Background: Syndromic obesity (SO) refers to obesity with additional phenotypes, including intellectual disability (ID)/developmental delay (DD), dysmorphic features, or organ-specific abnormalities. SO is rare, has high phenotypic variability, and frequently follows a monogenic pattern of inheritance. However, the genetic etiology of most cases of SO has not been elucidated. Subjects and methods: In this study, we investigated 20 SO patients by whole-exome sequencing (WES) trios to identify causal genetic variants. Results: 4/20 patients had negative results for array comparative genomic hybridization (aCGH) analyses. In the remaining 15 patients, in addition to SNVs and indels, CNVs were also evaluated. Pathogenic/likely pathogenic (P/LP) SNVs/indels were detected in 6/20 patients (involving MED13L, AHDC1, EHMT1, MYT1L, GRIA3, and SETD1A), while two patients carried an inherited VUS. In addition, P/LP CNVs were observed in 3/15 patients (involving SATG2, KIAA0442, and MEIS2). Conclusions: All nine detected P/LP variants involved genes already known to lead to syndromic ID/DD; however, for only two genes (EHMT1 and MYT1L) is the link with obesity well established. This is the first study applying a comprehensive genomic investigation of an SO cohort, showing a high diagnostic yield (~47%). Additionally, our findings suggested that several known ID/DD genes may also predispose individuals to SO.
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Data on the genetic variants relevant to this study are openly available in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/). Accession codes are given below: SCV002060423; SCV002060422; SCV002060421; SCV002060420; SCV002060419; SCV002060418; SCV001478246; SCV001432217.
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We are grateful to the families of patients involved in this study. We also thank the Xia-Gibbs Society (parent organization) and Dr. Richard Gibbs (Baylor College of Medicine - USA) for relevant communication. Additionally, it is important to thank Claudia Castro, Luceleni da Silva, Maraisa de Castro Sebastião, Mariana Barros, Dr. Naila Lourenço and Dr. Mustafa Zogbi for technical support. This study was supported by the São Paulo Research Foundation—FAPESP (2018/08486-3, 2012/50981-5, and 2013/08028-1), National Council for Scientific and Technological Development—CNPq (305806/2019-0) and Coordination for the Improvement of Higher Education Personnel—CAPES (1805008).
The authors declare no competing interests.
This research is in accordance with ethical standards established in the Declaration of Helsinki (1964), its subsequent revisions, and Resolution 466/2012 of the Brazilian National Health Council. The project was approved by the Research Ethics Committee of the Biosciences Institute of the University of São Paulo (CEP protocol — IBUSP 021/2004). Blood samples of the patients and their parents were collected after informed consent was signed.
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Carvalho, L.M.L., D’Angelo, C.S., Villela, D. et al. Genetic investigation of syndromic forms of obesity. Int J Obes (2022). https://doi.org/10.1038/s41366-022-01149-5