@article {777, title = {Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.}, journal = {Eur J Hum Genet}, volume = {28}, year = {2020}, month = {2020 09}, pages = {1243-1264}, abstract = {

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM $\#$615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

}, keywords = {Abnormalities, Multiple, Adolescent, Animals, Bone Development, Child, Child, Preschool, Consanguinity, Extracellular Matrix, Female, Fibrillar Collagens, Founder Effect, Gene Frequency, Hip Dislocation, Homozygote, Humans, Male, Mice, Mice, Inbred C57BL, Mutation, Pedigree, Scoliosis, Syndrome}, issn = {1476-5438}, doi = {10.1038/s41431-020-0632-x}, author = {Gonzaga-Jauregui, Claudia and Yesil, G{\"o}zde and Nistala, Harikiran and Gezdirici, Alper and Bayram, Yavuz and Nannuru, Kalyan C and Pehlivan, Davut and Yuan, Bo and Jimenez, Johanna and Sahin, Yavuz and Paine, Ingrid S and Akdemir, Zeynep Coban and Rajamani, Saathyaki and Staples, Jeffrey and Dronzek, John and Howell, Kristen and Fatih, Jawid M and Smaldone, Silvia and Schlesinger, Alan E and Ram{\'\i}rez, Norman and Cornier, Alberto S and Kelly, Melissa A and Haber, Robert and Chim, Shek Man and Nieman, Kristy and Wu, Nan and Walls, Johnathon and Poueymirou, William and Siao, Chia-Jen and Sutton, V Reid and Williams, Marc S and Posey, Jennifer E and Gibbs, Richard A and Carlo, Simon and Tegay, David H and Economides, Aris N and Lupski, James R} } @article {720, title = {Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 01}, pages = {150-168}, abstract = {

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM$\#$ 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization~and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65\%) and the clustering of ~47\% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.

}, keywords = {Child, Child, Preschool, Chromosome Breakpoints, Chromosome Deletion, Chromosome Mapping, Chromosomes, Human, X, Comparative Genomic Hybridization, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Nervous System Diseases, Pedigree, Phenotype, Quantitative Trait, Heritable, Repetitive Sequences, Nucleic Acid, Sex Factors, Syndrome, X Chromosome Inactivation}, issn = {1098-1004}, doi = {10.1002/humu.23902}, author = {Hijazi, Hadia and Coelho, Fernanda S and Gonzaga-Jauregui, Claudia and Bernardini, Laura and Mar, Soe S and Manning, Melanie A and Hanson-Kahn, Andrea and Naidu, Sakkubai and Srivastava, Siddharth and Lee, Jennifer A and Jones, Julie R and Friez, Michael J and Alberico, Thomas and Torres, Barbara and Fang, Ping and Cheung, Sau Wai and Song, Xiaofei and Davis-Williams, Angelique and Jornlin, Carly and Wight, Patricia A and Patyal, Pankaj and Taube, Jennifer and Poretti, Andrea and Inoue, Ken and Zhang, Feng and Pehlivan, Davut and Carvalho, Claudia M B and Hobson, Grace M and Lupski, James R} } @article {368, title = {An exome sequencing study of Moebius syndrome including atypical cases reveals an individual with CFEOM3A and a mutation.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {3}, year = {2017}, month = {2017 03}, pages = {a000984}, abstract = {

Moebius syndrome is characterized by congenital unilateral or bilateral facial and abducens nerve palsies (sixth and seventh cranial nerves) causing facial weakness, feeding difficulties, and restricted ocular movements. Abnormalities of the chest wall such as Poland anomaly and variable limb defects are frequently associated with this syndrome. Most cases are isolated; however, rare families with autosomal dominant transmission with incomplete penetrance and variable expressivity have been described. The genetic basis of this condition remains unknown. In a cohort study of nine individuals suspected to have Moebius syndrome (six typical, three atypical), we performed whole-exome sequencing to try to identify a commonly mutated gene. Although no such gene was identified and we did not find mutations in and , we found a de novo heterozygous mutation, p.E410K, in the gene encoding tubulin beta 3 class III (), in an individual with atypical Moebius syndrome. This individual was diagnosed with near-complete ophthalmoplegia, agenesis of the corpus callosum, and absence of the septum pellucidum. No substantial limb abnormalities were noted. Mutations in have been associated with complex cortical dysplasia and other brain malformations and congenital fibrosis of extraocular muscles type 3A (CFEOM3A). Our report highlights the overlap of genetic etiology and clinical differences between CFEOM and Moebius syndrome and describes our approach to identifying candidate genes for typical and atypical Moebius syndrome.

