@article {719,
	title = {Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.},
	journal = {Am J Hum Genet},
	volume = {105},
	year = {2019},
	month = {2019 Oct 03},
	pages = {689-705},
	abstract = {<p>Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.</p>},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2019.08.006},
	author = {Magini, Pamela and Smits, Daphne J and Vandervore, Laura and Schot, Rachel and Columbaro, Marta and Kasteleijn, Esmee and van der Ent, Mees and Palombo, Flavia and Lequin, Maarten H and Dremmen, Marjolein and de Wit, Marie Claire Y and Severino, Mariasavina and Divizia, Maria Teresa and Striano, Pasquale and Ordonez-Herrera, Natalia and Alhashem, Amal and Al Fares, Ahmed and Al Ghamdi, Malak and Rolfs, Arndt and Bauer, Peter and Demmers, Jeroen and Verheijen, Frans W and Wilke, Martina and van Slegtenhorst, Marjon and van der Spek, Peter J and Seri, Marco and Jansen, Anna C and Stottmann, Rolf W and Hufnagel, Robert B and Hopkin, Robert J and Aljeaid, Deema and Wiszniewski, Wojciech and Gawlinski, Pawel and Laure-Kamionowska, Milena and Alkuraya, Fowzan S and Akleh, Hanah and Stanley, Valentina and Musaev, Damir and Gleeson, Joseph G and Zaki, Maha S and Brunetti-Pierri, Nicola and Cappuccio, Gerarda and Davidov, Bella and Basel-Salmon, Lina and Bazak, Lily and Shahar, Noa Ruhrman and Bertoli-Avella, Aida and Mirzaa, Ghayda M and Dobyns, William B and Pippucci, Tommaso and Fornerod, Maarten and Mancini, Grazia M S}
}
@article {698,
	title = {Paralog Studies Augment Gene Discovery: DDX and DHX Genes.},
	journal = {Am J Hum Genet},
	volume = {105},
	year = {2019},
	month = {2019 Aug 01},
	pages = {302-316},
	abstract = {<p>Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four~individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.</p>},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2019.06.001},
	author = {Paine, Ingrid and Posey, Jennifer E and Grochowski, Christopher M and Jhangiani, Shalini N and Rosenheck, Sarah and Kleyner, Robert and Marmorale, Taylor and Yoon, Margaret and Wang, Kai and Robison, Reid and Cappuccio, Gerarda and Pinelli, Michele and Magli, Adriano and Coban Akdemir, Zeynep and Hui, Joannie and Yeung, Wai Lan and Wong, Bibiana K Y and Ortega, Lucia and Bekheirnia, Mir Reza and Bierhals, Tatjana and Hempel, Maja and Johannsen, Jessika and Santer, Ren{\'e} and Aktas, Dilek and Alika{\c s}ifo{\u g}lu, Mehmet and Bozdogan, Sevcan and Aydin, Hatip and Karaca, Ender and Bayram, Yavuz and Ityel, Hadas and Dorschner, Michael and White, Janson J and Wilichowski, Ekkehard and Wortmann, Saskia B and Casella, Erasmo B and Kitajima, Joao Paulo and Kok, Fernando and Monteiro, Fabiola and Muzny, Donna M and Bamshad, Michael and Gibbs, Richard A and Sutton, V Reid and Van Esch, Hilde and Brunetti-Pierri, Nicola and Hildebrandt, Friedhelm and Brautbar, Ariel and Van den Veyver, Ignatia B and Glass, Ian and Lessel, Davor and Lyon, Gholson J and Lupski, James R}
}
