title: The presence of two rare genomic syndromes, 1q21 deletion and Xq28 duplication, segregating independently in a family with intellectual disability.
abstract: BACKGROUND
  1q21 microdeletion syndrome is a rare contiguous gene deletion disorder withde novoor autosomal dominant inheritance patterns and its phenotypic features include intellectual disability, distinctive facial dysmorphism, microcephaly, cardiac abnormalities, and cataracts.MECP2duplication syndrome is an X-linked recessive neurodevelopmental disorder characterized by intellectual disability, global developmental delay, and other neurological complications including late-onset seizures. Previously, these two different genetic syndromes have not been reported segregating independently in a same family.
  
  
  METHODS
  Here we describe two siblings carrying either a chromosome 1q21 microdeletion or a chromosome Xq28 duplication. Using a comparative genomic hybridization (CGH) array, we identified a 1.24 Mb heterozygous deletion at 1q21 resulting in the loss of 9 genes in a girl with learning disability, hypothyroidism, short stature, sensory integration disorder, and soft dysmorphic features including cupped ears and a unilateral ear pit. We also characterized a 508 kb Xq28 duplication encompassingMECP2in her younger brother with hypotonia, poor speech, cognitive and motor impairment. The parental CGH and quantitative PCR (qPCR) analyses revealed that the 1q21 deletion in the elder sister isde novo, but the Xq28 duplication in the younger brother was originally inherited from the maternal grandmother through the mother, both of whom are asymptomatic carriers. RT-qPCR assays revealed that the affected brother has almost double the amount ofMECP2mRNA expression compared to other family members of both genders including maternal grandmother and mother who have the same Xq28 duplication with no phenotype. This suggests the X chromosome with an Xq28 duplication in the carrier females is preferentially silenced.
  
  
  CONCLUSIONS
  From our understanding, this would be the first report showing the independent segregation of two genetically unrelated syndromes, 1q21 microdeletion and Xq28 duplication, in a same family, especially in siblings. Although these two chromosomal abnormalities share some similar phenotypes such as intellectual disability, mild dysmorphic features, and cardiac abnormalities, the presence of two unrelated and rare syndromes in siblings is very unusual. Therefore, further comprehensive investigations in similar cases are required for future studies.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030 USA ; Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912 USA.
authors.forename: Kyungsoo
authors.initials: K
authors.lastname: Ha
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912 USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Graves
authors.affiliation: Department of Biology, Chungnam National University, Daejeon, 34134 South Korea.
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912 USA ; Department of Neuroscience and Regenerative Medicine, Augusta University, 1120 15th Street, Augusta, GA 30912 USA.
authors.forename: Hyung-Goo
authors.initials: HG
authors.lastname: Kim
keywords: 1q21 microdeletion; Intellectual disability; MECP2; Segregation of two rare syndromes; X chromosome inactivation; Xq28 duplication