@article {566, title = {ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 01}, pages = {42-50}, abstract = {

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2\%) that frequently presents with ascending aortic aneurysm (AscAA). BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for <=1\% of nonsyndromic BAV cases with and without AscAA, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

}, keywords = {Animals, Aortic Aneurysm, Thoracic, Aortic Valve, Cells, Cultured, Disease Models, Animal, Endothelial Cells, Female, Heart Valve Diseases, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Phenotype, Receptors, Cell Surface, Zebrafish}, issn = {1546-1718}, doi = {10.1038/s41588-018-0265-y}, author = {Gould, Russell A and Aziz, Hamza and Woods, Courtney E and Seman-Senderos, Manuel Alejandro and Sparks, Elizabeth and Preuss, Christoph and W{\"u}nnemann, Florian and Bedja, Djahida and Moats, Cassandra R and McClymont, Sarah A and Rose, Rebecca and Sobreira, Nara and Ling, Hua and MacCarrick, Gretchen and Kumar, Ajay Anand and Luyckx, Ilse and Cannaerts, Elyssa and Verstraeten, Aline and Bj{\"o}rk, Hanna M and Lehsau, Ann-Cathrin and Jaskula-Ranga, Vinod and Lauridsen, Henrik and Shah, Asad A and Bennett, Christopher L and Ellinor, Patrick T and Lin, Honghuang and Isselbacher, Eric M and Lino Cardenas, Christian Lacks and Butcher, Jonathan T and Hughes, G Chad and Lindsay, Mark E and Mertens, Luc and Franco-Cereceda, Anders and Verhagen, Judith M A and Wessels, Marja and Mohamed, Salah A and Eriksson, Per and Mital, Seema and Van Laer, Lut and Loeys, Bart L and Andelfinger, Gregor and McCallion, Andrew S and Dietz, Harry C} } @article {533, title = {Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 Oct}, pages = {e1006335}, abstract = {

Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlations. Screening a multitude of 10 overlapping phenotypes revealed disease associated and co-segregating variants in 12 families. These rare or novel protein altering mutations cluster predominantly in genes (NOTCH1, ARHGAP31, MAML1, SMARCA4, JARID2, JAG1) along the Notch signaling cascade. This is in line with a significant enrichment (Wilcoxon, p< 0.05) of variants with a higher pathogenicity in the Notch signaling pathway in patients compared to controls. The significant enrichment of novel protein truncating and missense mutations in NOTCH1 highlights the allelic and phenotypic heterogeneity in our pediatric cohort. We identified novel co-segregating pathogenic mutations in NOTCH1 associated with left and right-sided cardiac malformations in three independent families with a total of 15 affected individuals. In summary, our results suggest that a small but highly pathogenic fraction of family specific mutations along the Notch cascade are a common cause of LVOTO.

}, keywords = {Aortic Valve, Codon, Nonsense, Constriction, Pathologic, Exome, Female, Genetic Association Studies, Genetic Linkage, Genome, Human, Heart Defects, Congenital, Humans, Male, Pedigree, Receptor, Notch1, Receptors, Notch, Sequence Deletion, Signal Transduction, Ventricular Outflow Obstruction}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006335}, author = {Preuss, Christoph and Capredon, Melanie and W{\"u}nnemann, Florian and Chetaille, Philippe and Prince, Andrea and Godard, Beatrice and Leclerc, Severine and Sobreira, Nara and Ling, Hua and Awadalla, Philip and Thibeault, Maryse and Khairy, Paul and Samuels, Mark E and Andelfinger, Gregor} } @article {115, title = {Whole-Exome Sequencing in Familial Parkinson Disease.}, journal = {JAMA Neurol}, volume = {73}, year = {2016}, month = {2016 Jan}, pages = {68-75}, abstract = {

IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.

OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD.

DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD.

MAIN OUTCOMES AND MEASURES: Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design.

RESULTS: The 93 individuals from 32 families in the discovery cohort (49.5\% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6\% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing.

CONCLUSIONS AND RELEVANCE: TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

}, keywords = {Adult, Aged, Cohort Studies, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Male, Middle Aged, Parkinsonian Disorders, Protein-Tyrosine Kinases, Sequence Analysis, DNA, Tenascin}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2015.3266}, author = {Farlow, Janice L and Robak, Laurie A and Hetrick, Kurt and Bowling, Kevin and Boerwinkle, Eric and Coban-Akdemir, Zeynep H and Gambin, Tomasz and Gibbs, Richard A and Gu, Shen and Jain, Preti and Jankovic, Joseph and Jhangiani, Shalini and Kaw, Kaveeta and Lai, Dongbing and Lin, Hai and Ling, Hua and Liu, Yunlong and Lupski, James R and Muzny, Donna and Porter, Paula and Pugh, Elizabeth and White, Janson and Doheny, Kimberly and Myers, Richard M and Shulman, Joshua M and Foroud, Tatiana} } @article {199, title = {Assessment of incidental findings in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.}, journal = {Genet Med}, volume = {17}, year = {2015}, month = {2015 Oct}, pages = {782-8}, abstract = {

PURPOSE: In March 2013 the American College of Medical Genetics and Genomics published a list of 56 genes with the recommendation that pathogenic and likely pathogenic variants detected incidentally by clinical sequencing be reported to patients. As an initial step in determining the practical consequences of this recommendation in the research setting, we searched for variants in these genes in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.

