Genetic investigation of syndromic forms of obesity

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Lara Carvalho, Laura Machado ; D'Angelo, Carla Sustek ; Villela, Darine ; da Costa, Silvia Souza ; de Lima Jorge, Alexander Augusto ; da Silva, Israel Tojal ; Scliar, Marilia de Oliveira ; Chaves, Luiza Dias ; Victorino Krepischi, Ana Cristina ; Koiffmann, Celia Priszkulnik ; Rosenberg, Carla

• Document type: Journal article
• Source: International Journal of Obesity; v. N/A, p. 5-pg., 2022-05-21.

Abstract

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, GR1A3, and SETD1A), while two patients carried an inherited VUS. In addition, P/LP CNVs were observed in 3/15 patients (involving SATG2, KlAA0442, and ME1S2). 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. (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 18/08486-3 - Genetic bases of Syndromic Obesity and molecular mechanisms involved in its physiopathology
• Grantee: Laura Machado Lara Carvalho
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 12/50981-5 - High resolution genomic arrays and next generation sequencing in mental deficiency and congenital anomalies diagnosis
• Grantee: Francine Campagnari Guilhem
• Support Opportunities: Research Grants - Innovative Research in Small Business - PIPE