A Loss or a Gain, Is It Not All the Same

morphism in the general population and provokes no phenotype [Tam et al., 2008]. This indicates that severance of the WBS locus within 7q11.23 by a genomic rearrangement would not disrupt a putative transcription-associated domain [Spielmann and Klopocki, 2013; Spielmann and Mundlos, 2013; Poot and Haaf, 2015]. Being flanked by blocks of inverted low copy repeats, the WBS locus within the 7q11.23 region often gives rise to ring(7) chromosomes [Velagaleti et al., 2002]. Patients with a supernumerary ring(7) share speech difficulties, irrespective of whether the ring(7) is present in 100% of the cells or as a highor low-grade mosaicism [Lichtenbelt et al., 2005]. For a girl with a ring(7) between 12 and 22 Mb in size and present in 50% of lymphocytes, the authors searched for potential candidate genes that may account for her problems with speech acquisition. Bearing in mind that candidate genes should be dosage-sensitive, they pinpointed 2 genes: STX1A and LIMK1 . This reasoning was supported by functional data. The STX1A geneencoded syntaxin protein mediates vesicle docking, fusion, and neurotransmitter release. Overexpression of STX1A reduces the nerve growth factor-induced neurite extension in vitro [Zhou et al., 2000]. The LIMK1 and LIMK2 genes encode kinases that regulate actin dynamics by phosphorylating cofilin and thus affect neuronal function, neurodevelopment and synaptic plasticity [Cuberos et al., 2015]. Given that this patient carried a 50% mosaicism for ring(7), an increase of only 25% of syntaxin protein and/or LIMK1-encoded kinase activity would be sufficient to account for her clinical phenotypes [Lichtenbelt et al., 2005]. The human genome contains numerous loci of which losses or gains provoke clinical phenotypes, albeit often of quite a different nature. Apparently, the genes within these loci have to exist in exactly 2 copies. If there are 3 copies, due to a duplication, or only 1 copy, after a deletion, genes within the locus may exert ‘dosage-sensitive’ effects. This can only be the case if both alleles are being transcribed. If transcripts and proteins of only one copy were to be produced, this would result in haploinsufficiency. Also in the reciprocal situation, in which the cell transcribes 3 copies, transcript imbalance may arise. The gene dosage balance hypothesis provides a molecular framework for how genes encoding transcription factors and proteins involved in signal transduction and macromolecular complexes in general may cause clinical phenotypes [Veitia and Birchler, 2010; Poot et al., 2011]. Disorders resulting from losses or gains of dosage-sensitive genes often show remarkable phenotypic variability. Within the region 7q11.23, a loss causes WilliamsBeuren syndrome (WBS; OMIM 194050) and a duplication results in the 7q11.23 duplication syndrome (Dup7; OMIM 609757) [Osborne and Mervis, 2007]. The WBS is characterized by mild to moderate intellectual disability or learning difficulties, with relative cognitive abilities in verbal short-term memory and in language use but weaknesses in visuospatial construction, anxiety, attention deficit hyperactivity disorder, and social disinhibition. Patients with Dup7 syndrome show severely delayed speech and expressive language acquisition but relative good visuospatial functioning. A common inversion within the 7q11.23 region, WBSinv-1, exists as a polyAccepted: November 16, 2015 by M. Schmid Published online: February 5, 2016