METHODS: We identified rare, nonsynonymous, and splicing single-nucleotide variants and insertions/deletions and assessed variant classification using the Human Gene Mutation, Emory, and ClinVar databases. We analyzed the burden of mutation in each of the 56 genes and determined which variants should be reported to patients.

RESULTS: Our filtering resulted in 249 distinct variants, with a mean of 1.69 variants per individual. Half of these were novel missense mutations not classified by any of the three reference databases. Of 101 variants listed in the Human Gene Mutation Database, 48 were also in ClinVar and 3 were also in Emory; half of these shared variants were classified discordantly between databases. Some genes consistently had greater variation than others. In total, 0.86\% of individuals had a reportable incidental variant.

CONCLUSION: These observations demonstrate some current challenges of assessing phenotypic consequences of incidental variants for counseling patients.

}, keywords = {Databases, Nucleic Acid, Exome, Female, Genetic Diseases, Inborn, Genomics, High-Throughput Nucleotide Sequencing, Humans, Incidental Findings, Male, Mutation, Polymorphism, Single Nucleotide}, issn = {1530-0366}, doi = {10.1038/gim.2014.196}, author = {Jurgens, Julie and Ling, Hua and Hetrick, Kurt and Pugh, Elizabeth and Schiettecatte, Fran{\c c}ois and Doheny, Kimberly and Hamosh, Ada and Avramopoulos, Dimitri and Valle, David and Sobreira, Nara} } @article {149, title = {The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Aug 06}, pages = {199-215}, abstract = {

Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying \~{}50\% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.

}, keywords = {Genetic Diseases, Inborn, Genetics, Medical, Humans, Phenotype, Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.06.009}, author = {Chong, Jessica X and Buckingham, Kati J and Jhangiani, Shalini N and Boehm, Corinne and Sobreira, Nara and Smith, Joshua D and Harrell, Tanya M and McMillin, Margaret J and Wiszniewski, Wojciech and Gambin, Tomasz and Coban Akdemir, Zeynep H and Doheny, Kimberly and Scott, Alan F and Avramopoulos, Dimitri and Chakravarti, Aravinda and Hoover-Fong, Julie and Mathews, Debra and Witmer, P Dane and Ling, Hua and Hetrick, Kurt and Watkins, Lee and Patterson, Karynne E and Reinier, Frederic and Blue, Elizabeth and Muzny, Donna and Kircher, Martin and Bilguvar, Kaya and L{\'o}pez-Gir{\'a}ldez, Francesc and Sutton, V Reid and Tabor, Holly K and Leal, Suzanne M and G{\"u}nel, Murat and Mane, Shrikant and Gibbs, Richard A and Boerwinkle, Eric and Hamosh, Ada and Shendure, Jay and Lupski, James R and Lifton, Richard P and Valle, David and Nickerson, Deborah A and Bamshad, Michael J} } @article {275, title = {Mutations in PCYT1A, encoding a key regulator of phosphatidylcholine metabolism, cause spondylometaphyseal dysplasia with cone-rod dystrophy.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jan 02}, pages = {105-12}, keywords = {Alleles, Child, Preschool, Choline-Phosphate Cytidylyltransferase, Female, Humans, Infant, Male, Middle Aged, Mutation, Missense, Osteochondrodysplasias, Pedigree, Phosphatidylcholines, Retinitis Pigmentosa}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.11.018}, author = {Hoover-Fong, Julie and Sobreira, Nara and Jurgens, Julie and Modaff, Peggy and Blout, Carrie and Moser, Ann and Kim, Ok-Hwa and Cho, Tae-Joon and Cho, Sung Yoon and Kim, Sang Jin and Jin, Dong-Kyu and Kitoh, Hiroshi and Park, Woong-Yang and Ling, Hua and Hetrick, Kurt N and Doheny, Kimberly F and Valle, David and Pauli, Richard M} } @article {200, title = {Novel Deletion of SERPINF1 Causes Autosomal Recessive Osteogenesis Imperfecta Type VI in Two Brazilian Families.}, journal = {Mol Syndromol}, volume = {5}, year = {2014}, month = {2014 Dec}, pages = {268-75}, abstract = {

Autosomal recessive osteogenesis imperfecta (OI) accounts for 10\% of all OI cases, and, currently, mutations in 10 genes (CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, SERPINF1, SP7, BMP1, TMEM38B, and WNT1) are known to be responsible for this form of the disease. PEDF is a secreted glycoprotein of the serpin superfamily that maintains bone homeostasis and regulates osteoid mineralization, and it is encoded by SERPINF1, currently associated with OI type VI (MIM 172860). Here, we report a consanguineous Brazilian family in which multiple individuals from at least 4 generations are affected with a severe form of OI, and we also report an unrelated individual from the same small city in Brazil with a similar but more severe phenotype. In both families the same homozygous SERPINF1 19-bp deletion was identified which is not known in the literature yet. We described intra- and interfamilial clinical and radiological phenotypic variability of OI type VI caused by the same homozygous SERPINF1 19-bp deletion and suggest a founder effect. Furthermore, the SERPINF1 genotypes/phenotypes reported so far in the literature are reviewed.

}, issn = {1661-8769}, doi = {10.1159/000369108}, author = {Minillo, Renata Moldenhauer and Sobreira, Nara and de Faria Soares, Maria de Fatima and Jurgens, Julie and Ling, Hua and Hetrick, Kurt N and Doheny, Kimberly F and Valle, David and Brunoni, Decio and Perez, Ana B Alvarez} }