Gain of FAM123B and ARHGEF9 in an Obese Man with Intellectual Disability, Congenital Heart Defects and Multiple...

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 GABAA 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.