptidases, Mutation, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2012.11.014}, author = {McMillin, Margaret J and Below, Jennifer E and Shively, Kathryn M and Beck, Anita E and Gildersleeve, Heidi I and Pinner, Jason and Gogola, Gloria R and Hecht, Jacqueline T and Grange, Dorothy K and Harris, David J and Earl, Dawn L and Jagadeesh, Sujatha and Mehta, Sarju G and Robertson, Stephen P and Swanson, James M and Faustman, Elaine M and Mefford, Heather C and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {320, title = {Utilizing graph theory to select the largest set of unrelated individuals for genetic analysis.}, journal = {Genet Epidemiol}, volume = {37}, year = {2013}, month = {2013 Feb}, pages = {136-41}, abstract = {

Many statistical analyses of genetic data rely on the assumption of independence among samples. Consequently, relatedness is either modeled in the analysis or samples are removed to "clean" the data of any pairwise relatedness above a tolerated threshold. Current methods do not maximize the number of unrelated individuals retained for further analysis, and this is a needless loss of resources. We report a novel application of graph theory that identifies the maximum set of unrelated samples in any dataset given a user-defined threshold of relatedness as well as all networks of related samples. We have implemented this method into an open source program called Pedigree Reconstruction and Identification of a Maximum Unrelated Set, PRIMUS. We show that PRIMUS outperforms the three existing methods, allowing researchers to retain up to 50\% more unrelated samples. A unique strength of PRIMUS is its ability to weight the maximum clique selection using additional criteria (e.g. affected status and data missingness). PRIMUS is a permanent solution to identifying the maximum number of unrelated samples for a genetic analysis.

}, keywords = {Algorithms, Genome-Wide Association Study, HapMap Project, Humans, Models, Theoretical}, issn = {1098-2272}, doi = {10.1002/gepi.21684}, author = {Staples, Jeffrey and Nickerson, Deborah A and Below, Jennifer E} } @article {313, title = {Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Jan 10}, pages = {137-43}, abstract = {

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ~60\% of cases overall, including both of the families in our cohort with more than one affected child and 50\% of the simplex cases.

}, keywords = {Child, Child, Preschool, Female, Genome, Human, Humans, Infant, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2012.11.011}, author = {Below, Jennifer E and Earl, Dawn L and Shively, Kathryn M and McMillin, Margaret J and Smith, Joshua D and Turner, Emily H and Stephan, Mark J and Al-Gazali, Lihadh I and Hertecant, Jozef L and Chitayat, David and Unger, Sheila and Cohn, Daniel H and Krakow, Deborah and Swanson, James M and Faustman, Elaine M and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} }