%0 Journal Article %J Am J Med Genet A %D 2017 %T Corner fracture type spondylometaphyseal dysplasia: Overlap with type II collagenopathies. %A Machol, Keren %A Jain, Mahim %A Almannai, Mohammed %A Orand, Thibault %A Lu, James T %A Tran, Alyssa %A Chen, Yuqing %A Schlesinger, Alan %A Gibbs, Richard %A Bonafe, Luisa %A Campos-Xavier, Ana Belinda %A Unger, Sheila %A Superti-Furga, Andrea %A Lee, Brendan H %A Campeau, Philippe M %A Burrage, Lindsay C %K Alleles %K Amino Acid Substitution %K Bone Diseases, Developmental %K Child, Preschool %K Collagen Type II %K Diagnosis, Differential %K Exome %K Genetic Association Studies %K Genotype %K Growth Disorders %K High-Throughput Nucleotide Sequencing %K Hip Joint %K Humans %K Infant %K Male %K Mutation %K Osteochondrodysplasias %K Phenotype %K Radiography %K Tibial Fractures %X

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. © 2016 Wiley Periodicals, Inc.

%B Am J Med Genet A %V 173 %P 733-739 %8 2017 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/27888646?dopt=Abstract %R 10.1002/ajmg.a.38059 %0 Journal Article %J Cold Spring Harb Mol Case Stud %D 2017 %T An exome sequencing study of Moebius syndrome including atypical cases reveals an individual with CFEOM3A and a mutation. %A Patel, Ronak M %A Liu, David %A Gonzaga-Jauregui, Claudia %A Jhangiani, Shalini %A Lu, James T %A Sutton, V Reid %A Fernbach, Susan D %A Azamian, Mahshid %A White, Lisa %A Edmond, Jane C %A Paysse, Evelyn A %A Belmont, John W %A Muzny, Donna %A Lupski, James R %A Gibbs, Richard A %A Lewis, Richard Alan %A Lee, Brendan H %A Lalani, Seema R %A Campeau, Philippe M %K Child %K Child, Preschool %K Cohort Studies %K Exome %K Exome Sequencing %K Eye Diseases, Hereditary %K Facial Paralysis %K Female %K Humans %K Infant %K Male %K Malformations of Cortical Development %K Mobius Syndrome %K Muscular Diseases %K Mutation %K Ocular Motility Disorders %K Ophthalmoplegia %K Orbital Diseases %K Pedigree %K Tubulin %X

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.

%B Cold Spring Harb Mol Case Stud %V 3 %P a000984 %8 2017 Mar %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/28299356?dopt=Abstract %R 10.1101/mcs.a000984 %0 Journal Article %J J Clin Endocrinol Metab %D 2014 %T Exome sequencing identifies a novel homozygous mutation in the phosphate transporter SLC34A1 in hypophosphatemia and nephrocalcinosis. %A Rajagopal, Abbhirami %A Braslavsky, Débora %A Lu, James T %A Kleppe, Soledad %A Clément, Florencia %A Cassinelli, Hamilton %A Liu, David S %A Liern, Jose Miguel %A Vallejo, Graciela %A Bergadá, Ignacio %A Gibbs, Richard A %A Campeau, Phillipe M %A Lee, Brendan H %K Child %K Child, Preschool %K DNA Mutational Analysis %K Exome %K Female %K Humans %K Hypercalcemia %K Hypercalciuria %K Hypophosphatemia %K Male %K Mutation %K Nephrocalcinosis %K Parathyroid Hormone %K Pedigree %K Phenotype %K Sodium-Phosphate Cotransporter Proteins, Type IIa %X

CONTEXT: Two Argentinean siblings (a boy and a girl) from a nonconsanguineous family presented with hypercalcemia, hypercalciuria, hypophosphatemia, low parathyroid hormone (PTH), and nephrocalcinosis.

OBJECTIVE: The goal of this study was to identify genetic causes of the clinical findings in the two siblings.

DESIGN: Whole exome sequencing was performed to identify disease-causing mutations in the youngest sibling, and a candidate variant was screened in other family members by Sanger sequencing. In vitro experiments were conducted to determine the effects of the mutation that was identified.

PATIENTS AND OTHER PARTICIPANTS: Affected siblings (2 y.o. female and 10 y.o male) and their parents were included in the study. Informed consent was obtained for genetic studies.

RESULTS: A novel homozygous mutation in the gene encoding the renal sodium-dependent phosphate transporter SLC34A1 was identified in both siblings (c.1484G>A, p.Arg495His). In vitro studies showed that the p.Arg495His mutation resulted in decreased phosphate uptake when compared to wild-type SLC34A1.

CONCLUSIONS: The homozygous G>A transition that results in the substitution of histidine for arginine at position 495 of the renal sodium-dependent phosphate transporter, SLC34A1, is involved in disease pathogenesis in these patients. Our report of the second family with two mutated SLC34A1 alleles expands the known phenotype of this rare condition.

