Obesity with associated developmental delay and/or learning disability in patients exhibiting additional features: Report of novel pathogenic copy number variants

Abstract

Obesity is a major threat to public health worldwide, and there is now mounting evidence favoring a role for the central nervous system (CNS) in weight control. A causal relationship has been recognized in both monogenic (e.g., BDNF, TRKB, and SIM1 deficiencies) and syndromic forms of obesity [e.g., Prader-Willi syndrome (PWS)]. Syndromic obesity arising from chromosomal abnormalities, that typically also affect learning and development, are often associated with congenital malformations and behavioral characteristics. We report on nine unrelated patients with a diagnosis of learning disability and/or developmental delay (DD) in addition to obesity that were found to have copy number variants (CNVs) by single nucleotide polymorphism array-based analysis. Each patient also had a distinct and complex phenotype, and most had hypotonia and other neuroendocrine issues, such as hyperphagia and hypogonadism. Molecular and clinical characterization of these patients enabled us to determine with confidence that the CNVs we observed were pathogenic or likely to be pathogenic. Overall, the CNVs reported here encompassed a candidate gene or region (e.g., SIM1) that has been reported in patients associating obesity and DD and/or intellectual disability (ID) and novel candidate genes and regions.

Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity

“…1,2,11,14,16 Obesity or overweight is noted in 17 patients (10 of 14 patients with a deletion, 5 of 6 with a duplication, and 2 of 2 with a point mutation) and has an onset during (late) childhood (Supplementary Table S1 online). Other prevalent symptoms are a wide range of behavioral problems (11 of 14 patients with a deletion, 6 of 6 with a duplication, and 2 of 2 with a point mutation), such as aggressive, autistiform, and hyperactive behavior; stereotypic hand movements; and sleep disturbances.…”

“…[21][22][23] It was suggested that perturbed TMEM18 expression in the brain, and particularly in the hypothalamus, would translate into aberrant feeding behavior. Doco-Fenzy et al 2 and d' Angelo et al 16 reported a total of six patients carrying 2p25.3 deletions who had ID associated with obesity. It is interesting to note that in the five patients with a deletion reported by Doco-Fenzy et al, all deletions resided on the paternal allele, suggesting a paternal effect.…”

“…This cohort consists of 13 sporadic patients with 2p25.3 deletions (patients 1-10) or duplications (patients 11-13); two cases with a de novo MYT1L mutation (patients 14 and 15), of which one was identified in a previous study 4 ; and two families with a 2p25.3 chromosomal aberration. Family 1 comprises three affected siblings and their father (patients [16][17][18][19], and family 2 includes two affected children and their father (patients [20][21][22]. Informed consent was obtained from all patients, and institutional approval was given by the local medical ethical committee.…”

“…Using genomic microarrays, a deletion involving chromosome band 2p25.3 was detected in 14 patients, that is, 10 sporadic patients (patients 1-10) and the four members of family 1 (patients [16][17][18][19]. The aberrations range in size from 120 kb to 6.07 Mb and contain 1-16 genes (Figure 2).…”

Análise cromossômica por microarray em pacientes com deficiência intelectual associada à obesidade

“…A obesidade frequentemente está associada a outras alterações, incluindo malformações congênitas, dismorfias, distúrbios comportamentais e deficiência intelectual (6,11,12). Já foram descritas na literatura mais de 30 síndromes relacionadas à obesidade, entretanto a etiologia da maior parte dos casos permanece desconhecida (3,12).…”