title: Expanding the MYBPC1 phenotypic spectrum: a novel homozygous mutation causes arthrogryposis multiplex congenita.
abstract: Arthrogryposis multiplex congenita (AMC) is characterized by heterogeneous nonprogressive multiple joint contractures appearing at birth. We present a consanguineous Israeli-Druze family with several members presenting with AMC. A variable intra-familial phenotype and pected autosomal recessive inheritance prompted molecular diagnosis by whole-exome sequencing. Variant analysis focused on rare homozygous changes, revealed a missense variant in MYBPC1, NM_002465:c.556G>A (p.E286K), affecting the last nucleotide of Exon 8. This novel variant was not observed in the common variant databases and co-segregated as expected within the extended family. MYBPC1 encodes a slow skeletal muscle isoform, essential for muscle contraction. Heterozygous mutations in this gene are associated with distal arthrogryposis types 1b and 2, whereas a homozygous nonsense mutation is implicated in one family with lethal congenital contractural syndrome 4. We present a novel milder MYBPC1 homozygous phenotype.
authors.affiliation: The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Ekhilevitch
authors.affiliation: The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Kurolap
authors.affiliation: The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Oz-Levi
authors.affiliation: The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Mory
authors.affiliation: The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Hershkovitz
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: G
authors.initials: G
authors.lastname: Ast
authors.affiliation: Metabolic Unit, Rambam Health Care Campus, Haifa, Israel.|Rappaport School of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Mandel
authors.affiliation: The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.|Rappaport School of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
authors.forename: H N
authors.initials: HN
authors.lastname: Baris
mesh_terms: D001176:Arthrogryposis / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D003241:Consanguinity; D005006:Ethnicity; D059472:Exome; D005091:Exons; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007223:Infant; D007557:Israel; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C
keywords: MYBPC1; arthrogryposis multiplex congenita; contractures; exome sequencing