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Genetics and Epigenetics

Genetic investigation of syndromic forms of obesity


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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Fig. 1: Genetic investigation workflow of SO etiology in our cohort and positive results distribution.

Data availability

Data on the genetic variants relevant to this study are openly available in 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).

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Authors and Affiliations



CR and CPK conceived and designed the study. CPK, LMLC, and CSD performed the research subject selection. LMLC performed the NGS data analysis and interpretation of genetic variants under the guidance of CR, AK, and DV. SSC and LDC provided relevant technical support. AALJ made important contributions to the discussion of the results. ITS and MOS contributed to bioinformatics processing (alignment to the reference genome and calling of variants). LMLC was responsible for the initial writing of the manuscript and produced the figures and tables under the guidance of CR and AK. All authors have read, edited, and approved the final manuscript.

Corresponding author

Correspondence to Carla Rosenberg.

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The authors declare no competing interests.

Ethical approval

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).

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