Syndromic and monogenic obesity: Is clinical exome sequencing necessary?

Hatice Nursoy; Yasemin Denkboy-Ongen; Meltem Buhur-Pirimoglu; Erdal Eren

Introduction: Syndromic and monogenic obesities are rare and may have different treatment challenges and options. Patients with POMC, PCSK1, and LEPR mutations can receive setmelanotide therapy. Setmelanotide acts on the melanocortin 4 receptor. Here, as a participant in the Rare Obesity Advanced Diagnosis Project, the results of our patient data are presented.

Method: Patients who became obese before the age of 5 and/or patients with syndromic features accompanying obesity (urinary anomalies, infantile hypotonia, developmental delay, polydactyly) were included in the study. DNA samples are collected as buccal swap between January 2023 and April 2024. Eighty genes were studied from these samples. Reports were classified as pathogenic, likely pathogenic, and VUS variants or no pathogenic variant was detected. Some VUS, likely benign or benign, were also reported as "potentially relevant variants."

Results: 29 patients aged between 3 and 19.9 years were included in the study. Their median BMI was 32.27 (min:20.37, max:54.65), and the median BMI SDS was 3.27 (min:1.98, max: 6.8). Ten patients had clinically significant variants (Table 1). Patient 6 had a homozygote LEPR mutation and was a candidate for setmelanotide treatment. Patient 1 was diagnosed with Bardet-Biedl Syndrome. His clinical evaluation has been expanded.

Conclusion: Selected patients may benefit from clinical exome sequencing for obesity.

Table 1. Rare obesity panel; clinically relevant pathogenic, likely pathogenic, VUS variants and patient's clinical features
	Gene	Description	Zygosity	Variant status	Gender	Expected clinical features*	Patient’s clinical features
Patient 1	BBS1	c.48-1G>A	Homozygote	Pathogenic	Male	Cliopathy, retinitis pigmentosa, Bardet Biedl syndrome	Polidacthly, obesity, intellectual disability
Patient 2	seq[GRCh37] del(16)(p11.2)	Chr16:g.29548560_30292931del	Heterozygote	Pathogenic	Male	İntellectual disability, obesity, glomerulopathy	Obesity, glomerulopathy
Patient 3	MAGEL2	c.290dup	Heterozygote	Pathogenic	Male	Prader Willi Syndrome, autism, Schaaf-Yang Syndrome	Obesity, hyperphagia, intellectual disability, epilepsy, infantile hypotonia
Patient 4	MC4R	c.380C>T	Heterozygote	Pathogenic	Female	Obesity	Obesity
Patient 5	GNAS	c.682C>T	Heterozygote	Pathogenic	Male	Disorder of GNAS inactivation, pseudohypoparathyroidism	Obesity, hypothyroidism
Patient 6	LEPR	c.2929G>T	Homozygote	Likely pathogenic	Male	Obesity	Obesity
Patient 7	TBX3	c.1267T>G	Heterozygote	VUS	Male	Ulnar-Mammary Syndrome; Skeletal anomalies, delayed puberty, genital anomaly, obesity	Obesity, developmental delay, infantile hypotonia
Patient 8	NR0B2	c.134G>C	Heterozygote	VUS	Female	Obesity	Obesity
Patient 9	PHIP	c.4895C>T	Heterozygote	VUS	Female	Behavioral problems, intellectual disability, obesity, dysmorphic features	Obesity
Patient 10	CREBBP / MECP2	c.7162G>A/c.1040_1063del	Heterozygote/Heterozygote	VUS/VUS	Female	Rubinstein-Tayvi Syndrome Obesity after puberty/Rett Syndrome	Obesity, hyperphagia, developmental delay, infantile hypotonia
*From https://franklin.genoox.com/ and https://www.omim.org/

Keywords: POMC, PCSK1, LEPR, setmelanotide

ESPE Abstracts

P3-106