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Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray-based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6).

Thirty patients have been described with cytogenetically visible deletion of the short arm of chromosome 6. However, subtelomeric 6p deletion detected by subtelomeric specific probes has been reported only twice. We report two new patients with terminal 6p deletion detected by subtelomeric screening using fluorescence in situ hybridization (FISH). The two patients exhibited mental retardation, ocular abnormalities, hearing loss, and a characteristic facial appearance. Detailed FISH analyses with probes covering the distal 6p25 region estimated the size of the terminal deletions to approximately 5.5 Mb and approximately 4.8 Mb. Array-based comparative genomic hybridization (array CGH) was used to confirm the cryptic deletions. Most patients with subtelomeric defects lack a characteristic phenotype. However, some of the subtelomeric deletions result in a specific phenotype, which can direct the clinician towards the diagnosis. Submicroscopic 6p deletion appears to be a recognizable clinical phenotype, and this region should be thoroughly investigated with FISH probes, including at least a subtelomeric 6p probe and a probe covering FOXC1, for patients presenting with a characteristic facial appearance, ocular abnormalities, predominantly anterior-chamber eye defects, hearing loss, and mental retardation.

The Albright hereditary osteodystrophy-like (AHO-like) syndrome was recently defined as a rare dysmorphic syndrome including brachymetaphalangism and mental retardation. This phenotype occurs in Albright hereditary osteodystrophy (AHO) but unlike it, the level of the Gs alpha protein activity is not reduced. To date 59 patients with these clinical and biochemical features have been reported, and for the majority of them (57/59) a cytogenetically visible 2q37 deletion has been observed. We report a new case of typical AHO-like syndrome with normal karyotype. Using the polymorphic marker D2S125 we found a loss of heterozygosity suggestive of a de novo 2q37 deletion of maternal origin. This hypothesis was confirmed by FISH analysis with a subtelomeric 2q probe containing the D2S90 marker. Genotypic analysis allowed us to map the proximal breakpoint of the subtelomeric deletion within an interval delimited by D2S2338 (present) and D2S2253 (deleted). This 2q subtelomeric deletion as small as 4 Mb is to date the smallest one observed in association with a typical AHO-like phenotype, and allows us to move the centromeric boundary of the AHO-like critical region by 750 kb towards the 2q telomere.