615 - Screening for Rare Genetic Diseases of Obesity in Children

Rare genetic variants in the MC4R pathway that regulates central control over hunger can lead to early onset severe obesity regardless of environmental factors or association with syndromic features. Genetic screening is recommended for individuals with clinical features of genetic obesity syndromes or early onset severe obesity.

Objective:

Identify genetic variants in our cohort of pediatric patients with early onset obesity, irrespective of their clinical presentation (hyperphagia, developmental delay, etc).

Design/Methods:

We report 20 patients with severe obesity (BMI >97%) screened using Rhythm® Genetics Test panel from 2021-22, through Uncovering Rare Obesity® program. This is a clinically approved free buccal test targeting 79 genes and 1 chromosomal region. Medical records were reviewed for all 20 patients to include demographic, clinical features, anthropometrics and labs.

Results:

Of the 20 patients, 13 (65%) consisting of 7 females and 6 males were positive for genetic variants (table 1), many of them are variants of uncertain significance (VUS). All variants were heterozygous. Single genetic variant was detected in 6 (46%) patients, while 7 (53%) had 2-3 variants. Except for MC4R likely pathogenic, all reported were VUS due to absence of conclusive functional and genetic evidence. The most frequently noted clinical feature was autistic spectrum disorder with learning disability in 5 (38%) followed by extreme hyperphagia  in 3 (23%).

PCNT is the most common variant detected in 4 (30%), followed by SEMA3 in 3 (23 %), MC4R in 2 (15%), BBS in 2 (15%), SDCCAG8 in 2 (15%) and PLXNA1 in 2 (15%). Pathogenic variants of PCNT are associated with microcephalic osteodysplastic primordial dwarfism type II, and intracranial aneurysm/subarachnoid hemorrhage, while MC4R variant is associated with severe early-onset obesity with hyperphagia, increased linear growth, hyperinsulinemia and preserved reproductive function. SDCCAG8 have been associated with Bardet-Biedl syndrome 16 and Senior-Loken syndrome 7. Lastly, PLXNA1 has been reported in individuals with developmental delay and autism spectrum disorder.

Conclusion(s):

Targeted genetic screening for children with early onset obesity is easy, free and clinically important in detecting variants that could explain patient’s early onset obesity.  Since introduction into our clinical practice, we were able to identify a likely pathogenic variant in MC4R to guide subsequent therapy. A majority of patients had one or more variants of uncertain significance which warrants further investigation.