}, keywords = {Child, Child, Preschool, Cohort Studies, Exome, Eye Diseases, Hereditary, Facial Paralysis, Female, Humans, Infant, Male, Malformations of Cortical Development, Mobius Syndrome, Muscular Diseases, Mutation, Ocular Motility Disorders, Ophthalmoplegia, Orbital Diseases, Pedigree, Tubulin, Whole Exome Sequencing}, issn = {2373-2873}, doi = {10.1101/mcs.a000984}, author = {Patel, Ronak M and Liu, David and Gonzaga-Jauregui, Claudia and Jhangiani, Shalini and Lu, James T and Sutton, V Reid and Fernbach, Susan D and Azamian, Mahshid and White, Lisa and Edmond, Jane C and Paysse, Evelyn A and Belmont, John W and Muzny, Donna and Lupski, James R and Gibbs, Richard A and Lewis, Richard Alan and Lee, Brendan H and Lalani, Seema R and Campeau, Philippe M} } @article {173, title = {COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Jun}, pages = {654-60}, abstract = {

Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.

}, keywords = {Amino Acid Sequence, Arthritis, Autoimmune Diseases, Child, Preschool, Coatomer Protein, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Female, Genetic Association Studies, Genetic Predisposition to Disease, Golgi Apparatus, HEK293 Cells, Humans, Infant, Lod Score, Lung Diseases, Interstitial, Male, Molecular Sequence Data, Pedigree, Protein Transport}, issn = {1546-1718}, doi = {10.1038/ng.3279}, author = {Watkin, Levi B and Jessen, Birthe and Wiszniewski, Wojciech and Vece, Timothy J and Jan, Max and Sha, Youbao and Thamsen, Maike and Santos-Cortez, Regie L P and Lee, Kwanghyuk and Gambin, Tomasz and Forbes, Lisa R and Law, Christopher S and Stray-Pedersen, Asbj{\o}rg and Cheng, Mickie H and Mace, Emily M and Anderson, Mark S and Liu, Dongfang and Tang, Ling Fung and Nicholas, Sarah K and Nahmod, Karen and Makedonas, George and Canter, Debra L and Kwok, Pui-Yan and Hicks, John and Jones, Kirk D and Penney, Samantha and Jhangiani, Shalini N and Rosenblum, Michael D and Dell, Sharon D and Waterfield, Michael R and Papa, Feroz R and Muzny, Donna M and Zaitlen, Noah and Leal, Suzanne M and Gonzaga-Jauregui, Claudia and Boerwinkle, Eric and Eissa, N Tony and Gibbs, Richard A and Lupski, James R and Orange, Jordan S and Shum, Anthony K} } @article {135, title = {Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.}, journal = {Cell Rep}, volume = {12}, year = {2015}, month = {2015 Aug 18}, pages = {1169-83}, abstract = {

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in \~{} 45\% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.

}, keywords = {Animals, Charcot-Marie-Tooth Disease, Exome, Female, Genetic Load, Genetic Variation, HSP40 Heat-Shock Proteins, Humans, Male, Mutation, Myelin P2 Protein, Pedigree, Penetrance, Peripheral Nervous System Diseases, Phenotype, Serine C-Palmitoyltransferase, Suppression, Genetic, Zebrafish}, issn = {2211-1247}, doi = {10.1016/j.celrep.2015.07.023}, author = {Gonzaga-Jauregui, Claudia and Harel, Tamar and Gambin, Tomasz and Kousi, Maria and Griffin, Laurie B and Francescatto, Ludmila and Ozes, Burcak and Karaca, Ender and Jhangiani, Shalini N and Bainbridge, Matthew N and Lawson, Kim S and Pehlivan, Davut and Okamoto, Yuji and Withers, Marjorie and Mancias, Pedro and Slavotinek, Anne and Reitnauer, Pamela J and Goksungur, Meryem T and Shy, Michael and Crawford, Thomas O and Koenig, Michel and Willer, Jason and Flores, Brittany N and Pediaditrakis, Igor and Us, Onder and Wiszniewski, Wojciech and Parman, Yesim and Antonellis, Anthony and Muzny, Donna M and Katsanis, Nicholas and Battaloglu, Esra and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R} } @article {121, title = {Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.}, journal = {Neuron}, volume = {88}, year = {2015}, month = {2015 Nov 04}, pages = {499-513}, abstract = {

Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85\% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

}, keywords = {Brain, Cohort Studies, Databases, Genetic, Female, Gene Regulatory Networks, Genetic Association Studies, Genetic Variation, Humans, Male, Mendelian Randomization Analysis, Nervous System Diseases, Pedigree}, issn = {1097-4199}, doi = {10.1016/j.neuron.2015.09.048}, author = {Karaca, Ender and Harel, Tamar and Pehlivan, Davut and Jhangiani, Shalini N and Gambin, Tomasz and Coban Akdemir, Zeynep and Gonzaga-Jauregui, Claudia and Erdin, Serkan and Bayram, Yavuz and Campbell, Ian M and Hunter, Jill V and Atik, Mehmed M and Van Esch, Hilde and Yuan, Bo and Wiszniewski, Wojciech and Isikay, Sedat and Yesil, G{\"o}zde and Yuregir, Ozge O and Tug Bozdogan, Sevcan and Aslan, Huseyin and Aydin, Hatip and Tos, Tulay and Aksoy, Ayse and De Vivo, Darryl C and Jain, Preti and Geckinli, B Bilge and Sezer, Ozlem and Gul, Davut and Durmaz, Burak and Cogulu, Ozgur and Ozkinay, Ferda and Topcu, Vehap and Candan, Sukru and Cebi, Alper Han and Ikbal, Mevlit and Yilmaz Gulec, Elif and Gezdirici, Alper and Koparir, Erkan and Ekici, Fatma and Coskun, Salih and Cicek, Salih and Karaer, Kadri and Koparir, Asuman and Duz, Mehmet Bugrahan and Kirat, Emre and Fenercioglu, Elif and Ulucan, Hakan and Seven, Mehmet and Guran, Tulay and Elcioglu, Nursel and Yildirim, Mahmut Selman and Aktas, Dilek and Alika{\c s}ifo{\u g}lu, Mehmet and Ture, Mehmet and Yakut, Tahsin and Overton, John D and Yuksel, Adnan and Ozen, Mustafa and Muzny, Donna M and Adams, David R and Boerwinkle, Eric and Chung, Wendy K and Gibbs, Richard A and Lupski, James R} } @article {237, title = {Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population.}, journal = {Eur J Hum Genet}, volume = {23}, year = {2015}, month = {2015 Mar}, pages = {342-6}, abstract = {

Osteochondrodysplasias represent a large group of developmental structural disorders that can be caused by mutations in a variety of genes responsible for chondrocyte development, differentiation, mineralization and early ossification. The application of whole-exome sequencing to disorders apparently segregating as Mendelian traits has proven to be an effective approach to disease gene identification for conditions with unknown molecular etiology. We identified a homozygous missense variant p.(Gly697Arg) in COL27A1, in a family with Steel syndrome and no consanguinity. Interestingly, the identified variant seems to have arisen as a founder mutation in the Puerto Rican population.

}, keywords = {Amino Acid Sequence, Child, Preschool, Comparative Genomic Hybridization, Exome, Female, Fibrillar Collagens, Follow-Up Studies, Founder Effect, Genotype, Hispanic Americans, Humans, Infant, Male, Molecular Sequence Data, Mutation, Osteochondrodysplasias, Pedigree, Polymorphism, Single Nucleotide, Prostaglandins F, Puerto Rico, Sequence Alignment}, issn = {1476-5438}, doi = {10.1038/ejhg.2014.107}, author = {Gonzaga-Jauregui, Claudia and Gamble, Candace N and Yuan, Bo and Penney, Samantha and Jhangiani, Shalini and Muzny, Donna M and Gibbs, Richard A and Lupski, James R and Hecht, Jacqueline T} } @article {243, title = {Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jun 05}, pages = {915-23}, abstract = {

We identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with bilateral eye malformations from five unrelated families via three independent exome sequencing projects. Three mutational events altered the same amino acid (Arg51), and two were identical de novo mutations (c.151C>T [p.Arg51Cys]) in unrelated children with bilateral anophthalmia, intellectual disability, and rhizomelic skeletal dysplasia. c.152G>A (p.Arg51His) segregated with autosomal-dominant bilateral colobomatous microphthalmia in a large multiplex family. The fourth heterozygous mutation (c.145G>A [p.Glu49Lys]) affected an amino acid within two residues of Arg51 in an adult male with bilateral colobomata. In a fifth family, a homozygous mutation (c.740G>A [p.Arg247Gln]) altering a different region of the protein was identified in two male siblings with bilateral retinal colobomata. In mouse embryos, Mab21l2 showed strong expression in the developing eye, pharyngeal arches, and limb bud. As predicted by structural homology, wild-type MAB21L2 bound single-stranded RNA, whereas this activity was lost in all altered forms of the protein. MAB21L2 had no detectable nucleotidyltransferase activity in~vitro, and its function remains unknown. Induced expression of wild-type MAB21L2 in human embryonic kidney 293 cells increased phospho-ERK (pERK1/2) signaling. Compared to the wild-type and p.Arg247Gln proteins, the proteins with the Glu49 and Arg51 variants had increased stability. Abnormal persistence of pERK1/2 signaling in MAB21L2-expressing cells during development is a plausible pathogenic mechanism for the heterozygous mutations. The phenotype associated with the homozygous mutation might be a consequence of complete loss of MAB21L2 RNA binding, although the cellular function of this interaction remains unknown.

}, keywords = {Adult, Alleles, Animals, Anophthalmos, Brain Diseases, Metabolic, Inborn, Coloboma, Corneal Opacity, Exome, Eye Proteins, Female, Gene Expression, HEK293 Cells, Heterozygote, Homozygote, Humans, Intellectual Disability, Intracellular Signaling Peptides and Proteins, Male, Mice, Microcephaly, Microphthalmos, Mutation, Missense, Pedigree, Phenotype, Protein Conformation, Signal Transduction}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.05.005}, author = {Rainger, Joe and Pehlivan, Davut and Johansson, Stefan and Bengani, Hemant and Sanchez-Pulido, Luis and Williamson, Kathleen A and Ture, Mehmet and Barker, Heather and Rosendahl, Karen and Spranger, J{\"u}rgen and Horn, Denise and Meynert, Alison and Floyd, James A B and Prescott, Trine and Anderson, Carl A and Rainger, Jacqueline K and Karaca, Ender and Gonzaga-Jauregui, Claudia and Jhangiani, Shalini and Muzny, Donna M and Seawright, Anne and Soares, Dinesh C and Kharbanda, Mira and Murday, Victoria and Finch, Andrew and Gibbs, Richard A and van Heyningen, Veronica and Taylor, Martin S and Yakut, Tahsin and Knappskog, Per M and Hurles, Matthew E and Ponting, Chris P and Lupski, James R and Houge, Gunnar and FitzPatrick, David R} } @article {233, title = {Whole exome sequencing identifies three novel mutations in ANTXR1 in families with GAPO syndrome.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Sep}, pages = {2328-34}, abstract = {

GAPO syndrome (OMIM$\#$230740) is the acronym for growth retardation, alopecia, pseudoanodontia, and optic atrophy. About 35 cases have been reported, making it among one of the rarest recessive conditions. Distinctive craniofacial features including alopecia, rarefaction of eyebrows and eyelashes, frontal bossing, high forehead, mid-facial hypoplasia, hypertelorism, and thickened eyelids and lips make GAPO syndrome a clinically recognizable phenotype. While this genomic study was in progress mutations in ANTXR1 were reported to cause GAPO syndrome. In our study we performed whole exome sequencing (WES) for five affected individuals from three Turkish kindreds segregating the GAPO trait. Exome sequencing analysis identified three novel homozygous mutations including; one frame-shift (c.1220_1221insT; p.Ala408Cysfs*2), one splice site (c.411A>G; p.Gln137Gln), and one non-synonymous (c.1150G>A; p.Gly384Ser) mutation in the ANTXR1 gene. Our studies expand the allelic spectrum in this rare condition and potentially provide insight into the role of ANTXR1 in the regulation of the extracellular matrix.

}, keywords = {Adolescent, Adult, Alopecia, Anodontia, Base Sequence, Child, Chromosome Segregation, DNA Mutational Analysis, Exome, Facies, Family, Female, Growth Disorders, Humans, Male, Molecular Sequence Data, Mutation, Neoplasm Proteins, Optic Atrophies, Hereditary, Pedigree, Protein Structure, Tertiary, Receptors, Cell Surface}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36678}, author = {Bayram, Yavuz and Pehlivan, Davut and Karaca, Ender and Gambin, Tomasz and Jhangiani, Shalini N and Erdin, Serkan and Gonzaga-Jauregui, Claudia and Wiszniewski, Wojciech and Muzny, Donna and Elcioglu, Nursel H and Yildirim, M Selman and Bozkurt, Banu and Zamani, Ayse Gul and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R} }