%B J Clin Endocrinol Metab %V 99 %P E2451-6 %8 2014 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/25050900?dopt=Abstract %R 10.1210/jc.2014-1517 %0 Journal Article %J N Engl J Med %D 2014 %T Genotype-phenotype correlation--promiscuity in the era of next-generation sequencing. %A Lu, James T %A Campeau, Philippe M %A Lee, Brendan H %K Exome %K Genetic Predisposition to Disease %K Genetic Testing %K Genome-Wide Association Study %K Genotype %K Genotyping Techniques %K High-Throughput Nucleotide Sequencing %K Humans %K Mutation %K Phenotype %K Polymorphism, Genetic %X

Newly cost-effective next-generation sequencing has led to an explosion of discoveries of novel genetic mutations that reveal the rampant "promiscuity" of genotype-phenotype relationships. Such discoveries should ultimately revolutionize clinical care.

%B N Engl J Med %V 371 %P 593-6 %8 2014 Aug 14 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/25119605?dopt=Abstract %R 10.1056/NEJMp1400788 %0 Journal Article %J Hum Mutat %D 2012 %T The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms. %A Campeau, Philippe M %A Lu, James T %A Dawson, Brian C %A Fokkema, Ivo F A C %A Robertson, Stephen P %A Gibbs, Richard A %A Lee, Brendan H %K Abnormalities, Multiple %K Base Sequence %K Blepharophimosis %K Blepharoptosis %K Craniofacial Abnormalities %K Databases, Nucleic Acid %K DNA %K Female %K Genetic Association Studies %K Haploinsufficiency %K Heart Defects, Congenital %K Histone Acetyltransferases %K Humans %K Intellectual Disability %K Kidney %K Male %K Molecular Sequence Data %K Mutation %K Patella %K Psychomotor Disorders %K Scrotum %K Sequence Deletion %K Urogenital Abnormalities %X

Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) have both recently been shown to be caused by distinct mutations in the histone acetyltransferase KAT6B (a.k.a. MYST4/MORF). All variants are de novo dominant mutations that lead to protein truncation. Mutations leading to GPS occur in the proximal portion of the last exon and lead to the expression of a protein without a C-terminal domain. Mutations leading to SBBYSS occur either throughout the gene, leading to nonsense-mediated decay, or more distally in the last exon. Features present only in GPS are contractures, anomalies of the spine, ribs and pelvis, renal cysts, hydronephrosis, and agenesis of the corpus callosum. Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities. Several features occur in both, such as intellectual disability, congenital heart defects, and genital and patellar anomalies. We propose that haploinsufficiency or loss of a function mediated by the C-terminal domain causes the common features, whereas gain-of-function activities would explain the features unique to GPS. Further molecular studies and the compilation of mutations in a database for genotype-phenotype correlations (www.LOVD.nl/KAT6B) might help tease out answers to these questions and understand the developmental programs dysregulated by the different truncations.

%B Hum Mutat %V 33 %P 1520-5 %8 2012 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/22715153?dopt=Abstract %R 10.1002/humu.22141 %0 Journal Article %J Am J Hum Genet %D 2012 %T Mutations in KAT6B, encoding a histone acetyltransferase, cause Genitopatellar syndrome. %A Campeau, Philippe M %A Kim, Jaeseung C %A Lu, James T %A Schwartzentruber, Jeremy A %A Abdul-Rahman, Omar A %A Schlaubitz, Silke %A Murdock, David M %A Jiang, Ming-Ming %A Lammer, Edward J %A Enns, Gregory M %A Rhead, William J %A Rowland, Jon %A Robertson, Stephen P %A Cormier-Daire, Valérie %A Bainbridge, Matthew N %A Yang, Xiang-Jiao %A Gingras, Marie-Claude %A Gibbs, Richard A %A Rosenblatt, David S %A Majewski, Jacek %A Lee, Brendan H %K Abnormalities, Multiple %K Animals %K Blepharophimosis %K Blepharoptosis %K Bone Diseases, Developmental %K Cerebellum %K Epigenomics %K Exome %K Female %K Heart Defects, Congenital %K Heterozygote %K Histone Acetyltransferases %K Humans %K Intellectual Disability %K Male %K Mice %K Mice, Inbred C57BL %K Musculoskeletal Abnormalities %K Mutation %K Phenotype %K Rubinstein-Taybi Syndrome %K Sequence Analysis, DNA %K Urogenital Abnormalities %X

Genitopatellar syndrome (GPS) is a skeletal dysplasia with cerebral and genital anomalies for which the molecular basis has not yet been determined. By exome sequencing, we found de novo heterozygous truncating mutations in KAT6B (lysine acetyltransferase 6B, formerly known as MYST4 and MORF) in three subjects; then by Sanger sequencing of KAT6B, we found similar mutations in three additional subjects. The mutant transcripts do not undergo nonsense-mediated decay in cells from subjects with GPS. In addition, human pathological analyses and mouse expression studies point to systemic roles of KAT6B in controlling organismal growth and development. Myst4 (the mouse orthologous gene) is expressed in mouse tissues corresponding to those affected by GPS. Phenotypic differences and similarities between GPS, the Say-Barber-Biesecker variant of Ohdo syndrome (caused by different mutations of KAT6B), and Rubinstein-Taybi syndrome (caused by mutations in other histone acetyltransferases) are discussed. Together, the data support an epigenetic dysregulation of the limb, brain, and genital developmental programs.

%B Am J Hum Genet %V 90 %P 282-9 %8 2012 Feb 10 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/22265014?dopt=Abstract %R 10.1016/j.ajhg.2011.11.023