@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 {389, title = {MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Sep}, pages = {2415-2421}, abstract = {

Multiple Epiphyseal Dysplasia (MED) is a relatively mild skeletal dysplasia characterized by mild short stature, joint pain, and early-onset osteoarthropathy. Dominantly inherited mutations in COMP, MATN3, COL9A1, COL9A2, and COL9A3, and recessively inherited mutations in SLC26A2, account for the molecular basis of disease in about 80-85\% of the cases. In two families with recurrent MED of an unknown molecular basis, we used exome sequencing and candidate gene analysis to identify homozygosity for recessively inherited missense mutations in CANT1, which encodes calcium-activated nucleotidase 1. The MED phenotype is thus allelic to the more severe Desbuquois dysplasia phenotype and the results identify CANT1 as a second locus for recessively inherited MED.

}, keywords = {Adult, Base Sequence, Child, Child, Preschool, Exome, Female, Genes, Recessive, Humans, Male, Mutation, Missense, Nucleotidases, Osteochondrodysplasias, Pedigree, Radiography}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38349}, author = {Balasubramanian, Karthika and Li, Bing and Krakow, Deborah and Nevarez, Lisette and Ho, Patric J and Ainsworth, Julia A and Nickerson, Deborah A and Bamshad, Michael J and Immken, LaDonna and Lachman, Ralph S and Cohn, Daniel H} } @article {422, title = {Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {815-823}, abstract = {

Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo~FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70~kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.

}, keywords = {Adolescent, Adult, Bone and Bones, Bone Diseases, Developmental, Cartilage, Child, Child, Preschool, Exome, Female, Fibronectins, Fractures, Bone, Humans, Male, Mutation, Osteochondrodysplasias, Phenotype, Scoliosis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.019}, author = {Lee, Chae Syng and Fu, He and Baratang, Nissan and Rousseau, Justine and Kumra, Heena and Sutton, V Reid and Niceta, Marcello and Ciolfi, Andrea and Yamamoto, Guilherme and Bertola, D{\'e}bora and Marcelis, Carlo L and Lugtenberg, Dorien and Bartuli, Andrea and Kim, Choel and Hoover-Fong, Julie and Sobreira, Nara and Pauli, Richard and Bacino, Carlos and Krakow, Deborah and Parboosingh, Jillian and Yap, Patrick and Kariminejad, Ariana and McDonald, Marie T and Aracena, Mariana I and Lausch, Ekkehart and Unger, Sheila and Superti-Furga, Andrea and Lu, James T and Cohn, Dan H and Tartaglia, Marco and Lee, Brendan H and Reinhardt, Dieter P and Campeau, Philippe M} } @article {454, title = {P4HA1 mutations cause a unique congenital disorder of connective tissue involving tendon, bone, muscle and the eye.}, journal = {Hum Mol Genet}, volume = {26}, year = {2017}, month = {2017 06 15}, pages = {2207-2217}, abstract = {

Collagen prolyl 4-hydroxylases (C-P4Hs) play a central role in the formation and stabilization of the triple helical domain of collagens. P4HA1 encodes the catalytic α(I) subunit of the main C-P4H isoenzyme (C-P4H-I). We now report human bi-allelic P4HA1 mutations in a family with a congenital-onset disorder of connective tissue, manifesting as early-onset joint hypermobility, joint contractures, muscle weakness and bone dysplasia as well as high myopia, with evidence of clinical improvement of motor function over time in the surviving patient. Similar to P4ha1 null mice, which die prenatally, the muscle tissue from P1 and P2 was found to have reduced collagen IV immunoreactivity at the muscle basement membrane. Patients were compound heterozygous for frameshift and splice site mutations leading to reduced, but not absent, P4HA1 protein level and C-P4H activity in dermal fibroblasts compared to age-matched control samples. Differential scanning calorimetry revealed reduced thermal stability of collagen in patient-derived dermal fibroblasts versus age-matched control samples. Mutations affecting the family of C-P4Hs, and in particular C-P4H-I, should be considered in patients presenting with congenital connective tissue/myopathy overlap disorders with joint hypermobility, contractures, mild skeletal dysplasia and high myopia.

