@article {780, title = {De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 04 02}, pages = {570-583}, abstract = {

EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

}, keywords = {Adolescent, Ataxia, Child, Child, Preschool, Developmental Disabilities, eIF-2 Kinase, Female, Genetic Variation, Hereditary Central Nervous System Demyelinating Diseases, Humans, Infant, Leukoencephalopathies, Male, Nervous System Malformations, White Matter}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.02.016}, author = {Mao, Dongxue and Reuter, Chloe M and Ruzhnikov, Maura R Z and Beck, Anita E and Farrow, Emily G and Emrick, Lisa T and Rosenfeld, Jill A and Mackenzie, Katherine M and Robak, Laurie and Wheeler, Matthew T and Burrage, Lindsay C and Jain, Mahim and Liu, Pengfei and Calame, Daniel and K{\"u}ry, S{\'e}bastien and Sillesen, Martin and Schmitz-Abe, Klaus and Tonduti, Davide and Spaccini, Luigina and Iascone, Maria and Genetti, Casie A and Koenig, Mary K and Graf, Madeline and Tran, Alyssa and Alejandro, Mercedes and Lee, Brendan H and Thiffault, Isabelle and Agrawal, Pankaj B and Bernstein, Jonathan A and Bellen, Hugo J and Chao, Hsiao-Tuan} } @article {972, title = {Genetic Burden Contributing to Extremely Low or High Bone Mineral Density in a Senior Male Population From the Osteoporotic Fractures in Men Study (MrOS).}, journal = {JBMR Plus}, volume = {4}, year = {2020}, month = {2020 Mar}, pages = {e10335}, abstract = {

Worldwide, one in five men aged over 50 years will experience osteoporosis or a clinical bone fracture, with a greater fracture-related mortality rate than women. However, the genetic etiology of osteoporosis in men is still poorly understood. We aimed to identify the genetic variants and candidate genes associated with extremely low or high BMD for a better understanding of the biology underlying low bone density that may point to potential therapeutic targets for increasing bone mass. Subjects from the Osteoporotic Fractures in Men Study (MrOS) cohort were evaluated by age and BMI-adjusted total hip BMD. Those with BMD values 3 SDs away from the mean were selected and the remaining individuals whose adjusted BMD ranked at the highest or lowest 100 were included. Men with the lowest adjusted BMD ( = 98) and highest adjusted BMD ( = 110) were chosen for exome sequencing. Controls ( = 82) were men of Northern and Western European descent from the US Utah population of the 1000 Genomes Project. Fisher{\textquoteright}s exact test was performed to compare low- or high-BMD subjects with controls for single-gene associations. Additionally, sets of candidate genes causative of heritable disorders of connective tissue, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), were grouped for multigene and mutation burden analyses. No single-gene associations with rare variants were found for either the low BMD group (33 genes) or high BMD group (18 genes). In the group of OI genes, we detected a significant threefold increased accumulation of rare variants in low-BMD subjects compared with controls ( = 0.009). Additionally, genes associated with EDS had a twofold increased frequency in low-BMD subjects compared with controls ( = 0.03). These findings reveal a rare variant burden in OI and EDS disease genes at low BMD, which suggests a potential gene-panel approach to screen for multivariant associations in larger cohorts. {\textcopyright} 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

}, issn = {2473-4039}, doi = {10.1002/jbm4.10335}, author = {Chen, Shan and Jain, Mahim and Jhangiani, Shalini and Akdemir, Zeynep C and Campeau, Philippe M and Klein, Robert F and Nielson, Carrie and Dai, Hongzheng and Muzny, Donna M and Boerwinkle, Eric and Gibbs, Richard A and Orwoll, Eric S and Lupski, James R and Posey, Jennifer E and Lee, Brendan} } @article {593, title = {Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 03 07}, pages = {422-438}, abstract = {

