Human knockout of a cell cycle gene CDC25B: a novel disease-causing gene for an Alström-like syndrome with cataract, dilated cardiomyopathy and multiple endocrinopathies

Abstract

The cell division cycle 25 (CDC25) phosphatases families are a key player regulating the cell cycle phases during cell divisions and maintaining the genetic stability, and an overexpression of the proto-oncogenes, CDC25A or CDC25B had been shown in various cancers. Here, we report a loss-of-function mutation of CDC25B in a girl who presented with a new syndrome, involving multiple systems. The patient was an 11-year-old Chinese girl born to consanguineous asymptomatic parents with history of one fetal and one infancy death with unknown causes. The proband suffered from intrauterine growth retardation, delayed development, bilateral cataract (at 5 yrs), primary hypothyroidism, growth hormone deficiency and heart failure (at 9 yrs). Echocardiogram showed dilated cardiomyopathy involving mainly the right heart and progressively the left heart. The patient had no intellectual disability. Extensive biochemical workups were unremarkable. Karyotyping was normal. Magnetic resonance imaging of the pituitary gland was also unremarkable. Given the clinical presentations, provisional diagnoses of Alström syndrome and POLG-related mitochondrial disorders had been made but later being excluded after a negative sequencing result of ALMS1 and POLG genes respectively. This undiagnosed case was subsequently referred to the Clinics for Rare Diseases Referral (CRareDr) and the Undiagnosed Diseases Program, to end the diagnostic odyssey. Clinical whole exome sequencing (WES) was performed in the proband and we identified a novel homozygous nonsense variant in the CDC25B gene, NM_021873:c.313G>T (p.Glu105*). This novel variant was located in a runs of homozygosity (ROH) of 25 Mb on chromosome 20. Her parents and two asymptomatic sisters were confirmed to be carriers, and the asymptomatic brother was homozygous for the wild-type allele. The presence of c.313G>T in the proband is expected to produce a truncated protein, terminated at codon 105 and a loss of downstream phosphorylation sites. Importantly, the human phenotypes has not been reported in Cdc25b knockout mice. Because CDC25B and ALMS1 are both involved in maintaining centrosome integrity, we propose a loss-of-function CDC25B in humans will result in a new autosomal recessive syndrome, mimicking Alström syndrome.