19p13.2 microduplication causes a Sotos syndrome‐like phenotype and alters gene expression

Abstract

Up to 90% of individuals affected by Sotos syndrome have a pathogenic alteration of NSD1 (encodes nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1), a histone methyltransferase that functions as both a transcriptional activator and a repressor. Genomic copy number variations may also cause a Sotos-like phenotype. We evaluated a three-generation family segregating a Sotos-like disorder characterized by typical facial features, overgrowth, learning disabilities, and advanced bone age. Affected individuals did not have a detectable NSD1 mutation, but rather were found to have a 1.9 Mb microduplication of 19p13.2 with breakpoints in two highly homologous Alu elements. Because the duplication included the DNA methyltransferase gene (DNMT1), we assessed DNA methylation of peripheral blood and buccal cell DNA and detected no alterations. We also examined peripheral blood gene expression and found evidence for increased expression of genes within the duplicated region. We conclude that microduplication of 19p13.2 is a novel genomic disorder characterized by variable neurocognitive disability, overgrowth, and facial dysmorphism similar to Sotos syndrome. Failed compensation of gene duplication at the transcriptional level, as seen in peripheral blood, supports gene dosage as the cause of this disorder.

Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations

“…Moreover, several studies have demonstrated various genetic abnormalities including epigenetic alteration of KCNQ1T1, microduplication of 19p13.2, and a STK11 mutation in patients with Sotos-like features. [25][26][27] Therefore, further genetic investigation is needed for the patients without NSD1 mutation, while epigenetic alteration of KCNQ1T1, which is known to be the cause of BeckwithWiedemann syndrome, did not be found in our three patients.…”

Clinical and molecular characterization of an infant with a tandem duplication and deletion of 19p13

“…Lehman et al [] describe a familial 1.9 Mb duplication on chromosome 19p13.2 which causes features similar to Sotos syndrome. In a report describing a patient of Gomez–Lopez–Hernandez syndrome, a partial duplication of 19p13.2 is described, but its size is not reported and it is discarded as a polymorphism [Schell‐Apacik et al, ].…”

Neonatal Marshall–Smith syndrome

“…Abnormal radiographs are required to make the diagnosis. The differential diagnosis mainly includes Sotos syndrome, Weaver syndrome, and 19p13.2 microduplications (Lehman et al, 2012). Airway support is required in the majority of cases either by tracheostomy or by a tube that keeps the nasopharyngeal airway open.…”