}, keywords = {Animals, Basement Membrane, Bone and Bones, Child, Collagen Type IV, Connective Tissue, Humans, Male, Mice, Mice, Knockout, Muscles, Mutation, Osteochondrodysplasias, Procollagen-Proline Dioxygenase, Prolyl Hydroxylases, Tendons}, issn = {1460-2083}, doi = {10.1093/hmg/ddx110}, author = {Zou, Yaqun and Donkervoort, Sandra and Salo, Antti M and Foley, A Reghan and Barnes, Aileen M and Hu, Ying and Makareeva, Elena and Leach, Meganne E and Mohassel, Payam and Dastgir, Jahannaz and Deardorff, Matthew A and Cohn, Ronald D and DiNonno, Wendy O and Malfait, Fransiska and Lek, Monkol and Leikin, Sergey and Marini, Joan C and Myllyharju, Johanna and B{\"o}nnemann, Carsten G} } @article {29, title = {Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 Dec}, pages = {3298-3302}, abstract = {

Dominant mutations in TRPV4, which encodes the Transient Receptor Potential Cation Channel Subfamily V Member 4 calcium channel, result in a series of musculoskeletal disorders that include a set of peripheral neuropathies and a broad phenotypic spectrum of skeletal dysplasias. The skeletal phenotypes range from brachyolmia, in which there is scoliosis with mild short stature, through perinatal lethal metatropic dysplasia. We describe a case with phenotypic findings consistent with metatropic dysplasia, but in whom no TRPV4 mutation was detected by Sanger sequence analysis. Exome sequence analysis identified a known lethal metatropic dysplasia mutation, TRPV4 , which was present at lower frequency than would be expected for a heterozygous change. The affected individual was shown to be a somatic mosaic for the mutation, providing an explanation for the milder than expected phenotype. The data illustrate that high-throughput sequencing of genomic DNA can facilitate detection of mosaicism with higher sensitivity than Sanger sequence analysis and identify a new genetic mechanism for metatropic dysplasia. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Alleles, DNA Mutational Analysis, Dwarfism, Exons, Genetic Association Studies, Humans, Infant, Magnetic Resonance Imaging, Mosaicism, Mutation, Osteochondrodysplasias, Phenotype, Physical Examination, Radiography, TRPV Cation Channels}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37942}, author = {Weinstein, Michael M and Kang, Taekyu and Lachman, Ralph S and Bamshad, Michael and Nickerson, Deborah A and Krakow, Deborah and Cohn, Daniel H} } @article {641, title = {An anadysplasia-like, spontaneously remitting spondylometaphyseal dysplasia secondary to lamin B receptor (LBR) gene mutations: further definition of the phenotypic heterogeneity of LBR-bone dysplasias.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Jan}, pages = {159-63}, abstract = {

We describe a boy who has an anadysplasia-like spondylometaphyseal dysplasia. By whole exome sequencing he was shown to have compound heterozygous mutations of LBR that codes for the lamin B receptor. He shares many similarities with a case previously described, but in whom the early natural history could not be established [Borovik et al., 2013]. Thus, in addition to Greenberg dysplasia (a perinatal lethal disorder), homozygosity or compound heterozygosity of mutations in LBR can result in a mild, spontaneously regressing bone dysplasia.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phenotype, Pregnancy, Radiography, Receptors, Cytoplasmic and Nuclear, Spine}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36808}, author = {Sobreira, Nara and Modaff, Peggy and Steel, Gary and You, Jing and Nanda, Sonia and Hoover-Fong, Julie and Valle, David and Pauli, Richard M} } @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 {144, title = {Novel COL2A1 variant (c.619G>A, p.Gly207Arg) manifesting as a phenotype similar to progressive pseudorheumatoid dysplasia and spondyloepiphyseal dysplasia, Stanescu type.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {1004-8}, abstract = {

Progressive pseudorheumatoid dysplasia (PPRD) is a rare, autosomal-recessive condition characterized by mild spondyloepiphyseal dysplasia (SED) and severe, progressive, early-onset arthritis due to WISP3 mutations. SED, Stanescu type, is a vaguely delineated autosomal-dominant dysplasia of unknown genetic etiology. Here, we report three individuals from two unrelated families with radiological features similar to PPRD and SED, Stanescu type who share the same novel COL2A1 variant and were matched following discussion at an academic conference. In the first family, we performed whole-exome sequencing on three family members, two of whom have a PPRD-like phenotype, and identified a heterozygous variant (c.619G>A, p.Gly207Arg) in both affected individuals. Independently, targeted sequencing of the COL2A1 gene in an unrelated proband with a similar phenotype identified the same heterozygous variant. We suggest that the p.Gly207Arg variant causes a distinct type II collagenopathy with features of PPRD and SED, Stanescu type.

