@article {538, title = {Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 01}, pages = {152-166}, abstract = {

Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.

}, keywords = {Ciliopathies, Cytoplasmic Dyneins, Genetic Association Studies, Genetic Markers, Genetic Variation, Genotype, Humans, Mutation, Phenotype, Proteins, Radiography, Skeleton, Whole Exome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23362}, author = {Zhang, Wenjuan and Taylor, S Paige and Ennis, Hayley A and Forlenza, Kimberly N and Duran, Ivan and Li, Bing and Sanchez, Jorge A Ortiz and Nevarez, Lisette and Nickerson, Deborah A and Bamshad, Michael and Lachman, Ralph S and Krakow, Deborah and Cohn, Daniel H} } @article {522, title = {Whole exome sequencing analysis in severe chronic obstructive pulmonary disease.}, journal = {Hum Mol Genet}, volume = {27}, year = {2018}, month = {2018 11 01}, pages = {3801-3812}, abstract = {

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene). Applying a gene-based segregation test in the family-based data, we identified significant segregation of rare loss of function variants in TBC1D10A and RFPL1 (P-value~<~2x10-6), but were unable to find similar variants in the case-control study. In single-variant, gene-based and pathway association analyses, we were unable to find significant findings that replicated or were significant in meta-analysis. However, we found that the top results in the two datasets were in proximity to each other in the protein-protein interaction network (P-value~=~0.014), suggesting enrichment of these results for similar biological processes. A network of these association results and their neighbors was significantly enriched in the transforming growth factor beta-receptor binding and cilia-related pathways. Finally, in a more detailed examination of candidate genes, we identified individuals with putative high-risk variants, including patients harboring homozygous mutations in genes associated with cutis laxa and Niemann-Pick Disease Type C. Our results likely reflect heterogeneity of genetic risk for COPD along with limitations of statistical power and functional annotation, and highlight the potential of network analysis to gain insight into genetic association studies.

}, keywords = {Adolescent, Adult, Aged, Case-Control Studies, DNA Mutational Analysis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Whole Exome Sequencing, Young Adult}, issn = {1460-2083}, doi = {10.1093/hmg/ddy269}, author = {Qiao, Dandi and Ameli, Asher and Prokopenko, Dmitry and Chen, Han and Kho, Alvin T and Parker, Margaret M and Morrow, Jarrett and Hobbs, Brian D and Liu, Yanhong and Beaty, Terri H and Crapo, James D and Barnes, Kathleen C and Nickerson, Deborah A and Bamshad, Michael and Hersh, Craig P and Lomas, David A and Agusti, Alvar and Make, Barry J and Calverley, Peter M A and Donner, Claudio F and Wouters, Emiel F and Vestbo, J{\o}rgen and Par{\'e}, Peter D and Levy, Robert D and Rennard, Stephen I and Tal-Singer, Ruth and Spitz, Margaret R and Sharma, Amitabh and Ruczinski, Ingo and Lange, Christoph and Silverman, Edwin K and Cho, Michael H} } @article {29, title = {Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 Dec}, pages = {3298-3302}, abstract = {

Dominant mutations in TRPV4, which encodes the Transient Receptor Potential Cation Channel Subfamily V Member 4 calcium channel, result in a series of musculoskeletal disorders that include a set of peripheral neuropathies and a broad phenotypic spectrum of skeletal dysplasias. The skeletal phenotypes range from brachyolmia, in which there is scoliosis with mild short stature, through perinatal lethal metatropic dysplasia. We describe a case with phenotypic findings consistent with metatropic dysplasia, but in whom no TRPV4 mutation was detected by Sanger sequence analysis. Exome sequence analysis identified a known lethal metatropic dysplasia mutation, TRPV4 , which was present at lower frequency than would be expected for a heterozygous change. The affected individual was shown to be a somatic mosaic for the mutation, providing an explanation for the milder than expected phenotype. The data illustrate that high-throughput sequencing of genomic DNA can facilitate detection of mosaicism with higher sensitivity than Sanger sequence analysis and identify a new genetic mechanism for metatropic dysplasia. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Alleles, DNA Mutational Analysis, Dwarfism, Exons, Genetic Association Studies, Humans, Infant, Magnetic Resonance Imaging, Mosaicism, Mutation, Osteochondrodysplasias, Phenotype, Physical Examination, Radiography, TRPV Cation Channels}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37942}, author = {Weinstein, Michael M and Kang, Taekyu and Lachman, Ralph S and Bamshad, Michael and Nickerson, Deborah A and Krakow, Deborah and Cohn, Daniel H} } @article {531, title = {Update on the Toriello-Carey syndrome.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 10}, pages = {2551-8}, abstract = {

Toriello and Carey described a provisionally-unique syndrome comprised of agenesis of the corpus callosum, Pierre Robin anomaly, and a characteristic facial phenotype. Because the condition affected siblings, this entity was postulated to be an autosomal recessive multiple anomaly syndrome. Several patients were subsequently reported, and over time, it became apparent that the Toriello-Carey syndrome was etiologically heterogeneous. Based on previous reports, it is estimated that at least 20\% of patients with a clinical diagnosis of Toriello-Carey syndrome have a chromosomal anomaly as the basis of the phenotype. However, no basis for the non-chromosomal cases has been found. This review summarizes the literature to date and provides speculation regarding the possible explanations for failing to find the cause of Toriello-Carey syndrome. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Agenesis of Corpus Callosum, Chromosome Aberrations, Craniofacial Abnormalities, Female, Genetic Association Studies, Heart Defects, Congenital, Humans, Limb Deformities, Congenital, Male, Phenotype, Pierre Robin Syndrome, Urogenital Abnormalities}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37735}, author = {Toriello, Helga V and Colley, Chelsey and Bamshad, Michael} }