Identifying candidate genes and subsequently attributing their biological function(s) to specific clinical phenotypes remains an enduring challenge in medical genetics. During the past decades refinements in clinical phenotyping concomitantly with ever increasing resolution of classical karyotyping, fluorescence in situ hybridization, arrayand next-generation-based methods have allowed us to pinpoint ever more specific ‘‘deletion syndromes’’ in the human genome. Research and clinical diagnosis progressed from early detection of losses of small parts of chromosome1q [Johnson et al., 1985;Meinecke andVogtel, 1987] to the more circumscribed ‘‘1q44 deletion syndrome De Vries et al. [2001].’’ This subsequently needed refinement in view of new patients which no longer conformed to the early pattern of the ‘‘1q44 deletion syndrome’’ [Gentile et al., 2003; van Bever et al., 2005; Poot et al., 2007; Hill et al., 2007; Merritt et al., 2007]. In a second wave of research cohorts of patients were compared to derive a minimal region of phenotypic and genotypic overlap [Boland et al., 2007; van Bon et al., 2008; Caliebe et al., 2010]. Boland et al. [2007], thus identified the serine/threonine kinase AKT3 as a candidate gene for microcephaly and agenesis of the corpus callosum.The series of patients investigated by vanBon et al. [2008] and Caliebe et al. [2010], however, carried losses in 1q44, which did not overlap with AKT3. This finding challenged the notion that haploinsufficiency for AKT3 would lead to microcephaly associated with an abnormal corpus callosum [Poot et al., 2008]. It does not exclude, however, that a combination of a hemizygous loss of and a mutation in the AKT3 gene would be pathogenic. This, in turn, may explain the variability of the corpus callosum phenotype in particular among patients with 1q44 losses [Poot et al., 2011a]. Sequencing AKT3 in 66 patients with an abnormal corpus callosum did not reveal any mutations [Boland et al., 2007; van Bon, 2008].Meanwhile,AKT3mutations have been described in two sporadic cortical malformation disorders: hemimegalencephaly [Lee et al., 2012] and themegalencephaly-capillary malformation and megalencephaly-polymicrogyria-polydactylyhydrocephalus syndromes [Rivi ere et al., 2012]. These findings allow to pinpoint a role of AKT3 in cortical development, which goes well beyond the realm of 1q44 deletions. After trying to find a minimal region of overlap, scientists followed a converse approach, that is, linking individual genes to specific phenotypes in larger series of patients with different 1q44 losses andmore diverging combinations of phenotypes [Ballif et al., 2012; Thierry et al., 2012]. By comparing published cases with 22 new patients with 1q44 deletions Ballif et al. [2012] discerned three critical regions within 1q44. The most proximal, containing only AKT3, was linked to microcephaly, a second region, confined to ZNF238, was connected to an abnormal corpus callosum, and a third region, covering FAM36A, C1orf199, and HNRNPU, was thought to be responsible for the seizure phenotype of deletion 1q44 patients. In an independent series of 11 patients, Thierry et al. [2012] identified a slightly larger region, containing FAM36A, C1orf199, andHNRNPU and one exon of EFCAB21, as a candidate for intellectual delay and seizures in their patients. The authors did not find any potentially pathogenic HNRNPU mutations in 191 patients with intellectual delay of whom 112 were diploid for their entire genome [Thierry et al., 2012]. Recombinant inbred mouse strains represent a resource to identify eQTLs for phenotypes such as strain variation in neuro-anatomical structures. Using this resource, cross-species analysis revealed an association between HNRNPU genetic variation and corpus callosum integrity inmouse and human, suggesting that neurodevelopmental processes underlying corpus callosumdevelopmentmay be evolutionary conserved