title: Multiple Small Supernumerary Marker Chromosomes Resulting from Maternal Meiosis I or II Errors.
abstract: We present 2 cases with multiple de novo supernumerary marker chromosomes (sSMCs), each derived from a different chromosome. In a prenatal case, we found mosaicism for an sSMC(4), sSMC(6), sSMC(9), sSMC(14) and sSMC(22), while a postnatal case had an sSMC(4), sSMC(8) and an sSMC(11). SNP-marker segregation indicated that the sSMC(4) resulted from a maternal meiosis II error in the prenatal case. Segregation of short tandem repeat markers on the sSMC(8) was consistent with a maternal meiosis I error in the postnatal case. In the latter, a boy with developmental/psychomotor delay, autism, hyperactivity, speech delay, and hypotonia, the sSMC(8) was present at the highest frequency in blood. By comparison to other patients with a corresponding duplication, a minimal region of overlap for the phenotype was identified, with CHRNB3 and CHRNA6 as dosage-sensitive candidate genes. These genes encode subunits of nicotinic acetylcholine receptors (nAChRs). We propose that overproduction of these subunits leads to perturbed component stoichiometries with dominant negative effects on the function of nAChRs, as was shown by others in vitro. With the limitation that in each case only one sSMC could be studied, our findings demonstrate that different meiotic errors lead to multiple sSMCs. We relate our findings to age-related aneuploidy in female meiosis and propose that predivision sister-chromatid separation during meiosis I or II, or both, may generate multiple sSMCs.
authors.affiliation: Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Hochstenbach
authors.affiliation: Department of Medical Genetics, Institute of the Mother and Child, Warsaw, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Nowakowska
authors.affiliation: Department of Human Genetics, Magdeburg, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Volleth
authors.affiliation: Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Amber
authors.initials: A
authors.lastname: Ummels
authors.affiliation: Department of Medical Genetics, Institute of the Mother and Child, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kutkowska-Kaźmierczak
authors.affiliation: Department of Medical Genetics, Institute of the Mother and Child, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Obersztyn
authors.affiliation: Department of Medical Genetics, Institute of the Mother and Child, Warsaw, Poland.
authors.forename: Kamila
authors.initials: K
authors.lastname: Ziemkiewicz
authors.affiliation: University Women's Clinic, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gerloff
authors.affiliation: Department of Human Genetics, Magdeburg, Germany.
authors.forename: Denny
authors.initials: D
authors.lastname: Schanze
authors.affiliation: Department of Human Genetics, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: Department of Human Genetics, Magdeburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Muschke
authors.affiliation: Department of Human Genetics, Magdeburg, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Schanze
authors.affiliation: Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Poot
authors.affiliation: Department of Human Genetics, University Clinic, Jena, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Liehr
keywords: CHRNA6; CHRNB3; Dominant negative effect; Maternal meiotic segregation error; Mental retardation; Multiple supernumerary marker chromosomes; Nicotinic acetylcholine receptors; Predivision chromatid separation