@article {891, title = {Germline mutation in : a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation.}, journal = {HGG Adv}, volume = {2}, year = {2021}, month = {2021 Jan 14}, abstract = {

germline variation in was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic or inherited variants in , detail their phenotypes, and map all known variants to the domain structure of and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance-with yeast functional assays further supporting altered function-one affected by a in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7\%) than previously reported (3/15, 20\%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7\%) than previously reported (14/15, 93.3\%) (p value = 0.076309). -related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.

}, issn = {2666-2477}, doi = {10.1016/j.xhgg.2020.100014}, author = {Hansen, Adam W and Arora, Payal and Khayat, Michael M and Smith, Leah J and Lewis, Andrea M and Rossetti, Linda Z and Jayaseelan, Joy and Cristian, Ingrid and Haynes, Devon and DiTroia, Stephanie and Meeks, Naomi and Delgado, Mauricio R and Rosenfeld, Jill A and Pais, Lynn and White, Susan M and Meng, Qingchang and Pehlivan, Davut and Liu, Pengfei and Gingras, Marie-Claude and Wangler, Michael F and Muzny, Donna M and Lupski, James R and Kaplan, Craig D and Gibbs, Richard A} } @article {854, title = {Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 12}, pages = {2094-2104}, abstract = {

KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of KIF1A-associated phenotypes to include hip subluxation and dystonia~as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system. We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with variable involvement of other organ systems than a set of discrete disorders converging at a single locus.

}, issn = {1098-1004}, doi = {10.1002/humu.24118}, author = {Montenegro-Garreaud, Ximena and Hansen, Adam W and Khayat, Michael M and Chander, Varuna and Grochowski, Christopher M and Jiang, Yunyun and Li, He and Mitani, Tadahiro and Kessler, Elena and Jayaseelan, Joy and Shen, Hua and Gezdirici, Alper and Pehlivan, Davut and Meng, Qingchang and Rosenfeld, Jill A and Jhangiani, Shalini N and Madan-Khetarpal, Suneeta and Scott, Daryl A and Abarca-Barriga, Hugo and Trubnykova, Milana and Gingras, Marie-Claude and Muzny, Donna M and Posey, Jennifer E and Liu, Pengfei and Lupski, James R and Gibbs, Richard A} } @article {563, title = {Genetic architecture of laterality defects revealed by whole exome sequencing.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 Apr}, pages = {563-573}, abstract = {

Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20\% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1\% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.

}, issn = {1476-5438}, doi = {10.1038/s41431-018-0307-z}, author = {Li, Alexander H and Hanchard, Neil A and Azamian, Mahshid and D{\textquoteright}Alessandro, Lisa C A and Coban-Akdemir, Zeynep and Lopez, Keila N and Hall, Nancy J and Dickerson, Heather and Nicosia, Annarita and Fernbach, Susan and Boone, Philip M and Gambin, Tomaz and Karaca, Ender and Gu, Shen and Yuan, Bo and Jhangiani, Shalini N and Doddapaneni, HarshaVardhan and Hu, Jianhong and Dinh, Huyen and Jayaseelan, Joy and Muzny, Donna and Lalani, Seema and Towbin, Jeffrey and Penny, Daniel and Fraser, Charles and Martin, James and Lupski, James R and Gibbs, Richard A and Boerwinkle, Eric and Ware, Stephanie M and Belmont, John W} }