Learning disabilities (LDs) are a clinically and genetically heterogeneous group of diseases. Array-CGH and high-throughput sequencing have dramatically expanded the number of genes implicated in isolated intellectual disabilities and LDs, highlighting the implication of neuron-specific post-mitotic transcription factors and synaptic proteins as candidate genes. We report a unique family diagnosed with autosomal dominant learning disability and a 6p21 microdeletion segregating in three patients. The 870 kb microdeletion encompassed the brain-expressed gene LRFN2, which encodes for a synaptic cell adhesion molecule. Neuropsychological assessment identified selective working memory deficits, with borderline intellectual functioning. Further investigations identified a defect in executive function, and auditory-verbal processes. These data were consistent with brain MRI and FDG-PET functional brain imaging, which, when compared with controls, revealed abnormal brain volume and hypometabolism of gray matter structures implicated in working memory. We performed electron microscopy immunogold labeling demonstrating the localization of LRFN2 at synapses of cerebellar and hippocampal rat neurons, often associated with the NR1 subunit of N-methyl-D-aspartate receptors (NMDARs). Altogether, the combined approaches imply a role for LRFN2 in LD, specifically for working memory processes and executive function. In conclusion, the identification of familial cases of clinically homogeneous endophenotypes of LD might help in both the management of patients and genetic counseling for families.

It has recently been suggested that working memory could be conceived as two symmetrical subsystems with analogous structure and processing principles: a declarative working memory storing objects of thought available for cognitive operations, and a procedural working memory holding representations of what to do with these objects (Oberauer, Psychology of learning and motivation 51: 45-100, 2009). Within this theoretical framework, the two subsystems are thought to be independent and fueled by their own capacity. The present study tested this hypothesis through two experiments using a complex span task in which participants were asked to maintain consonants for further recall while performing response selection tasks. In line with Oberauer's conception, the load of the procedural working memory was varied by manipulating the number of stimulus-response mappings of the response selection task. Increasing the number of these mappings had a strong detrimental effect on recall performance. Besides contradicting Oberauer's proposal, this finding supports models that assume a resource-sharing between processing and storage in working memory.

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