title: A de novo 1.58 Mb deletion, including MAP2K6 and mapping 1.28 Mb upstream to SOX9, identified in a patient with Pierre Robin sequence and osteopenia with multiple fractures.
abstract: Defects of long-range regulatory elements of dosage-sensitive genes represent an under-recognized mechanism underlying genetic diseases. Haploinsufficiency of SOX9, the gene essential for development of testes and differentiation of chondrocytes, results in campomelic dysplasia, a skeletal malformation syndrome often associated with sex reversal. Chromosomal rearrangements with breakpoints mapping up to 1.6 Mb up- and downstream to SOX9, and disrupting its distant cis-regulatory elements, have been described in patients with milder forms of campomelic dysplasia, Pierre Robin sequence, and sex reversal. We present an ∼1.58 Mb deletion mapping ∼1.28 Mb upstream to SOX9 that encompasses its putative long-range cis-regulatory element(s) and MAP2K6 in a patient with Pierre Robin sequence and osteopenia with multiple fractures. Low bone mass panel testing using massively parallel sequencing of 23 nuclear genes, including COL1A1 and COL1A2 was negative. Based on the previous mouse model of Map2k6, suggesting that Sox9 is likely a downstream target of the p38 MAPK pathway, and our previous chromosome conformation capture-on-chip (4C) data showing potential interactions between SOX9 promoter and MAP2K6, we hypothesize that deletion of MAP2K6 might have affected SOX9 expression and contributed to our patient's phenotype.
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Smyk
authors.affiliation: Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, Texas.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Roeder
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Szafranski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
mesh_terms: D000293:Adolescent; D000328:Adult; D001851:Bone Diseases, Metabolic / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005260:Female; D050723:Fractures, Bone / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D048669:MAP Kinase Kinase 6 / Q000235:genetics*; D010855:Pierre Robin Syndrome; D011247:Pregnancy; D055758:SOX9 Transcription Factor / Q000235:genetics*; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human
keywords: chromatin looping; long distance gene regulation; low bone mass