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive~inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.01.007}, author = {Burrage, Lindsay C and Reynolds, John J and Baratang, Nissan Vida and Phillips, Jennifer B and Wegner, Jeremy and McFarquhar, Ashley and Higgs, Martin R and Christiansen, Audrey E and Lanza, Denise G and Seavitt, John R and Jain, Mahim and Li, Xiaohui and Parry, David A and Raman, Vandana and Chitayat, David and Chinn, Ivan K and Bertuch, Alison A and Karaviti, Lefkothea and Schlesinger, Alan E and Earl, Dawn and Bamshad, Michael and Savarirayan, Ravi and Doddapaneni, Harsha and Muzny, Donna and Jhangiani, Shalini N and Eng, Christine M and Gibbs, Richard A and Bi, Weimin and Emrick, Lisa and Rosenfeld, Jill A and Postlethwait, John and Westerfield, Monte and Dickinson, Mary E and Beaudet, Arthur L and Ranza, Emmanuelle and Huber, Celine and Cormier-Daire, Val{\'e}rie and Shen, Wei and Mao, Rong and Heaney, Jason D and Orange, Jordan S and Bertola, D{\'e}bora and Yamamoto, Guilherme L and Baratela, Wagner A R and Butler, Merlin G and Ali, Asim and Adeli, Mehdi and Cohn, Daniel H and Krakow, Deborah and Jackson, Andrew P and Lees, Melissa and Offiah, Amaka C and Carlston, Colleen M and Carey, John C and Stewart, Grant S and Bacino, Carlos A and Campeau, Philippe M and Lee, Brendan} } @article {473, title = {Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 06 07}, pages = {1126-1142}, abstract = {

The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that~perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in~any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune~phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.

}, keywords = {Base Sequence, Cell Line, Endoplasmic Reticulum Stress, Exons, Family, Frameshift Mutation, Genetic Predisposition to Disease, Heterozygote, Humans, Immunologic Deficiency Syndromes, Immunophenotyping, Infant, Newborn, Inflammation, Interferon Type I, Male, Molecular Chaperones, Mutant Proteins, Mutation, Nonsense Mediated mRNA Decay, Phenotype, Proteasome Endopeptidase Complex, RNA, Messenger, Syndrome, Unfolded Protein Response}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.04.010}, author = {Poli, M Cecilia and Ebstein, Fr{\'e}d{\'e}ric and Nicholas, Sarah K and de Guzman, Marietta M and Forbes, Lisa R and Chinn, Ivan K and Mace, Emily M and Vogel, Tiphanie P and Carisey, Alexandre F and Benavides, Felipe and Coban-Akdemir, Zeynep H and Gibbs, Richard A and Jhangiani, Shalini N and Muzny, Donna M and Carvalho, Claudia M B and Schady, Deborah A and Jain, Mahim and Rosenfeld, Jill A and Emrick, Lisa and Lewis, Richard A and Lee, Brendan and Zieba, Barbara A and K{\"u}ry, S{\'e}bastien and Kr{\"u}ger, Elke and Lupski, James R and Bostwick, Bret L and Orange, Jordan S} } @article {437, title = {Asprosin is a centrally acting orexigenic hormone.}, journal = {Nat Med}, volume = {23}, year = {2017}, month = {2017 Dec}, pages = {1444-1453}, abstract = {

Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.

}, keywords = {Adolescent, Adult, Animals, Appetite Depressants, Appetite Regulation, Female, Humans, Hypothalamus, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Neurons, Peptide Fragments, Peptide Hormones, Rats, Signal Transduction, Young Adult}, issn = {1546-170X}, doi = {10.1038/nm.4432}, author = {Duerrschmid, Clemens and He, Yanlin and Wang, Chunmei and Li, Chia and Bournat, Juan C and Romere, Chase and Saha, Pradip K and Lee, Mark E and Phillips, Kevin J and Jain, Mahim and Jia, Peilin and Zhao, Zhongming and Farias, Monica and Wu, Qi and Milewicz, Dianna M and Sutton, V Reid and Moore, David D and Butte, Nancy F and Krashes, Michael J and Xu, Yong and Chopra, Atul R} } @article {353, title = {Corner fracture type spondylometaphyseal dysplasia: Overlap with type II collagenopathies.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Mar}, pages = {733-739}, abstract = {

