@article {923, title = {Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 01}, pages = {119-133}, abstract = {

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48\%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26\%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61926}, author = {Dyment, David A and O{\textquoteright}Donnell-Luria, Anne and Agrawal, Pankaj B and Coban Akdemir, Zeynep and Aleck, Kyrieckos A and Antaki, Danny and Al Sharhan, Hind and Au, Ping-Yee B and Aydin, Hatip and Beggs, Alan H and Bilguvar, Kaya and Boerwinkle, Eric and Brand, Harrison and Brownstein, Catherine A and Buyske, Steve and Chodirker, Bernard and Choi, Jungmin and Chudley, Albert E and Clericuzio, Carol L and Cox, Gerald F and Curry, Cynthia and de Boer, Elke and de Vries, Bert B A and Dunn, Kathryn and Dutmer, Cullen M and England, Eleina M and Fahrner, Jill A and Geckinli, Bilgen B and Genetti, Casie A and Gezdirici, Alper and Gibson, William T and Gleeson, Joseph G and Greenberg, Cheryl R and Hall, April and Hamosh, Ada and Hartley, Taila and Jhangiani, Shalini N and Karaca, Ender and Kernohan, Kristin and Lauzon, Julie L and Lewis, M E Suzanne and Lowry, R Brian and L{\'o}pez-Gir{\'a}ldez, Francesc and Matise, Tara C and McEvoy-Venneri, Jennifer and McInnes, Brenda and Mhanni, Aziz and Garcia Minaur, Sixto and Moilanen, Jukka and Nguyen, An and Nowaczyk, Malgorzata J M and Posey, Jennifer E and {\~O}unap, Katrin and Pehlivan, Davut and Pajusalu, Sander and Penney, Lynette S and Poterba, Timothy and Prontera, Paolo and Doriqui, Maria Juliana Rodovalho and Sawyer, Sarah L and Sobreira, Nara and Stanley, Valentina and Torun, Deniz and Wargowski, David and Witmer, P Dane and Wong, Isaac and Xing, Jinchuan and Zaki, MAH S and Zhang, Yeting and Boycott, Kym M and Bamshad, Michael J and Nickerson, Deborah A and Blue, Elizabeth E and Innes, A Micheil} } @article {827, title = {Congenital Heart Defects Due to Missense Variants.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 06}, pages = {e002843}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002843}, author = {Morton, Sarah U and Agarwal, Radhika and Madden, Jill A and Genetti, Casie A and Brownstein, Catherine A and L{\'o}pez-Gir{\'a}ldez, Francesc and Choi, Jungmin and Seidman, Christine E and Seidman, Jonathan G and Lyon, Gholson J and Agrawal, Pankaj B} } @article {925, title = {Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia.}, journal = {iScience}, volume = {23}, year = {2020}, month = {2020 Oct 23}, pages = {101552}, abstract = {

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated mutation (p.Cys188Trp) in the GABA receptor Cl channel γ-1 subunit () exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na and Ca channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca channel Ca3.2 (). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

}, issn = {2589-0042}, doi = {10.1016/j.isci.2020.101552}, author = {Dong, Weilai and Jin, Sheng Chih and Allocco, August and Zeng, Xue and Sheth, Amar H and Panchagnula, Shreyas and Castonguay, Annie and Lorenzo, Louis-{\'E}tienne and Islam, Barira and Brindle, Genevi{\`e}ve and Bachand, Karine and Hu, Jamie and Sularz, Agata and Gaillard, Jonathan and Choi, Jungmin and Dunbar, Ashley and Nelson-Williams, Carol and Kiziltug, Emre and Furey, Charuta Gavankar and Conine, Sierra and Duy, Phan Q and Kundishora, Adam J and Loring, Erin and Li, Boyang and Lu, Qiongshi and Zhou, Geyu and Liu, Wei and Li, Xinyue and Sierant, Michael C and Mane, Shrikant and Castaldi, Christopher and L{\'o}pez-Gir{\'a}ldez, Francesc and Knight, James R and Sekula, Raymond F and Simard, J Marc and Eskandar, Emad N and Gottschalk, Christopher and Moliterno, Jennifer and G{\"u}nel, Murat and Gerrard, Jason L and Dib-Hajj, Sulayman and Waxman, Stephen G and Barker, Fred G and Alper, Seth L and Chahine, Mohamed and Haider, Shozeb and De Koninck, Yves and Lifton, Richard P and Kahle, Kristopher T} } @article {794, title = {Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.}, journal = {Nat Genet}, volume = {52}, year = {2020}, month = {2020 10}, pages = {1046-1056}, abstract = {

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14\% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

