Consanguine 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. We 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. We 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. Mutation 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.

中文翻译：

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在 23 名患有早发性儿童肥胖的巴基斯坦先证者中筛选与单基因肥胖相关的 31 个基因：病例报告

近亲家庭表现出高度的纯合性，这增加了家庭成员患常染色体隐性遗传病的风险。因此，单基因肥胖基因的纯合突变可能是近亲人群中儿童肥胖的更常见原因。我们从 23 个巴基斯坦家庭中鉴定出 23 名先证者，这些先证者表现出常染色体隐性肥胖。我们之前已经排除了所有先证者的 MC4R、LEP 和 LEPR 突变。使用基于芯片的目标区域捕获阵列，在所有先证者中筛选了与单基因肥胖相关的 31 个基因。我们在 31 个选定的基因中鉴定出了 31 个罕见的非同义可能致病变异（28 个错义和 3 个无义）。所有变异均为杂合子，因此未发现纯合致病变异。在一名先证者的 BBS9 中发现了两个罕见的杂合无义变异（p.R75X 和 p.R481X），表明肥胖是由复合杂合性引起的。对父母的测序支持了肥胖的复合杂合性质，因为每个父母都携带一种变异。随后的临床调查强烈表明先证者患有 Bardet-Biedl 综合征。对来自巴基斯坦家庭的严重早发性肥胖先证者的 31 个基因进行突变筛查，未发现存在导致肥胖的纯合子变异。然而，鉴定出BBS9突变的复合杂合子携带者，表明在研究高度近亲人群中严重儿童肥胖的遗传病因时，不能忽视复合杂合性。