Spondylometaphyseal dysplasia (SMD) corner fracture type (also known as SMD "Sutcliffe" type, MIM 184255) is a rare skeletal dysplasia that presents with mild to moderate short stature, developmental coxa vara, mild platyspondyly, corner fracture-like lesions, and metaphyseal abnormalities with sparing of the epiphyses. The molecular basis for this disorder has yet to be clarified. We describe two patients with SMD corner fracture type and heterozygous pathogenic variants in COL2A1. These two cases together with a third case of SMD corner fracture type with a heterozygous COL2A1 pathogenic variant previously described suggest that this disorder overlaps with type II collagenopathies. The finding of one of the pathogenic variants in a previously reported case of spondyloepimetaphyseal dysplasia (SEMD) Strudwick type and the significant clinical similarity suggest an overlap between SMD corner fracture and SEMD Strudwick types. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Alleles, Amino Acid Substitution, Bone Diseases, Developmental, Child, Preschool, Collagen Type II, Diagnosis, Differential, Exome, Genetic Association Studies, Genotype, Growth Disorders, High-Throughput Nucleotide Sequencing, Hip Joint, Humans, Infant, Male, Mutation, Osteochondrodysplasias, Phenotype, Radiography, Tibial Fractures}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38059}, author = {Machol, Keren and Jain, Mahim and Almannai, Mohammed and Orand, Thibault and Lu, James T and Tran, Alyssa and Chen, Yuqing and Schlesinger, Alan and Gibbs, Richard and Bonafe, Luisa and Campos-Xavier, Ana Belinda and Unger, Sheila and Superti-Furga, Andrea and Lee, Brendan H and Campeau, Philippe M and Burrage, Lindsay C} } @article {391, title = {Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability.}, journal = {Hum Mutat}, volume = {38}, year = {2017}, month = {2017 10}, pages = {1365-1371}, abstract = {

Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to β-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

}, keywords = {Actins, Adolescent, Child, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, DNA Helicases, DNA-Binding Proteins, Exome, Face, Female, Hand Deformities, Congenital, Heterozygote, Humans, Intellectual Disability, Male, Micrognathism, Multiprotein Complexes, Mutation, Missense, Nuclear Proteins, Protein Binding, Transcription Factors}, issn = {1098-1004}, doi = {10.1002/humu.23282}, author = {Marom, Ronit and Jain, Mahim and Burrage, Lindsay C and Song, I-Wen and Graham, Brett H and Brown, Chester W and Stevens, Servi J C and Stegmann, Alexander P A and Gunter, Andrew T and Kaplan, Julie D and Gavrilova, Ralitza H and Shinawi, Marwan and Rosenfeld, Jill A and Bae, Yangjin and Tran, Alyssa A and Chen, Yuqing and Lu, James T and Gibbs, Richard A and Eng, Christine and Yang, Yaping and Rousseau, Justine and de Vries, Bert B A and Campeau, Philippe M and Lee, Brendan} } @article {384, title = {Neonatal fractures as a presenting feature of LMOD3-associated congenital myopathy.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Oct}, pages = {2789-2794}, abstract = {

Nemaline myopathy is a rare inherited disorder characterized by weakness, hypotonia, and depressed deep tendon reflexes. It is clinically and genetically heterogeneous, with the most severe phenotype presenting as perinatal akinesia, severe muscle weakness, feeding difficulties and respiratory failure, leading to early mortality. Pathogenic variants in 12 genes, encoding components of the sarcomere or factors related to myogenesis, have been reported in patients affected with the disorder. Here, we describe an early, lethal presentation of decreased fetal movements, hypotonia, muscle weakness, and neonatal respiratory failure requiring ventilator support in three siblings from a consanguineous family. All exhibited perinatal fractures, and thus, a skeletal dysplasia was considered as possibly contributing to the phenotype. However, whole exome sequencing revealed a homozygous, loss-of-function pathogenic variant in LMOD3, which has recently been associated with nemaline myopathy and, in a subset of patients, perinatal fractures. This case demonstrates the importance of considering congenital neuromuscular disorders in the differential diagnosis of perinatal fractures.