}, keywords = {Animals, beta Catenin, Cerebral Palsy, Cyclin D, Cytoskeleton, Drosophila, Exome, Extracellular Matrix, F-Box Proteins, Female, Focal Adhesions, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Mutation, Neurites, rhoB GTP-Binding Protein, Risk Factors, Sequence Analysis, DNA, Signal Transduction, Tubulin, Tumor Suppressor Proteins, Whole Exome Sequencing}, issn = {1546-1718}, doi = {10.1038/s41588-020-0695-1}, author = {Jin, Sheng Chih and Lewis, Sara A and Bakhtiari, Somayeh and Zeng, Xue and Sierant, Michael C and Shetty, Sheetal and Nordlie, Sandra M and Elie, Aureliane and Corbett, Mark A and Norton, Bethany Y and van Eyk, Clare L and Haider, Shozeb and Guida, Brandon S and Magee, Helen and Liu, James and Pastore, Stephen and Vincent, John B and Brunstrom-Hernandez, Janice and Papavasileiou, Antigone and Fahey, Michael C and Berry, Jesia G and Harper, Kelly and Zhou, Chongchen and Zhang, Junhui and Li, Boyang and Zhao, Hongyu and Heim, Jennifer and Webber, Dani L and Frank, MAHlia S B and Xia, Lei and Xu, Yiran and Zhu, Dengna and Zhang, Bohao and Sheth, Amar H and Knight, James R and Castaldi, Christopher and Tikhonova, Irina R and L{\'o}pez-Gir{\'a}ldez, Francesc and Keren, Boris and Whalen, Sandra and Buratti, Julien and Doummar, Diane and Cho, Megan and Retterer, Kyle and Millan, Francisca and Wang, Yangong and Waugh, Jeff L and Rodan, Lance and Cohen, Julie S and Fatemi, Ali and Lin, Angela E and Phillips, John P and Feyma, Timothy and MacLennan, Suzanna C and Vaughan, Spencer and Crompton, Kylie E and Reid, Susan M and Reddihough, Dinah S and Shang, Qing and Gao, Chao and Novak, Iona and Badawi, Nadia and Wilson, Yana A and McIntyre, Sarah J and Mane, Shrikant M and Wang, Xiaoyang and Amor, David J and Zarnescu, Daniela C and Lu, Qiongshi and Xing, Qinghe and Zhu, Changlian and Bilguvar, Kaya and Padilla-Lopez, Sergio and Lifton, Richard P and Gecz, Jozef and MacLennan, Alastair H and Kruer, Michael C} } @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 {142, title = {Identification and functional characterization of natural human melanocortin 1 receptor mutant alleles in Pakistani population.}, journal = {Pigment Cell Melanoma Res}, volume = {28}, year = {2015}, month = {2015 Nov}, pages = {730-5}, abstract = {

Melanocortin 1 receptor (MC1R), a Gs protein-coupled receptor of the melanocyte{\textquoteright}s plasma membrane, is a major determinant of skin pigmentation and phototype. Upon activation by α-melanocyte stimulating hormone, MC1R triggers the cAMP cascade to stimulate eumelanogenesis. We used whole-exome sequencing to identify causative alleles in Pakistani families with skin and hair hypopigmentation. Six MC1R mutations segregated with the phenotype in seven families, including a p.Val174del in-frame deletion and a p.Tyr298* nonsense mutation, that were analyzed for function in heterologous HEK293 cells. p.Tyr298* MC1R showed no agonist-induced signaling to the cAMP or ERK pathways, nor detectable agonist binding. Conversely, signaling was comparable for p.Val174del and wild-type in HEK cells overexpressing the proteins, but binding analysis suggested impaired cell surface expression. Flow cytometry and confocal imaging studies revealed reduced plasma membrane expression of p.Val174del and p.Tyr298*. Therefore, p.Tyr298* was a total loss-of-function (LOF) allele, while p.Val174del displayed a partial LOF attribute.

}, keywords = {Alleles, Family, Female, Humans, Hypopigmentation, Male, Mutation, Pakistan, Pedigree, Phenotype, Receptor, Melanocortin, Type 1}, issn = {1755-148X}, doi = {10.1111/pcmr.12400}, author = {Shahzad, Mohsin and Sires Campos, Julia and Tariq, Nabeela and Herraiz Serrano, Cecilia and Yousaf, Rizwan and Jim{\'e}nez-Cervantes, Celia and Yousaf, Sairah and Waryah, Yar M and Dad, Haseeb A and Blue, Elizabeth M and Sobreira, Nara and L{\'o}pez-Gir{\'a}ldez, Francesc and Kausar, Tasleem and Ali, Muhammad and Waryah, Ali M and Riazuddin, Saima and Shaikh, Rehan S and Garc{\'\i}a-Borr{\'o}n, Jos{\'e} C and Ahmed, Zubair M} }