medwireNews: A study of children from Qatar with severe early-onset obesity suggests that around 15% of cases may be explained by rare genetic variants within the leptin–melanocortin pathway and other signalling pathways.
Khalid Hussain, from Sidra Medicine in Doha, Qatar, and colleagues used a targeted gene panel to screen for possible genetic causes in 138 boys and 106 girls with a body mass index (BMI) in at least the 95th percentile and obesity onset before the age of 10 years. Overall, 68% of the group had signs of obesity between the ages of 3 months and 5 years.
The majority (64.6%) of patients were Qatari and the remainder had other Middle Eastern backgrounds, the researchers write in The Journal of Clinical Endocrinology & Metabolism.
Next-generation sequencing (NGS) was performed for 52 genes associated with energy homeostasis and adipose tissue proliferation and this identified 30 variants in 15 genes, including the melanocortin 4 receptor (MC4R), leptin (LEP), the leptin receptor (LEPR), retinoic acid induced 1 (RAI1) and Bardet–Biedl syndrome 2 (BBS2). The remaining affected genes were POMC, MC3R, MRAP2, SH2B1, BDNF, NTRK2, DYRK1B, SIM1, GNAS and ADCY3.
Overall, 36 (14.8%) children had one of these genetic variants, each thought to have a deleterious impact on the encoded protein and a model of inheritance that seemed likely to explain the disease. Seven of the variants were previously reported as monogenic causes of obesity and 23 were novel discoveries; two siblings were counted as one case when assessing pathogenicity.
A further 137 patients had a genetic variant of unknown function and 70 patients had no alterations in the genes examined, the team says.
A total of six variants were identified in MC4R in 10 patients, including two novel mutations, and Hussain et al remark that “most of the MC4R patients were noticed to have a tall stature (>95th height percentile).”
The most frequent variant was the c.485C>T p.T162I alteration, occurring in five children (four heterozygous, one homozygous) with an average BMI of 39 kg/m2. Noting that this mutation had previously been reported only in four severely obese adults from Qatar and the United Arab Emirates, the researchers suggest that the alteration “could be a founder variant in the Arabian Peninsula.”
In addition, the previously reported c.206T>G, p.Ile69Arg MC4R alteration was inherited in a homozygous state in two Omani siblings, who began to gain weight around 3 years of age, and were born to consanguineous parents, who were both severely obese and heterozygous carriers of the variant.
Two Egyptian sisters with BMIs of 48.4 and 44.2 kg/m2 were found to have pathogenic variants in LEP at c.-29+1G>A, a splice variant predicted to disrupt gene function. The girls were born to first-degree consanguineous parents and also had hyperphagia, obstructive sleep apnoea and fatty liver.
Furthermore, three rare variants of LEPR were identified. The first variant affected a 15-year-old Palestinian boy who gained weight from age 4 years and had a BMI of 33.0 kg/m2, insulin resistance and fatty parenchyma of the pancreas. A compound heterozygous variant of LEPR was also identified in four Qatari children of closely related Arab tribes and although of unknown significance, it was predicted to have a deleterious impact on the protein.
Other novel variants included a heterozygous alteration in RAI1 in a 4-year-old Egyptian boy with obesity, hyperphagia, inattentiveness, hyperactivity and developmental delay who had some features of Smith–Magenis syndrome, and a homozygous missense variant in BBS2 in a 5-year-old Somali boy who had some common features of Bardet–Biedl syndrome, including speech delay, polydactyly and hypothyroidism.
“The findings from this study emphasize that with the continuing reduction in costs of NGS, screening monogenic obesity genes should be considered routine practice for patients with early-onset obesity,” write Hussain and co-authors.
Recognising that glucagon-like peptide1 inhibitors have been used to induce weight loss caused by MC4R pathogenic mutations and other forms of monogenic obesity, the team concludes: “Early diagnosis potentially improves obesity management, early interventions, and helps to identify patients who may benefit from the emerging personalized therapeutic interventions for monogenic obesity.”
By Lynda Williams
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