While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.

Ephrin receptor and their ligands, the ephrins, are widely expressed in the developing brain. They are implicated in several developmental processes that are crucial for brain development. Deletions in genes encoding for members of the Eph/ephrin receptor family were reported in several neurodevelopmental disorders. The ephrin receptor A7 gene (EPHA7) encodes a member of ephrin receptor subfamily of the protein-tyrosine kinase family. EPHA7 plays a role in corticogenesis processes, determines brain size and shape, and is involved in development of the central nervous system. One patient only was reported so far with a de novo deletion encompassing EPHA7 in 6q16.1. We report 12 additional patients from nine unrelated pedigrees with similar deletions. The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance. Four patients had tiny deletions involving only EPHA7, suggesting a critical role of EPHA7 in a neurodevelopmental disability phenotype. We provide further evidence for EPHA7 deletion as a risk factor for neurodevelopmental disorder and delineate its clinical phenotype.

We present a patient with a 17.31 MB interstitial deletion of 6q16.3-6q22.31, who demonstrates a unique constellation of 6q- features. Among 6q- patients, he has limb reduction among the most severe reported, he is the second patient with duodenal atresia, and is the first documented case of diaphragmatic eventration.

Copy number variations play a significant role in the aetiology of developmental disabilities including non-syndromic intellectual disability and autism. We describe a 19-year old patient with intellectual disability and autism for whom chromosomal microarray (CMA) analysis showed the unusual finding of two de novo microdeletions in cis position on chromosome 6q16.1q16.2 and 6q16.3. The two deletions span 10 genes, including FBXL4, POU3F2, PRDM13, CCNC, COQ3 and GRIK2. We compared phenotypes of patients with similar deletions and looked at the involvement of the genes in neuronal networks in order to determine the pathogenicity of our patient's deletions. We suggest that both deletions on 6q are causing his disease phenotype since they harbour several genes which are implicated in pathways of neuronal development and function. Further studies regarding the interaction between PRDM13 and GRIK2 specifically may be interesting.

Obesity is a highly heritable but genetically heterogeneous disorder. Various well-known microdeletion syndromes (e.g. 1p36, 2q37, 6q16, 9q34, 17p11.2) can cause this phenotype along with intellectual disability (ID) and other findings. Chromosomal microarrays have identified 'new' microdeletion/duplication syndromes often associated with obesity. We report on 2 unrelated patients with an overlapping region of deletion at 1p21.3p21.2, and a third patient with a de novo recurrent unbalanced translocation der(8)t(8;12)(p23.1;p13.31), detected by 180K array CGH in a prospective cohort of syndromic obesity patients. Deletion of 1p21.3 is a rare condition, and there have been only 11 cases of the same recurrent translocation between chromosomes 8 and 12 [t(8;12)] reported to date. The former has been associated with ID, autistic spectrum disorder (ASD) and mild dysmorphic features, and in 4 patients who were obese or had a tendency to obesity, a minimal overlapping region of 2 genes, DPYD and MIR137, was detected; t(8;12) has recently been recognized to cause a childhood obesity syndrome due to duplication of the GNB3 gene. Thus, our findings add to the existing literature on the clinical description of these new syndromes, providing additional support that these loci are associated with syndromic obesity. We suggest that heterozygous loss of MIR137 may contribute to obesity as well as ID and ASD.