Severe Early-Onset Obesity and Diabetic Ketoacidosis due to a Novel Homozygous c.169C&gt;T p.Arg57* Variant in <i>CEP19</i> Gene

Abstract

<b><i>Introduction:</i></b> Early-onset severe obesity is usually the result of an underlying genetic disorder, and several genes have recently been shown to cause syndromic and nonsyndromic forms of obesity. The “<i>centrosomal protein 19</i> (<i>CEP19</i>)<i>”</i> gene encodes for a centrosomal and ciliary protein. Homozygous variants in the <i>CEP19</i> gene are extremely rare causes of early-onset severe monogenic obesity. Herein, we present a Turkish family with early-onset severe obesity with variable features. <b><i>Methods:</i></b> Sanger sequencing and whole-exome sequencing were performed to identify the genetic etiology in the family. <b><i>Results:</i></b> The index case was a 12-year-old female who presented with severe obesity (BMI of 62.7 kg/m²), metabolic syndrome, and diabetic ketoacidosis. Her nonidentical twin female siblings also had early-onset severe obesity, metabolic syndrome, and diabetes. In addition, one of the affected siblings had situs inversus abdominalis, polysplenia, lumbar vertebral fusion, and abnormal lateralization. A novel homozygous nonsense (c.169C&gt;T, p. Arg57*) pathogenic variant was detected in exon 3 of the <i>CEP19</i> gene in all affected members of the family. One unaffected sister and unaffected parents were heterozygous for the variant. This variant is predicted to cause a stop codon at amino acid sequence 57, leading to a truncated CEP19 protein. <b><i>Discussion/Conclusion:</i></b> Our study expands the phenotypical manifestations and variation database of <i>CEP19</i> variants. The findings in one of our patients reaffirm its role in the assembly and function of both motile and immotile cilia.