Gain of <b><i>FAM123B</i></b> and <b><i>ARHGEF9 </i></b>in an Obese Man with Intellectual Disability, Congenital Heart Defects and Multiple Supernumerary Ring Chromosomes

Abstract

In a 24-year-old man with mild intellectual disability, congenital heart defects and obesity, we identified up to 4 small supernumerary marker chromosomes (sSMCs) in blood metaphases. The ring-shaped sSMCs were derived from chromosomes 11, 12 and X as well as a fourth, unidentified chromosome. In interphase nuclei of epithelial cells from the urinary tract and buccal mucosa, the presence of the r(11), r(12) and r(X) was confirmed by FISH. Using Illumina Infinium 317K SNP-arrays, we detected 3 copies of the pericentromeric regions of chromosomes 11, 12 and X. The r(X) was present in 84–89% of cells in the various tissues examined, lacks the XIST gene, but contains FAM123B, a potential dosage-sensitive candidate gene for congenital cardiac abnormalities, and ARHGEF9, a candidate gene for intellectual disability. ARHGEF9 encodes collybistin (CB), which is required for localization of the inhibitory receptor-anchoring protein gephyrin and for formation and maintenance of postsynaptic GABA_A and glycine receptors. We propose that the 2-fold increase in dosage of ARHGEF9 disturbs the stoichiometry of CB with its interacting proteins at inhibitory postsynapses. SNP alleles and short tandem repeat markers on the r(11) and r(X) were compatible with a maternal origin of both sSMCs through a meiosis II error. The sSMCs may have resulted from predivision chromatid nondisjunction, leading to anaphase lagging, followed by incomplete degradation of the supernumerary chromosomes.

Multiple Small Supernumerary Marker Chromosomes Resulting from Maternal Meiosis I or II Errors

“…Our marker segregation data are compatible with a maternal origin of the multiple sSMCs in both the prenatal and the postnatal case. We propose, based on the cases described here and previously [Kogan et al, 2009;Hochstenbach et al, 2013], that multiple sSMCs arise through different types of subsequent segregation errors that affect multiple, different chromosomes during maternal meiosis I, II or both. A postzygotic origin of the multiple sSMCs during the cleavage stage divisions of the embryo cannot be completely excluded in the cases in which the segregation of the markers is consistent with a maternal meiosis II error.…”

“…In a previously reported case, we also found 2: 1 ratios for the STR markers on a maternally derived sSMC(11) and sSMC(X), indicating that both resulted from a meiosis II error. There were no informative markers on an sSMC(8) in this case [Hochstenbach et al, 2013]. Additional cases must be investigated to confirm the proposed model and its predictions.…”

“…The mechanism and parental origin have been ascertained by molecular approaches in only 4 patients. In a previous study, we showed that an sSMC(11) and an sSMC(X) in a man with obesity, congenital heart defect and moderate intellectual disability were maternally derived and originated from a meiosis II error [Hochstenbach et al, 2013]. In a boy with developmental delay, autism, verbal apraxia, and mild dysmorphic features, a maternal origin of both sSMC(13) and sSMC(17) was demonstrated as well [Kogan et al, 2009].…”

Molecular Cytogenetic Diagnostics of Marker Chromosomes: Analysis in Four Prenatal Cases and Long-Term Clinical Evaluation of Carriers

“…Generally, aCGH is useful in the specification of genes present on the sSMC, which may have prognostic consequences if any of them is dosage sensitive. Single nucleotide polymorphism arrays (SNPa) could be used for uniparental disomy (UPD) testing and assessment of the parental origin of the amplified material in one step and thus shed light onto the mechanism of formation of the sSMC as shown by Hochstenbach et al [2013]. If SNPa is not used, UPD testing using other methods should be performed at least for sSMCs derived from chromosomes with known imprinted loci, i.e., derivatives of chromosomes 6, 7, 11, 14, 15, and 20 [Mackay and Temple, 2017], which are also among those most frequently reported in association with UPD (chromosomes 6, 7, 14, 15, 16, and 20) [Liehr et al, 2011].…”

Neocentromeres to the Rescue of Acentric Chromosome Fragments

“…Ascertainment of sSMCs requires classical karyotyping followed by detailed molecular cytogenetic analyses, such as FISH and array CGH [Murmann et al, 2009;Burnside et al, 2011;Hochstenbach et al, 2013Hochstenbach et al, , 2016Hochstenbach et al, , 2017. Thus, sSMCs were found in 0.043% of live births [Liehr et al, 2004].…”