}, keywords = {Adolescent, Adult, Child, Collagen Type II, Exome, Female, Humans, Joint Diseases, Male, Osteochondrodysplasias, Pedigree, Polymorphism, Single Nucleotide, Radiography, Sequence Analysis, DNA}, issn = {1098-1004}, doi = {10.1002/humu.22839}, author = {Jurgens, Julie and Sobreira, Nara and Modaff, Peggy and Reiser, Catherine A and Seo, Soo Hyun and Seong, Moon-Woo and Park, Sung Sup and Kim, Ok Hwa and Cho, Tae-Joon and Pauli, Richard M} } @article {162, title = {A second locus for Schneckenbecken dysplasia identified by a mutation in the gene encoding inositol polyphosphate phosphatase-like 1 (INPPL1).}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Oct}, pages = {2470-3}, keywords = {Exome, Gene Expression, Genetic Loci, Gestational Age, Homozygote, Humans, Hydrops Fetalis, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases, Stillbirth}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37173}, author = {Lee, Hane and Nevarez, Lisette and Lachman, Ralph S and Wilcox, William R and Krakow, Deborah and Cohn, Daniel H} } @article {275, title = {Mutations in PCYT1A, encoding a key regulator of phosphatidylcholine metabolism, cause spondylometaphyseal dysplasia with cone-rod dystrophy.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jan 02}, pages = {105-12}, keywords = {Alleles, Child, Preschool, Choline-Phosphate Cytidylyltransferase, Female, Humans, Infant, Male, Middle Aged, Mutation, Missense, Osteochondrodysplasias, Pedigree, Phosphatidylcholines, Retinitis Pigmentosa}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.11.018}, author = {Hoover-Fong, Julie and Sobreira, Nara and Jurgens, Julie and Modaff, Peggy and Blout, Carrie and Moser, Ann and Kim, Ok-Hwa and Cho, Tae-Joon and Cho, Sung Yoon and Kim, Sang Jin and Jin, Dong-Kyu and Kitoh, Hiroshi and Park, Woong-Yang and Ling, Hua and Hetrick, Kurt N and Doheny, Kimberly F and Valle, David and Pauli, Richard M} } @article {239, title = {Opsismodysplasia resulting from an insertion mutation in the SH2 domain, which destabilizes INPPL1.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Sep}, pages = {2407-11}, keywords = {Adolescent, Amino Acid Sequence, Base Sequence, Child, Child, Preschool, Female, Humans, Infant, Molecular Sequence Data, Mutagenesis, Insertional, Mutation, Osteochondrodysplasias, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases, Protein Stability, Radiography, RNA Splice Sites, src Homology Domains}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36640}, author = {Li, Bing and Krakow, Deborah and Nickerson, Deborah A and Bamshad, Michael J and Chang, Yong and Lachman, Ralph S and Yilmaz, Alev and Kayserili, H{\"u}lya and Cohn, Daniel H} } @article {313, title = {Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Jan 10}, pages = {137-43}, abstract = {

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ~60\% of cases overall, including both of the families in our cohort with more than one affected child and 50\% of the simplex cases.

}, keywords = {Child, Child, Preschool, Female, Genome, Human, Humans, Infant, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2012.11.011}, author = {Below, Jennifer E and Earl, Dawn L and Shively, Kathryn M and McMillin, Margaret J and Smith, Joshua D and Turner, Emily H and Stephan, Mark J and Al-Gazali, Lihadh I and Hertecant, Jozef L and Chitayat, David and Unger, Sheila and Cohn, Daniel H and Krakow, Deborah and Swanson, James M and Faustman, Elaine M and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} }