Abstract
BackgroundConsanguine families display a high degree of homozygosity which increases the risk of family members suffering from autosomal recessive disorders. Thus, homozygous mutations in monogenic obesity genes may be a more frequent cause of childhood obesity in a consanguineous population.MethodsWe identified 23 probands from 23 Pakistani families displaying autosomal recessive obesity. We have previously excluded mutations in MC4R, LEP and LEPR in all probands. Using a chip-based, target-region capture array, 31 genes involved in monogenic forms of obesity, were screened in all probands.ResultsWe identified 31 rare non-synonymous possibly pathogenic variants (28 missense and three nonsense) within the 31 selected genes. All variants were heterozygous, thus no homozygous pathogenic variants were found. Two of the rare heterozygous nonsense variants identified (p.R75X and p.R481X) were found in BBS9 within one proband, suggesting that obesity is caused by compound heterozygosity. Sequencing of the parents supported the compound heterozygous nature of obesity as each parent was carrying one of the variants. Subsequent clinical investigation strongly indicated that the proband had Bardet-Biedl syndrome.ConclusionsMutation screening in 31 genes among probands with severe early-onset obesity from Pakistani families did not reveal the presence of homozygous obesity causing variants. However, a compound heterozygote carrier of BBS9 mutations was identified, indicating that compound heterozygosity must not be overlooked when investigating the genetic etiology of severe childhood obesity in populations with a high degree of consanguinity.
Highlights
Consanguine families display a high degree of homozygosity which increases the risk of family members suffering from autosomal recessive disorders
Most of the causative proteins in monogenic forms of obesity are acting in the hypothalamic leptin-melanocortin signalling pathway, Niazi et al BMC Medical Genetics (2019) 20:152 which is essential for the regulation of food intake, body weight and energy regulation [8, 9]
We investigated the level of relatedness in families with and without known consanguinity using the inbreeding coefficient
Summary
Consanguine families display a high degree of homozygosity which increases the risk of family members suffering from autosomal recessive disorders. Homozygous mutations in monogenic obesity genes may be a more frequent cause of childhood obesity in a consanguineous population. In rare monogenic forms of obesity, disruption of a single gene is the cause obesity and individuals typically display severe early-onset obesity along with hyperphagia and endocrine disorders [6, 7]. Mutations in leptin (LEP), the leptin receptor (LEPR) and the melanocortin 4 receptor (MC4R) represent the most common cause of monogenic forms of obesity and mutations within these genes have been demonstrated to cause childhood morbid obesity in probands of various ethnicities [10,11,12,13,14]. Other genes are involved in the melanocortin signalling pathway and many of these have been implicated in monogenic forms of obesity, including POMC, PCSK, SIM1, BDNF, NTRK2, SH2B1 and MRAP [6] Less than 5% of cases are explained by variants in these genes in out-bred populations [15] and possibly upto 30% in a consanguineous Pakistani population [12, 16].
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