Updates on Rare Genetic Variants, Genetic Testing, and Gene Therapy in Individuals With Obesity

Abstract

Purpose of review: The goal of this paper is to aggregate information on monogenic contributions to obesity in the past five years and to provide guidance for genetic testing in clinical care.

Recent findings: Advances in sequencing technologies, increasing awareness, access to testing, and new treatments have increased the utilization of genetics in clinical care. There is increasing recognition of the prevalence of rare genetic obesity from variants with mean allele frequency < 5% -new variants in known genes as well as identification of novel genes- causing monogenic obesity. While most of these genes are in the leptin melanocortin pathway, those in adipocytes may also contribute. Common variants may contribute either to higher lifetime tendency for weight gain or provide protection from monogenic obesity. While specific genetic mutations are rare, these segregate in individuals with early-onset severe obesity; thus, collectively genetic etiologies are not as rare. Some genetic conditions are amenable to targeted treatment. Research into the discovery of novel genetic causes as well as targeted treatment is growing over time. The utility of therapeutic strategies based on the genetic risk of obesity is an advancing frontier.

Keywords: Genetic testing; Genetics; Monogenic obesity; Precision medicine; Severe obesity.

Figure 1

A. Considerations for assigning possible causal genes for the phenotype of interest. B. Considerations for investigating the causality of identified variants. Both guidelines were defined according to the American College of Medical Genetics (ACMG) 2015 guidelines. C. Pedigree examples for various modes of inheritance illustrating the use of the segregation to assess variant pathogenicity. The coloring of the symbols represents the phenotype; black represents Class 2 obesity or higher (BMI ≥ 120% of the 95^th percentile for individuals < 18 years of age and ≥ 40 kg/m² for individuals ≥ 18 years of age), and gray represents overweight and Class 1 obesity (BMI between the 85^th and 120% of the 95^th percentile for individuals < 18 years of age or BMI 25-35 kg/m² for those ≥ 18 years of age). The variant information is reported, and segregation details where available. Pedigree 1: Autosomal dominant inheritance of the SIM1 variant. The patient is a 17-year-old black female with severe early-onset obesity. The variant was found de novo in the mother, who also has severe obesity and a BMI of 55 kg/m². Maternal grandparents are negative for the variant. The proband has no dysmorphism or developmental delay. Both the mother and daughter had short stature. Gene and transcript: SIM1, NM_005068.2. Pedigree 2: Autosomal recessive inheritance of the homozygous LEPR variant in a family without known nonconsanguinity. A 5-year-old Hispanic female with severe early-onset obesity. The parents were heterozygous for the variant without severe obesity. The proband has no dysmorphism or negative delay. Motor milestones are likely delayed due to significant obesity. Gene and transcript: LEPR, NM_002303.5. Pedigree 3: Compound heterozygous inheritance of MC4R variants. A 7-year-old white female from the Ashkenazi Jewish community with severe early-onset obesity-paternal variant (c.750_751del) was also present in sibling #1, and the maternal variant (c.873_875del) was also present in sibling #2. Sibling #5 inherited neither variant with no obesity. These two variants of MC4R are commonly observed in the Ashkenazi Jewish community, and many family members have obesity and have undergone metabolic and bariatric surgery (MBS). Gene and transcript: MC4R, NM_005912.2. Pedigree 4: Noncausal variants in two BBS genes inherited from mother. A 16-year-old Hispanic male with severe early-onset obesity and type 2 diabetes. Variants in BBS1 and BBS9 were inherited from mother with severe obesity who also had type 2 diabetes. As both of these variants are inherited from the mother, they are unlikely to be causal for obesity, although both the mother and the child have this phenotype. The etiology of obesity in this family currently remains unknown. The CEP290 variant is common in the population, is detected in unaffected sibling and is unlikely to contribute to the overall presentation. gnomAD: Allele frequency registered in a large population database(gnomad.broadinstitute.org). Value listed is the highest allele frequency reported within one of seven population categories recognized in gnomAD v.2.0 (“Other” population is excluded). Missense predictions: Summarized output (Damaging, Conflicting, or Tolerated) via PolyPhen-2, FIGT, MutationTaster, and FATHMM. Abbreviation: MBS, metabolic and bariatric surgery