}, keywords = {Female, Fractures, Bone, Homozygote, Humans, Infant, Newborn, Male, Muscle Proteins, Mutation, Myopathies, Structural, Congenital, Pedigree}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38383}, author = {Abbott, Megan and Jain, Mahim and Pferdehirt, Rachel and Chen, Yuqing and Tran, Alyssa and Duz, Mehmet B and Seven, Mehmet and Gibbs, Richard A and Muzny, Donna and Lee, Brendan and Marom, Ronit and Burrage, Lindsay C} } @article {66, title = {Asprosin, a Fasting-Induced Glucogenic Protein Hormone.}, journal = {Cell}, volume = {165}, year = {2016}, month = {2016 Apr 21}, pages = {566-79}, abstract = {

Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means~has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.

}, keywords = {Adipose Tissue, White, Amino Acid Sequence, Animals, Antibodies, Circadian Rhythm, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Fasting, Female, Fetal Growth Retardation, Glucose, Humans, Insulin, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Microfilament Proteins, Molecular Sequence Data, Peptide Fragments, Peptide Hormones, Progeria, Recombinant Proteins, Sequence Alignment}, issn = {1097-4172}, doi = {10.1016/j.cell.2016.02.063}, author = {Romere, Chase and Duerrschmid, Clemens and Bournat, Juan and Constable, Petra and Jain, Mahim and Xia, Fan and Saha, Pradip K and Del Solar, Maria and Zhu, Bokai and York, Brian and Sarkar, Poonam and Rendon, David A and Gaber, M Waleed and LeMaire, Scott A and Coselli, Joseph S and Milewicz, Dianna M and Sutton, V Reid and Butte, Nancy F and Moore, David D and Chopra, Atul R} } @article {91, title = {Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death.}, journal = {Mol Genet Genomic Med}, volume = {4}, year = {2016}, month = {2016 Jan}, pages = {77-94}, abstract = {

BACKGROUND: Juvenile-onset cataracts are known among the Hutterites of North America. Despite being identified over 30~years ago, this autosomal recessive condition has not been mapped, and the disease gene is unknown.

METHODS: We performed whole exome sequencing of three Hutterite-type cataract trios and follow-up genotyping and mapping in four extended kindreds.

RESULTS: Trio exomes enabled genome-wide autozygosity mapping, which localized the disease gene to a 9.5-Mb region on chromosome 6p. This region contained two candidate variants, LEMD2 c.T38G and MUC21 c.665delC. Extended pedigrees recruited for variant genotyping revealed multiple additional relatives with juvenile-onset cataract, as well as six deceased relatives with both cataracts and sudden cardiac death. The candidate variants were genotyped in 84 family members, including 17 with cataracts; only the variant in LEMD2 cosegregated with cataracts (LOD~=~9.62). SNP-based fine mapping within the 9.5~Mb linked region supported this finding by refining the cataract locus to a 0.5- to 2.9-Mb subregion (6p21.32-p21.31) containing LEMD2 but not MUC21. LEMD2 is expressed in mouse and human lenses and encodes a LEM domain-containing protein; the c.T38G missense mutation is predicted to mutate a highly conserved residue within this domain (p.Leu13Arg).

CONCLUSION: We performed a genetic and genomic study of Hutterite-type cataract and found evidence for an association of this phenotype with sudden cardiac death. Using combined genetic and genomic approaches, we mapped cataracts to a small portion of chromosome 6 and propose that they result from a homozygous missense mutation in LEMD2.

}, issn = {2324-9269}, doi = {10.1002/mgg3.181}, author = {Boone, Philip M and Yuan, Bo and Gu, Shen and Ma, Zhiwei and Gambin, Tomasz and Gonzaga-Jauregui, Claudia and Jain, Mahim and Murdock, Todd J and White, Janson J and Jhangiani, Shalini N and Walker, Kimberly and Wang, Qiaoyan and Muzny, Donna M and Gibbs, Richard A and Hejtmancik, J Fielding and Lupski, James R and Posey, Jennifer E and Lewis, Richard A} } @article {164, title = {Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3.}, journal = {Am J Hum Genet}, volume = {96}, year = {2015}, month = {2015 May 07}, pages = {841-9}, abstract = {

Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development.

}, keywords = {Arthrogryposis, Cytoskeletal Proteins, Exome, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Mutation, Myosins, Osteogenesis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.04.004}, author = {Chong, Jessica X and Burrage, Lindsay C and Beck, Anita E and Marvin, Colby T and McMillin, Margaret J and Shively, Kathryn M and Harrell, Tanya M and Buckingham, Kati J and Bacino, Carlos A and Jain, Mahim and Alanay, Yasemin and Berry, Susan A and Carey, John C and Gibbs, Richard A and Lee, Brendan H and Krakow, Deborah and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {235, title = {Diagnosis of ALG12-CDG by exome sequencing in a case of severe skeletal dysplasia.}, journal = {Mol Genet Metab Rep}, volume = {1}, year = {2014}, month = {2014}, pages = {213-219}, abstract = {

Congenital Disorder of Glycosylation type Ig (ALG12-CDG) is part of a group of autosomal recessive conditions caused by deficiency of proteins involved in the assembly of dolichol-oligosaccharides used for protein N-glycosylation. In ALG12-CDG, the enzyme affected is encoded by the gene. Affected individuals present clinically with neurodevelopmental delay, growth retardation, immune deficiency, male genital hypoplasia, and cardiomyopathy. A total of six individuals have been reported in the literature. Here, we present an infant with rhizomelic short stature, talipes equinovarus, platyspondyly, and joint dislocations. The infant had marked underossification of the pubic bones. Exome sequencing was performed and two deletions, each resulting in frameshifts, were found in . A review of the literature revealed two infants with ALG12-CDG and a severe skeletal dysplasia, including under-ossification of cervical vertebrae, pubic bones, and knees; in addition to talipes equinovarus and rhizomelic short stature. The phenotype of the individual we describe resembles pseudodiastrophic dysplasia and we discuss similarities and differences between ALG12-CDG and pseudodiastrophic dysplasia. The differential diagnosis in selected undiagnosed skeletal dysplasias should include CDGs.

}, issn = {2214-4269}, doi = {10.1016/j.ymgmr.2014.04.004}, author = {Murali, Chaya and Lu, James T and Jain, Mahim and Liu, David S and Lachman, Ralph and Gibbs, Richard A and Lee, Brendan H and Cohn, Daniel and Campeau, Philippe M} } @article {211, title = {Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Nov 06}, pages = {579-83}, abstract = {

5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-α, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Animals, Base Sequence, Caenorhabditis elegans, Chromosome Deletion, Chromosome Mapping, Chromosomes, Human, Pair 5, DNA-Binding Proteins, Humans, Molecular Sequence Data, Muscle Hypotonia, Mutation, Seizures, Sequence Analysis, DNA, Syndrome, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.09.014}, author = {Lalani, Seema R and Zhang, Jing and Schaaf, Christian P and Brown, Chester W and Magoulas, Pilar and Tsai, Anne Chun-Hui and El-Gharbawy, Areeg and Wierenga, Klaas J and Bartholomew, Dennis and Fong, Chin-To and Barbaro-Dieber, Tina and Kukolich, Mary K and Burrage, Lindsay C and Austin, Elise and Keller, Kory and Pastore, Matthew and Fernandez, Fabio and Lotze, Timothy and Wilfong, Angus and Purcarin, Gabriela and Zhu, Wenmiao and Craigen, William J and McGuire, Marianne and Jain, Mahim and Cooney, Erin and Azamian, Mahshid and Bainbridge, Matthew N and Muzny, Donna M and Boerwinkle, Eric and Person, Richard E and Niu, Zhiyv and Eng, Christine M and Lupski, James R and Gibbs, Richard A and Beaudet, Arthur L and Yang, Yaping and Wang, Meng C and Xia, Fan} }